TY - JOUR AU - Cramer, G.E. AU - Gommans, D.H.F. AU - Dieker, H.J. AU - Michels, M AU - Verheugt, F.W. AU - Boer, M.J. de AU - Bakker, J. den AU - Fouraux, M.A. AU - Timmermans, J. AU - Kofflard, M. AU - Brouwer, M.A. PY - 2020 UR - https://hdl.handle.net/2066/225444 AB - Objective: Troponin and high signal intensity on T2-weighted (HighT2) cardiovascular magnetic resonance imaging (CMRi) are both markers of myocardial injury in hypertrophic cardiomyopathy (HCM). The interplay between exercise and disease development remains uncertain in HCM. We sought to assess the occurrence of postexercise troponin rises and its determinants. Methods: Multicentre project on patients with HCM and mutation carriers without hypertrophy (controls). Participants performed a symptom limited bicycle test with hs-cTnT assessment pre-exercise and 6 hours postexercise. Pre-exercise CMRi was performed in patients with HCM to assess measures of hypertrophy and myocardial injury. Depending on baseline troponin (< or >13 ng/L), a rise was defined as a >50% or >20% increase, respectively. Results: Troponin rises occurred in 18% (23/127) of patients with HCM and 4% (2/53) in mutation carriers (p=0.01). Comparing patients with HCM with and without a postexercise troponin rise, maximum heart rates (157±19 vs 143±23, p=0.004) and maximal wall thickness (20 mm vs 17 mm, p=0.023) were higher in the former, as was the presence of late gadolinium enhancement (85% vs 57%, p=0.02). HighT2 was seen in 65% (13/20) and 19% (15/79), respectively (p<0.001). HighT2 was the only independent predictor of troponin rise (adjusted odds ratio 7.9; 95% CI 2.7 to 23.3; p<0.001). Conclusions: Postexercise troponin rises were seen in about 20% of patients with HCM, almost five times more frequent than in mutation carriers. HighT2 on CMRi may identify a group of particularly vulnerable patients, supporting the concept that HighT2 reflects an active disease state, prone to additional injury after a short episode of high oxygen demand. TI - Exercise and myocardial injury in hypertrophic cardiomyopathy EP - 1175 SN - 1355-6037 IS - iss. 15 SP - 1169 JF - Heart VL - vol. 106 DO - https://doi.org/10.1136/heartjnl-2019-315818 ER - TY - JOUR AU - Seelig, J. AU - Verheugt, F.W.A. AU - Hemels, M.E.W. AU - Illingworth, L. AU - Lucassen, A. AU - Adriaansen, H. AU - Bongaerts, M.C.M. AU - Pieterse, M.G.C. AU - Herrman, J.P. AU - Hoogslag, P. AU - Hermans, W. AU - Groenemeijer, B.E. AU - Boersma, L.V.A. AU - Pieper, K. AU - Cate, H. ten PY - 2020 UR - https://hdl.handle.net/2066/220887 AB - Background: For the improvement of AF care, it is important to gain insight into current anticoagulation prescription practices and guideline adherence. This report focuses on the largest Dutch subset of AF-patients, derived from the GARFIELD-AF registry. Methods: Across 35 countries worldwide, patients with newly diagnosed 'non-valvular' atrial fibrillation (AF) with at least one additional risk factor for stroke were included. Dutch patients were enrolled in five, independent, consecutive cohorts from 2010 until 2016. Results: In the Netherlands, 1189 AF-patients were enrolled. The prescription of non-vitamin K antagonist oral anticoagulants (NOAC) has increased sharply, and as per 2016, more patients were initiated on NOACs instead of vitamin K antagonists (VKA). In patients with a class I recommendation for anticoagulation, only 7.5% compared to 30.0% globally received no anticoagulation. Reasons for withholding anticoagulation in these patients were unfortunately often unclear. Conclusions: The data from the GARFIELD-AF registry shows the rapidly changing anticoagulation preference of Dutch physicians in newly diagnosed AF. Adherence to European AF guidelines in terms of anticoagulant regimen would appear to be appropriate. In absence of structured follow up of AF patients on NOAC, the impact of these rapid practice changes in anticoagulation prescription in the Netherlands remains to be established. TI - Changes in anticoagulant prescription in Dutch patients with recent-onset atrial fibrillation: observations from the GARFIELD-AF registry SN - 1477-9560 JF - Thrombosis Journal VL - vol. 18 DO - https://doi.org/10.1186/s12959-020-00218-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220887/220887.pdf?sequence=1 ER - TY - JOUR AU - Vugt, S.P. van AU - Aarts, G.W.A. AU - Lamfers, E.J.P. AU - Bloem-de Vries, L. AU - Kramers, C. AU - Boer, M.J. de AU - Verheugt, F.W. AU - Jaspers Focks, J. AU - Brouwer, M.A. PY - 2020 UR - https://hdl.handle.net/2066/220890 TI - Comorbidity Differentiation and Risk Stratification in the Elderly Patient with Polypharmacy: A Prospective Primary Care Registry on Oral Anticoagulation Therapy SN - 1758-3756 JF - European Cardiology VL - vol. 15 DO - https://doi.org/10.15420/ecr.2020.15.1.PO23 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220890/220890.pdf?sequence=1 ER - TY - JOUR AU - Brouwer, M.A. AU - Vugt, S.P.G. van AU - Jaspers Focks, J. AU - Damen, S.A.J. AU - Verheugt, F.W.A. PY - 2020 UR - https://hdl.handle.net/2066/229204 TI - Rivaroxaban Plasma Levels and Levetiracetam EP - 771 SN - 0003-4819 IS - iss. 9 SP - 770 JF - Annals of Internal Medicine C.2 VL - vol. 173 DO - https://doi.org/10.7326/L20-1063 ER - TY - JOUR AU - Korjian, S. AU - Daaboul, Y. AU - Laliberte, F. AU - Zhao, Q. AU - Mehran, R. AU - Bode, C. AU - Halperin, J. AU - Verheugt, F.W.A. AU - Lip, G.Y.H. AU - Cohen, M. AU - Peterson, E.D. AU - Fox, K.A. AU - Gibson, C. Michael AU - Pinto, D.S. PY - 2019 UR - https://hdl.handle.net/2066/209418 AB - The PIONEER AF-PCI trial demonstrated that in atrial fibrillation patients who underwent intracoronary stenting, either rivaroxaban 15 mg daily plus P2Y12 inhibitor monotherapy (Group 1) or 2.5 mg rivaroxaban twice daily plus dual antiplatelet therapy (DAPT) (Group 2) was associated with fewer recurrent hospitalizations, primarily for bleeding and cardiovascular events, compared with standard-of-care vitamin K antagonist and DAPT (Group 3). Associated costs are unknown. This study estimates costs associated with rivaroxaban strategies compared with vitamin K antagonist and DAPT. Medication costs were estimated using wholesale acquisition costs, medication discontinuation rates, and costs of monitoring. Using a large US healthcare claims database, the mean adjusted increase in 1-year cost of care for individuals with atrial fibrillation and percutaneous coronary intervention (PCI) rehospitalized for bleeding, cardiovascular, and other events was compared with those not rehospitalized. Using adjudicated rehospitalization rates from PIONEER AF-PCI, cost differences were estimated. Rates of rehospitalization for bleeding were 6.5%, 5.4%, 10.5%, and 20.3%, 20.3%, 28.4% for cardiovascular events in Groups 1, 2, and 3. Medication and monitoring costs were $3,942, $4,115, and $1,703. One-year costs for all recurrent hospitalization costs and/or patient for the groups were $24,535, $20,205, and $29,756. One-year cost increase associated with bleeding rehospitalizations and/or patient was $4,160, $3,212, and $6,876 and was $13,264, $11,545, and $17,220 for cardiovascular rehospitalizations and/or patient. Overall estimated cost per patient was $28,476, $24,320, and $31,458. Compared with warfarin, both rivaroxaban treatment strategies had higher medication costs, but these were more than accounted for by fewer hospitalizations. TI - Cost Implications of Anticoagulation Strategies After Percutaneous Coronary Intervention Among Patients With Atrial Fibrillation (A PIONEER-AF PCI Analysis) EP - 360 SN - 0002-9149 IS - iss. 3 SP - 355 JF - American Journal of Cardiology VL - vol. 123 DO - https://doi.org/10.1016/j.amjcard.2018.10.033 ER - TY - JOUR AU - Bassand, J.P. AU - Virdone, S. AU - Goldhaber, S.Z. AU - Camm, A.J. AU - Fitzmaurice, D.A. AU - Fox, K.A. AU - Goto, S. AU - Haas, S. AU - Hacke, W. AU - Kayani, G. AU - Mantovani, L.G. AU - Misselwitz, F. AU - Pieper, K.S. AU - Turpie, A.G.G. AU - Eickels, M. van AU - Verheugt, F.W.A. AU - Kakkar, A.K. PY - 2019 UR - https://hdl.handle.net/2066/209431 AB - BACKGROUND: Atrial fibrillation is associated with increased risks of death, stroke/systemic embolism, and bleeding (incurred by antithrombotic therapy), which may occur early after diagnosis. METHODS: We assessed the risk of early events (death, stroke/systemic embolism, and major bleeding) over 12 months and their relation to the time after diagnosis of atrial fibrillation in 52 014 patients prospectively enrolled in the GARFIELD-AF registry (Global Anticoagulant Registry in the FIELD-Atrial Fibrillation) between March 2010 and August 2016. RESULTS: Over 12 months, 2140 patients died (mortality rate, 4.3; 95% CI, 4.2-4.5 per 100 person-years), of whom 288 (13.5%) died in the first month (6.8; 95% CI, 6.1-7.6). Over 12 months, 657 patients had a stroke/systemic embolism (1.3; 95% CI, 1.2-1.4) and 411 had a major bleeding (0.8; 95% CI, 0.8-0.9). During the first month, the rates (per 100 person-years) of stroke/systemic embolism and major bleed were 2.3 (95% CI, 1.9-2.8) and 1.5 (95% CI, 1.2-1.9), respectively. The elevated 1-month mortality rate was mostly attributable to cardiovascular mortality (3.5; 95% CI, 3.0-4.1), in particular, heart failure, sudden death, and acute coronary syndromes (1.0 [95% CI, 0.8-1.4], 0.6 [95% CI, 0.4-0.8], and 0.5 [95% CI, 0.3-0.8], respectively). Age, heart failure, prior stroke, history of cirrhosis, vascular disease, moderate-to-severe kidney disease, diabetes mellitus, and living in North or Latin America were independent predictors of a higher risk of early death, whereas anticoagulation and living in Europe or Asia were independent predictors of a lower risk of early death. A predictive model developed for the 1-month risk of death had a C-statistic of 0.81 (95% CI, 0.78-0.83). CONCLUSIONS: The increased hazard of early events, in particular, cardiovascular mortality, in newly diagnosed atrial fibrillation points to the importance of comprehensive care for such patients and should alert clinicians to detect warning signs of possible early mortality. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01090362. TI - Early Risks of Death, Stroke/Systemic Embolism, and Major Bleeding in Patients With Newly Diagnosed Atrial Fibrillation EP - 798 SN - 0009-7322 IS - iss. 6 SP - 787 JF - Circulation VL - vol. 139 DO - https://doi.org/10.1161/CIRCULATIONAHA.118.035012 ER - TY - JOUR AU - Guimaraes, P.O. AU - Lopes, R.D. AU - Alexander, J.H. AU - Thomas, L. AU - Hellkamp, A.S. AU - Hijazi, Z. AU - Hylek, E.M. AU - Gersh, B.J. AU - Garcia, D.A. AU - Verheugt, F.W.A. AU - Hanna, M. AU - Flaker, G. AU - Vinereanu, D. AU - Granger, C.B. PY - 2019 UR - https://hdl.handle.net/2066/209456 AB - We explored associations between INR measures and clinical outcomes in patients with AF using warfarin, and whether INR history predicted future INR measurements. We included patients in ARISTOTLE who were randomized to and received warfarin. Among patients who had events, we included those with >/= 3 INR values in the 180 days prior to the event, with the most recent /= 180 days of warfarin exposure with >/= 3 INR measurements (n = 7259). The median (25th, 75th) number of INR values per patient was 29 (21, 38) over a median follow-up of 1.8 years. A total of 87% had at least one INR value < 1.5; 49% had at least one value > 4.0. The last INRs before events (median 14 [24, 7] days) were < 3.0 for at least 75% of patients with major bleeding and > 2.0 for half of patients with ischemic stroke. Historic time in therapeutic range (TTR) was weakly associated with future TTR (R(2) = 0.212). Historic TTR >/= 80% had limited predictive ability to discriminate future TTR >/= 80% (C index 0.61). In patients with AF receiving warfarin, most bleeding events may not have been preventable despite careful INR control. Our findings suggest that INRs collected through routine management are not sufficiently predictive to provide reassurance about future time in therapeutic range or to prevent subsequent outcomes, and might be over-interpreted in clinical practice. TI - International normalized ratio control and subsequent clinical outcomes in patients with atrial fibrillation using warfarin EP - 34 SN - 0929-5305 IS - iss. 1 SP - 27 JF - Journal of Thrombosis and Thrombolysis VL - vol. 48 DO - https://doi.org/10.1007/s11239-019-01858-1 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2019 UR - https://hdl.handle.net/2066/209469 TI - Low Body Weight and Prescribing DOACs in Atrial Fibrillation EP - 934 SN - 0735-1097 IS - iss. 8 SP - 932 JF - Journal of the American College of Cardiology VL - vol. 73 DO - https://doi.org/10.1016/j.jacc.2018.12.029 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2019 UR - https://hdl.handle.net/2066/209488 TI - Platelets: The Balance between Aggregation and Bleeding SN - 0340-6245 IS - iss. 10 SP - 1553 JF - Thrombosis and Haemostasis VL - vol. 19 DO - https://doi.org/10.1055/s-0039-1696984 ER - TY - JOUR AU - Haas, S. AU - Camm, A.J. AU - Bassand, J.P. AU - Angchaisuksiri, P. AU - Cools, F. AU - Corbalan, R. AU - Gibbs, H. AU - Jacobson, B. AU - Koretsune, Y. AU - Mantovani, L.G. AU - Misselwitz, F. AU - Panchenko, E. AU - Ragy, H.I. AU - Stepinska, J. AU - Turpie, A.G.G. AU - Sawhney, J.P. AU - Steffel, J. AU - Lim, T.W. AU - Pieper, K.S. AU - Virdone, S. AU - Verheugt, F.W.A. AU - Kakkar, A.K. PY - 2019 UR - https://hdl.handle.net/2066/209489 AB - INTRODUCTION: A principal aim of the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) was to document changes in treatment practice for patients with newly diagnosed atrial fibrillation during an era when non-vitamin K antagonist oral anticoagulants (NOACs) were becoming more widely adopted. In these analyses, the key factors which determined the choice between NOACs and vitamin K antagonists (VKAs) are explored. METHODS: Logistic least absolute shrinkage and selection operator regression determined predictors of NOAC and VKA use. Data were collected from 24,137 patients who were initiated on AC+/-antiplatelet (AP) therapy (NOAC [51.4%] or VKA [48.6%]) between April 2013 and August 2016. RESULTS: The most significant predictors of AC therapy were country, enrolment year, care setting at diagnosis, AF type, concomitant AP, and kidney disease. Patients enrolled in emergency care or in the outpatient setting were more likely to receive a NOAC than those enrolled in hospital (OR 1.16 [95% CI: 1.04-1.30], OR: 1.15 [95% CI: 1.05-1.25], respectively). NOAC prescribing seemed to be favored in lower-risk groups, namely, patients with paroxysmal AF, normotensive patients, and those with moderate alcohol consumption, but also the elderly and patients with acute coronary syndrome. By contrast, VKAs were preferentially used in patients with permanent AF, moderate to severe kidney disease, heart failure, vascular disease, and diabetes and with concomitant AP. CONCLUSION: GARFIELD-AF data highlight marked heterogeneity in stroke prevention strategies globally. Physicians are adopting an individualized approach to stroke prevention where NOACs are favored in patients with a lower stroke risk but also in the elderly and patients with acute coronary syndrome. TI - Predictors of NOAC versus VKA use for stroke prevention in patients with newly diagnosed atrial fibrillation: Results from GARFIELD-AF EP - 46 SN - 0002-8703 SP - 35 JF - American Heart Journal VL - vol. 213 DO - https://doi.org/10.1016/j.ahj.2019.03.013 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/209489/209489.pdf?sequence=1 ER - TY - JOUR AU - Corbalan, R. AU - Bassand, J.P. AU - Illingworth, L. AU - Ambrosio, G. AU - Camm, A.J. AU - Fitzmaurice, D.A. AU - Fox, K.A. AU - Goldhaber, S.Z. AU - Goto, S. AU - Haas, S. AU - Kayani, G. AU - Mantovani, L.G. AU - Misselwitz, F. AU - Pieper, K.S. AU - Turpie, A.G.G. AU - Verheugt, F.W.A. AU - Kakkar, A.K. PY - 2019 UR - https://hdl.handle.net/2066/209349 AB - Importance: Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes. Objective: To assess the treatment strategies and 1-year clinical outcomes of antithrombotic and CHF therapies for patients with newly diagnosed AF with concomitant CHF stratified by etiology (ischemic cardiomyopathy [ICM] vs nonischemic cardiomyopathy [NICM]). Design, Setting, and Participants: The GARFIELD-AF registry is a prospective, noninterventional registry. A total of 52014 patients with AF were enrolled between March 2010 and August 2016. A total of 11738 patients 18 years and older with newly diagnosed AF (/= 2%. It was only 1.2 to 1.3%, and thus in the range of other primary prevention trials in low-risk patients. Apart from potential compliance problems, possible explanations for the small cardioprotective effect of antiplatelet treatment include a healthy lifestyle as well as improved vascular protection by comedication with vasoactive and anti-inflammatory drugs, such as statins or antihypertensive agents, as well as proton-pump inhibitors that might modify bleeding, specifically in the upper gastrointestinal tract-the most frequently affected site. Also, the introduction of new antidiabetic drugs with more favorable cardiovascular effects may in part explain the low event rate. ASCEND, similar to ARRIVE, did not study patients at elevated (as planned) but only at low vascular risk and, therefore, was largely confirmatory of earlier primary prevention trials. TI - Aspirin and Primary Prevention in Patients with Diabetes-A Critical Evaluation of Available Randomized Trials and Meta-Analyses EP - 1582 SN - 0340-6245 IS - iss. 10 SP - 1573 JF - Thrombosis and Haemostasis VL - vol. 19 DO - https://doi.org/10.1055/s-0039-1694774 ER - TY - JOUR AU - Kerneis, M. AU - Yee, M.K. AU - Mehran, R. AU - Nafee, T. AU - Bode, C. AU - Halperin, J.L. AU - Peterson, E.D. AU - Verheugt, F.W.A. AU - Wildgoose, P. AU - Eickels, M. van AU - Lip, G.Y.H. AU - Cohen, M. AU - Fox, K.A. AU - Gibson, C. Michael PY - 2019 UR - https://hdl.handle.net/2066/209397 AB - BACKGROUND: Among atrial fibrillation patients undergoing percutaneous coronary intervention enrolled in PIONEER AF-PCI (An Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention), it is unclear if the observed reduction in bleeding events with rivaroxaban regimens is consistent across a range of the international normalized ratio (INR) among subjects administrated Vitamin K antagonist (VKA)-triple therapy. This analysis compares the occurrence of clinically significant bleeding between rivaroxaban and VKA strategies, according to INR stability of subjects administrated VKA. METHODS AND RESULTS: A total of 2124 atrial fibrillation patients undergoing percutaneous coronary intervention were randomized to 3 groups: rivaroxaban 15 mg od plus a P2Y12 inhibitor (group 1, n=709); rivaroxaban 2.5 mg bid plus dual antiplatelet therapy (group 2, n=709); and warfarin plus dual antiplatelet therapy (group 3, n=706). Subjects assigned to the VKA group were stratified according to time in therapeutic range and time spent with an INR >3. Kaplan-Meier estimates were calculated for clinically significant bleeding through 1 year and hazard ratios were derived using Cox Proportional Hazards models. Among group 3, 93.4% of the participants had a time in therapeutic range available (mean time in therapeutic range=65.0+/-24.8%). Both groups 1 and 2 were associated with a reduction in clinically significant bleeding compared with subjects in group 3, regardless of the time in therapeutic range (hazard ratio ranges=0.53-0.71 and 0.57-0.76; respectively, P<0.05 for all). Rivaroxaban strategies were associated with a reduction in clinically significant bleeding compared with VKA regardless of the proportion of time spent with an INR >3 (hazard ratio ranges=0.59-0.67 and 0.42-0.69; P<0.05 for all). CONCLUSIONS: Among atrial fibrillation patients undergoing percutaneous coronary intervention, rivaroxaban-based therapy was superior to warfarin plus dual antiplatelet therapy in lowering bleeding outcomes regardless of the INR stability. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01830543. TI - Association of International Normalized Ratio Stability and Bleeding Outcomes Among Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention SN - 1941-7640 IS - iss. 2 SP - e007124 JF - Circulation-Cardiovascular Interventions VL - vol. 12 DO - https://doi.org/10.1161/CIRCINTERVENTIONS.118.007124 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2019 UR - https://hdl.handle.net/2066/209406 TI - Cardioversion as bystander in atrial fibrillation-related thrombo-embolism EP - 3034 SN - 0195-668X IS - iss. 36 SP - 3033 JF - European Heart Journal VL - vol. 40 DO - https://doi.org/10.1093/eurheartj/ehz563 ER - TY - JOUR AU - Korjian, S. AU - Braunwald, Eugene AU - Daaboul, Y. AU - Verheugt, F.W.A. AU - Bode, C. AU - Tendera, M. AU - Burton, Paul AU - Gibson, C. Michael PY - 2019 UR - https://hdl.handle.net/2066/202137 TI - Safety and efficacy of rivaroxaban for the secondary prevention following acute coronary syndromes among biomarker-positive patients: Insights from the ATLAS ACS 2-TIMI 51 trial EP - 193 SN - 2048-8726 IS - iss. 2 SP - 186 JF - European Heart Journal Acute Cardiovascular Care VL - vol. 8 DO - https://doi.org/10.1177/2048872617745003 ER - TY - JOUR AU - Damen, S.A.J. AU - Vroemen, Wim H.M. AU - Brouwer, M.A. AU - Mezger, Stephanie T.P. AU - Suryapranata, H. AU - Royen, N. van AU - Verheugt, F.W.A. AU - Cramer, G.E. AU - Mingels, Alma M.A. PY - 2019 UR - https://hdl.handle.net/2066/208024 TI - Multi-Site Coronary Vein Sampling Study on Cardiac Troponin T Degradation in Non-ST-Segment-Elevation Myocardial Infarction: Toward a More Specific Cardiac Troponin T Assay SN - 2047-9980 IS - iss. 14 JF - Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease VL - vol. 8 DO - https://doi.org/10.1161/JAHA.119.012602 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208024/208024.pdf?sequence=1 ER - TY - JOUR AU - Aengevaeren, V.L. AU - Gommans, D.H.F. AU - Dieker, H.J. AU - Timmermans, J. AU - Verheugt, F.W.A. AU - Bakker, Jeannette AU - Hopman, M.T.E. AU - Boer, M.J. de AU - Brouwer, M.A. AU - Cramer, G.E. AU - Eijsvogels, T.M.H. PY - 2019 UR - https://hdl.handle.net/2066/208032 TI - Association between Lifelong Physical Activity and Disease Characteristics in HCM EP - 2002 SN - 0195-9131 IS - iss. 10 SP - 1995 JF - Medicine and Science in Sports and Exercise VL - vol. 51 DO - https://doi.org/10.1249/MSS.0000000000002015 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208032/208032.pdf?sequence=1 ER - TY - JOUR AU - Kerneis, M. AU - Yee, M.K. AU - Mehran, R. AU - Nafee, T. AU - Bode, C. AU - Halperin, J.L. AU - Peterson, E.D. AU - Verheugt, F.W.A. AU - Wildgoose, P. AU - Eickels, M. van AU - Lip, G.Y.H. AU - Cohen, M. AU - Fox, K.A. AU - Gibson, C. Michael PY - 2019 UR - https://hdl.handle.net/2066/215287 AB - BACKGROUND: Among stented patients with atrial fibrillation, double therapy with a novel oral anticoagulant plus single antiplatelet therapy (SAPT) reduces bleeding or cardiovascular rehospitalizations compared with a vitamin K antagonist (VKA) based triple therapy regimen. A recent study demonstrated that apixaban based double therapy reduced bleeding compared with VKA based double therapy. However, it remains unknown whether rivaroxaban based double therapy is superior to a VKA based double therapy. METHODS: Patient with stented atrial fibrillation (n=2124) were randomized to 3 groups: rivaroxaban 15 mg od plus a P2Y12 inhibitor (Group 1, n=709); rivaroxaban 2.5 mg bid plus dual antiplatelet therapy (DAPT; Group 2, n=709); and warfarin plus DAPT (Group 3, n=706). Before randomization, subjects were stratified according to a prespecified duration of DAPT (1, 6, or 12 months). After the prespecified DAPT duration, subjects in Group 2 were switched to rivaroxaban 15 mg plus low dose aspirin, and those in Group 3 were switched to VKA plus low dose aspirin. The Wei, Lin, and Weissfeld time to multiple events method was used to compare the occurrence of all bleeding and cardiovascular rehospitalizations among subjects on a novel oral anticoagulant versus VKA based double therapy. RESULTS: A total of 906 subjects were prespecified to a 1 or 6 months DAPT duration and received at least one dose of study drug. Twenty subjects (3.3%) assigned to novel oral anticoagulant+SAPT, and 15 (5.1%) subjects assigned to VKA+SAPT experienced multiple rehospitalizations. In total, 124 (20.3%) events occurred among subjects on novel oral anticoagulant+SAPT compared with 87 (29.6%) among subjects on VKA+SAPT (hazard ratio=0.65 [95% CI, 0.45-0.93], P=0.008). CONCLUSIONS: Among stented patients with atrial fibrillation, rivaroxaban plus SAPT was superior to warfarin plus SAPT in lowering total bleeding and cardiovascular rehospitalization. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01830543. TI - Novel Oral Anticoagulant Based Versus Vitamin K Antagonist Based Double Therapy Among Stented Patients With Atrial Fibrillation: Insights From the PIONEER AF-PCI Trial SN - 1941-7640 IS - iss. 11 SP - e008160 JF - Circulation-Cardiovascular Interventions VL - vol. 12 DO - https://doi.org/10.1161/CIRCINTERVENTIONS.119.008160 ER - TY - JOUR AU - Verheugt, F.W.A. AU - Ambrosio, G. AU - Atar, D. AU - Bassand, J.P. AU - Camm, A.J. AU - Costabel, J.P. AU - Fitzmaurice, D.A. AU - Illingworth, L. AU - Goldhaber, S.Z. AU - Goto, S. AU - Haas, S. AU - Jansky, P. AU - Kayani, G. AU - Stepinska, J. AU - Turpie, A.G.G. AU - Eickels, M. van AU - Kakkar, A.K. PY - 2019 UR - https://hdl.handle.net/2066/215292 AB - BACKGROUND: Many patients with atrial fibrillation have concomitant coronary artery disease with or without acute coronary syndromes and are in need of additional antithrombotic therapy. There are few data on the long-term clinical outcome of atrial fibrillation patients with a history of acute coronary syndrome. This is a 2-year study of atrial fibrillation patients with or without a history of acute coronary syndromes. METHODS: Adults with newly diagnosed atrial fibrillation and >/=1 investigator-defined stroke risk factor were enrolled in GARFIELD-AF between March 2010 and September 2015. The association between prior acute coronary syndromes and long-term outcomes was determined using a Cox proportional hazards model, adjusting for baseline risk factors, oral anticoagulation (OAC) +/- antiplatelet (AP) therapy, and usual care. RESULTS: Of 39,679 patients, 10.5% had a history of acute coronary syndromes. At 2-year follow-up, patients with prior acute coronary syndromes had higher adjusted risks of stroke/systemic embolism (hazard ratio [HR] 1.39; 95% confidence interval [CI], 1.08-1.78), major bleeding (HR 1.30; 95% CI, 0.95 -1.79), all-cause mortality (HR 1.34; 95% CI, 1.21 -1.49), cardiovascular mortality (HR 1.85; 95% CI, 1.51-2.26), and new acute coronary syndromes (HR 3.42; 95% CI, 2.62-4.45). Comparing antithrombotic therapy in the acute coronary syndromes vs no acute coronary syndromes groups, most patients received OAC +/- AP: 60.8% vs 66.1%, but AP therapy was more likely in the acute coronary syndromes group (68.1% vs 32.9%), either alone (34.9% vs 20.8%) or with OAC (33.2% vs 12.1%). Overall, 17.8% in the acute coronary syndromes group received dual AP therapy with (5.3%) or without OAC (12.5%). Among patients with moderate/high risk for stroke/systemic embolism, fewer in the acute coronary syndromes group received OAC with or without AP therapy (Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke, TIA, or thromboembolism, Vascular disease, Age 65-74 years, Sex category [CHA2DS2-VASc] 2: 52.1% vs 64.6%; CHA2DS2-VASc >/=3: 62.0% vs 70.7%), and the majority with a Hypertension (uncontrolled systolic blood pressure >160 mm Hg), Abnormal renal or liver function, previous Stroke, Bleeding history or predisposition, Labile international normalized ratios, Elderly, and concomitant Drugs or alcohol excess (HAS-BLED) score >/=3 were on AP therapy (83.8% vs 65.5%). CONCLUSIONS: In GARFIELD-AF, previous acute coronary syndromes are associated with worse 2-year outcomes and a greater likelihood of under-treatment with OAC, while two-thirds of patients receive AP therapy. Major bleeding was more common with previous acute coronary syndromes, even after adjusting for all risk factors. TI - Outcomes in Newly Diagnosed Atrial Fibrillation and History of Acute Coronary Syndromes: Insights from GARFIELD-AF EP - 1440.e7 SN - 0002-9343 IS - iss. 12 SP - 1431 JF - American Journal of Medicine VL - vol. 132 DO - https://doi.org/10.1016/j.amjmed.2019.06.008 ER - TY - JOUR AU - Serruys, P.W. AU - Tomaniak, M. AU - Chichareon, P. AU - Modolo, R. AU - Kogame, N. AU - Takahashi, K. AU - Chang, C.C. AU - Spitzer, E. AU - Walsh, S.J. AU - Adlam, D. AU - Hildick-Smith, D. AU - Edes, I. AU - Harst, P. van der AU - Krackhardt, F. AU - Tijssen, J.G. AU - Rademaker-Havinga, T. AU - Garg, S. AU - Steg, P.G. AU - Hamm, C. AU - Juni, P. AU - Vranckx, P. AU - Onuma, Y. AU - Verheugt, F.W.A. PY - 2019 UR - https://hdl.handle.net/2066/215297 AB - AIMS: The aim of this study was to evaluate the impact of 23-month ticagrelor monotherapy following one-month dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) on the rates of patient-oriented composite endpoints (POCE) and net adverse clinical events (NACE). METHODS AND RESULTS: The rates of site-reported Academic Research Consortium (ARC)-2 defined POCE (all-cause death, any stroke, any myocardial infarction or any revascularisation) and NACE (POCE or bleeding type 3 or 5 according to the Bleeding ARC [BARC]) were reported up to two years by intention-to-treat principle in the randomised, multicentre, open-label GLOBAL LEADERS study comparing two antiplatelet strategies in 15,991 patients undergoing PCI. The experimental strategy consisted of aspirin with ticagrelor for one month followed by ticagrelor monotherapy for 23 months, whereas the reference treatment consisted of 12-month DAPT followed by 12-month aspirin monotherapy. At two years, POCE occurred in 1,050 (13.2%) patients in the experimental group and in 1,131 (14.2%) in the reference group (HR 0.93, 95% CI: 0.85-1.01, p=0.085). NACE occurred in 1,145 (14.4%) patients in the experimental group and in 1,237 (15.5%) patients in the reference group (HR 0.92, 95% CI: 0.85-1.00, p=0.057). In pre-specified subgroup analyses, no significant treatment-by-subgroup interactions were found for either POCE or NACE at two years. CONCLUSIONS: The experimental treatment strategy of one-month DAPT followed by 23 months of ticagrelor alone did not result in a significant reduction in the rates of site-reported POCE or NACE, when compared to the reference treatment. ClinicalTrials.gov Identifier: NCT01813435. TI - Patient-oriented composite endpoints and net adverse clinical events with ticagrelor monotherapy following percutaneous coronary intervention: insights from the randomised GLOBAL LEADERS trial EP - e1098 SN - 1774-024X IS - iss. 12 SP - e1090 JF - Eurointervention VL - vol. 15 DO - https://doi.org/10.4244/EIJ-D-19-00202 ER - TY - JOUR AU - Bueno, H. AU - Graeff, P. de AU - Richard-Lordereau, I. AU - Emmerich, J. AU - Fox, K.A. AU - Friedman, C.P. AU - Gaudin, C. AU - El-Gazayerly, A. AU - Goldman, S. AU - Hemmrich, M. AU - Henderson, R.A. AU - Himmelmann, A. AU - Irs, A. AU - Jackson, N. AU - James, S.K. AU - Katus, H.A. AU - Laslop, A. AU - Laws, I. AU - Mehran, R. AU - Ong, S. AU - Prasad, K. AU - Roffi, M. AU - Rosano, G.M. AU - Rose, M. AU - Sinnaeve, P.R. AU - Stough, W.G. AU - Thygesen, K. AU - Werf, F. van de AU - Varin, C. AU - Verheugt, F.W.A. AU - Garcia, M. PY - 2019 UR - https://hdl.handle.net/2066/215308 AB - Regulatory authorities interpret the results of randomized controlled trials according to published principles. The European Medicines Agency (EMA) is planning a revision of the 2000 and 2003 guidance documents on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (ACS) to achieve consistency with current knowledge in the field. This manuscript summarizes the key output from a collaborative workshop, organized by the Cardiovascular Round Table and the European Affairs Committee of the European Society of Cardiology, involving clinicians, academic researchers, trialists, European and US regulators, and pharmaceutical industry researchers. Specific questions in four key areas were selected as priorities for changes in regulatory guidance: patient selection, endpoints, methodologic issues and issues related to the research for novel agents. Patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) should be studied separately for therapies aimed at the specific pathophysiology of either condition, particularly for treatment of the acute phase, but can be studied together for other treatments, especially long-term therapy. Unstable angina patients should be excluded from acute phase ACS trials. In general, cardiovascular death and reinfarction are recommended for primary efficacy endpoints; other endpoints may be considered if specifically relevant for the therapy under study. New agents or interventions should be tested against a background of evidence-based therapy with expanded follow-up for safety assessment. In conclusion, new guidance documents for randomized controlled trials in ACS should consider changes regarding patient and endpoint selection and definitions, and trial designs. Specific requirements for the evaluation of novel pharmacological therapies need further clarification. TI - Report of the European Society of Cardiology Cardiovascular Round Table regulatory workshop update of the evaluation of new agents for the treatment of acute coronary syndrome: Executive summary EP - 754 SN - 2048-8726 IS - iss. 8 SP - 745 JF - European Heart Journal Acute Cardiovascular Care VL - vol. 8 DO - https://doi.org/10.1177/2048872616649859 ER - TY - JOUR AU - Dalgaard, F. AU - Pieper, K. AU - Verheugt, F.W. AU - Camm, A.J. AU - Fox, K.A. AU - Kakkar, A.K. AU - Pallisgaard, J.L. AU - Rasmussen, P.V. AU - Weert, H.V. AU - Lindhardt, T.B. AU - Torp-Pedersen, C. AU - Gislason, G.H. AU - Ruwald, M.H. AU - Harskamp, R.E. PY - 2019 UR - https://hdl.handle.net/2066/215442 AB - OBJECTIVES: To externally validate the accuracy of the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) model against existing risk scores for stroke and major bleeding risk in patients with non-valvular AF in a population-based cohort. DESIGN: Retrospective cohort study. SETTING: Danish nationwide registries. PARTICIPANTS: 90 693 patients with newly diagnosed non-valvular AF were included between 2010 and 2016, with follow-up censored at 1 year. PRIMARY AND SECONDARY OUTCOME MEASURES: External validation was performed using discrimination and calibration plots. C-statistics were compared with CHA2DS2VASc score for ischaemic stroke/systemic embolism (SE) and HAS-BLED score for major bleeding/haemorrhagic stroke outcomes. RESULTS: Of the 90 693 included, 51 180 patients received oral anticoagulants (OAC). Overall median age (Q1, Q3) were 75 (66-83) years and 48 486 (53.5%) were male. At 1-year follow-up, a total of 2094 (2.3%) strokes/SE, 2642 (2.9%) major bleedings and 10 915 (12.0%) deaths occurred. The GARFIELD-AF model was well calibrated with the predicted risk for stroke/SE and major bleeding. The discriminatory value of GARFIELD-AF risk model was superior to CHA2DS2VASc for predicting stroke in the overall cohort (C-index: 0.71, 95% CI: 0.70 to 0.72 vs C-index: 0.67, 95% CI: 0.66 to 0.68, p<0.001) as well as in low-risk patients (C-index: 0.64, 95% CI: 0.59 to 0.69 vs C-index: 0.57, 95% CI: 0.53 to 0.61, p=0.007). The GARFIELD-AF model was comparable to HAS-BLED in predicting the risk of major bleeding in patients on OAC therapy (C-index: 0.64, 95% CI: 0.63 to 0.66 vs C-index: 0.64, 95% CI: 0.63 to 0.65, p=0.60). CONCLUSION: In a nationwide Danish cohort with non-valvular AF, the GARFIELD-AF model adequately predicted the risk of ischaemic stroke/SE and major bleeding. Our external validation confirms that the GARFIELD-AF model was superior to CHA2DS2VASc in predicting stroke/SE and comparable with HAS-BLED for predicting major bleeding. TI - GARFIELD-AF model for prediction of stroke and major bleeding in atrial fibrillation: a Danish nationwide validation study SN - 2044-6055 IS - iss. 11 SP - e033283 JF - BMJ Open VL - vol. 9 DO - https://doi.org/10.1136/bmjopen-2019-033283 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/215442/215442.pdf?sequence=1 ER - TY - JOUR AU - Franchi, F. AU - James, S.K. AU - Lakic, T. Ghukasyan AU - Budaj, A.J. AU - Cornel, J.H. AU - Verheugt, F.W. AU - Katus, H.A. AU - Keltai, M. AU - Kontny, F. AU - Lewis, B.S. AU - Storey, R.F. AU - Himmelmann, A. AU - Wallentin, L. AU - Angiolillo, D.J. PY - 2019 UR - https://hdl.handle.net/2066/215455 AB - Background There are limited data on how the combination of diabetes mellitus ( DM ) and chronic kidney disease ( CKD ) affects cardiovascular outcomes as well as response to different P2Y12 receptor antagonists, which represented the aim of the present investigation. Methods and Results In this post hoc analysis of the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized acute coronary syndrome patients to ticagrelor versus clopidogrel, patients (n=15 108) with available DM and CKD status were classified into 4 groups: DM +/ CKD + (n=1058), DM +/ CKD - (n=2748), DM -/ CKD + (n=2160), and DM -/ CKD - (n=9142). The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke at 12 months. The primary safety end point was PLATO major bleeding. DM +/ CKD + patients had a higher incidence of the primary end point compared with DM -/ CKD - patients (23.3% versus 7.1%; adjusted hazard ratio 2.22; 95% CI 1.88-2.63; P<0.001). Patients with DM +/ CKD - and DM -/ CKD + had an intermediate risk profile. The same trend was shown for the individual components of the primary end point and for major bleeding. Compared with clopidogrel, ticagrelor reduced the incidence of the primary end point consistently across subgroups ( P-interaction=0.264), but with an increased absolute risk reduction in DM +/ CKD +. The effects on major bleeding were also consistent across subgroups ( P-interaction=0.288). Conclusions In acute coronary syndrome patients, a gradient of risk was observed according to the presence or absence of DM and CKD , with patients having both risk factors at the highest risk. Although the ischemic benefit of ticagrelor over clopidogrel was consistent in all subgroups, the absolute risk reduction was greatest in patients with both DM and CKD . Clinical Trial Registration URL : http://www.clinicatrials.gov . Unique identifier: NCT 00391872. TI - Impact of Diabetes Mellitus and Chronic Kidney Disease on Cardiovascular Outcomes and Platelet P2Y12 Receptor Antagonist Effects in Patients With Acute Coronary Syndromes: Insights From the PLATO Trial SN - 2047-9980 IS - iss. 6 SP - e011139 JF - Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease VL - vol. 8 DO - https://doi.org/10.1161/JAHA.118.011139 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/215455/215455.pdf?sequence=1 ER - TY - JOUR AU - Alexander, Karen P. AU - Brouwer, M.A. AU - Mulder, Hillary AU - Vinereanu, D. AU - Lopes, Renato D. AU - Proietti, Marco AU - Verheugt, F.W.A. AU - Wallentin, L. AU - Granger, Christopher B. PY - 2019 UR - https://hdl.handle.net/2066/202099 TI - Outcomes of apixaban versus warfarin in patients with atrial fibrillation and multi-morbidity: Insights from the ARISTOTLE trial EP - 131 SN - 0002-8703 SP - 123 JF - American Heart Journal VL - vol. 208 DO - https://doi.org/10.1016/j.ahj.2018.09.017 ER - TY - JOUR AU - Washam, J.B. AU - Hohnloser, S.H. AU - Lopes, R.D. AU - Wojdyla, D.M. AU - Vinereanu, D. AU - Alexander, J.H. AU - Gersh, B.J. AU - Hanna, M. AU - Horowitz, J. AU - Hylek, E.M. AU - Xavier, D. AU - Verheugt, F.W.A. AU - Wallentin, L. AU - Granger, C.B. PY - 2019 UR - https://hdl.handle.net/2066/202664 AB - Warfarin is dependent on multiple hepatic enzymes for metabolism while apixaban is a substrate for P-glycoprotein (P-gp) transport and hepatic CYP3A4 metabolism. The aim of this analysis was to assess the impact of interacting medication use on the treatment effects of apixaban versus warfarin. Outcomes were compared between apixaban and warfarin using Cox proportional hazards modeling according to the use of interacting medications at randomization in ARISTOTLE (n = 18,201). Interacting medications for apixaban were identified as combined P-gp and 3A4 inhibitors or inducers while interacting medications for warfarin were defined as those highly probable for warfarin potentiation or inhibition. At randomization, 5547 (30.5%) patients were on an interacting medication, including 2722 on apixaban and 2825 on warfarin. Patients using an interacting medication were more likely to be female, taking aspirin, and have a history of prior bleeding and were less likely to have a prior stroke or transient ischemic attack. No significant differences were observed on the treatment effect of apixaban compared with warfarin in patients on and off interacting medications for outcomes including the primary efficacy outcome of stroke or systemic embolism (P for interaction = 0.79) or the primary safety outcome of major bleeding (P for interaction = 0.75). Use of interacting medications with anticoagulants occurs often in patients with atrial fibrillation. Despite the potential for altered exposure, interacting medication use was not associated with a significant change in the efficacy or safety of apixaban compared with warfarin in the ARISTOTLE trial.Trial registration ClinicalTrials.gov, NCT00412984. TI - Interacting medication use and the treatment effects of apixaban versus warfarin: results from the ARISTOTLE Trial EP - 352 SN - 0929-5305 IS - iss. 3 SP - 345 JF - Journal of Thrombosis and Thrombolysis VL - vol. 47 DO - https://doi.org/10.1007/s11239-019-01823-y ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2018 UR - https://hdl.handle.net/2066/200580 TI - Anticoagulation resumption after intracranial haemorrhage with mechanical valves: a data-free zone EP - 1725 SN - 0195-668X IS - iss. 19 SP - 1724 JF - European Heart Journal VL - vol. 39 DO - https://doi.org/10.1093/eurheartj/ehy116 ER - TY - JOUR AU - Rocca, B. AU - Fox, K.A. AU - Ajjan, R.A. AU - Andreotti, F. AU - Baigent, C. AU - Collet, J.P. AU - Grove, E.L. AU - Halvorsen, S. AU - Huber, K. AU - Morais, J. AU - Patrono, C. AU - Rubboli, A. AU - Seljeflot, I. AU - Sibbing, D. AU - Siegbahn, A. AU - Berg, J ten AU - Vilahur, G. AU - Verheugt, F.W.A. AU - Wallentin, L. AU - Weiss, T.W. AU - Wojta, J. AU - Storey, R.F. PY - 2018 UR - https://hdl.handle.net/2066/200583 TI - Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis EP - 1691 SN - 0195-668X IS - iss. 19 SP - 1672 JF - European Heart Journal VL - vol. 39 DO - https://doi.org/10.1093/eurheartj/ehy066 ER - TY - JOUR AU - Beygui, F. AU - Belle, E. van AU - Ecollan, P. AU - Machecourt, J. AU - Hamm, C.W. AU - Sa, E. Lopez De AU - Flather, M. AU - Verheugt, F.W.A. AU - Vicaut, E. AU - Zannad, F. AU - Pitt, B. AU - Montalescot, G. PY - 2018 UR - https://hdl.handle.net/2066/200187 AB - BACKGROUND: Two recent randomised trials studied the benefit of mineralocorticoid receptor antagonists (MRAs) in ST-segment elevation myocardial infarction (STEMI) irrespective or in absence of heart failure. The studies were both undersized to assess hard clinical endpoints. A pooled analysis was preplanned by the steering committees. METHODS: We conducted a prespecified meta-analysis of patient-level data of patients with STEMI recruited in two multicentre superiority trials, randomised within 72 hours after symptom onset. Patients were allocated (1:1) to two MRA regimens: (1) an intravenous bolus of potassium canrenoate (200 mg) followed by oral spironolactone (25 mg once daily) versus standard therapy or (2) oral eplerenone (25-50 mg) versus placebo. The primary and key secondary outcomes, all-cause death and the composite of all-cause death or resuscitated sudden death, respectively, were assessed in the intention-to-treat population using a Cox model stratified on the study identifier. RESULTS: Patients were randomly assigned to receive (n=1118) or not the MRA regimen (n=1123). After a median follow-up time of 188 days, the primary and secondary outcomes occurred in 5 (0.4%) and 17 (1.5%) patients (adjusted HR (adjHR) 0.31, 95% CI 0.11 to 0.86, p=0.03) and 6 (0.5%) and 22 (2%) patients (adjHR 0.26, 95% CI 0.10 to 0.65, p=0.004) in the MRA and control groups, respectively. There were also trends towards lower rates of cardiovascular death (p=0.06) and ventricular fibrillation (p=0.08) in the MRA group. CONCLUSION: Our analysis suggests that compared with standard therapy, MRA regimens are associated with a reduction of death and death or resuscitated sudden death in STEMI. TI - Individual participant data analysis of two trials on aldosterone blockade in myocardial infarction EP - 1849 SN - 1355-6037 IS - iss. 22 SP - 1843 JF - Heart VL - vol. 104 DO - https://doi.org/10.1136/heartjnl-2018-312950 ER - TY - JOUR AU - Ferreira, J.P. AU - Barros, A. AU - Pitt, B. AU - Montalescot, G. AU - Sa, E.L. de AU - Hamm, C.W. AU - Flather, M. AU - Verheugt, F.W.A. AU - Shi, H. AU - Leite-Moreira, A. AU - Vincent, J. AU - Rossignol, P. AU - Zannad, F. PY - 2018 UR - https://hdl.handle.net/2066/200001 TI - Collagen biomarker bioprofiles predicting the antifibrotic response to eplerenone in myocardial infarction: findings from the REMINDER trial EP - 1195 SN - 1861-0684 IS - iss. 12 SP - 1192 JF - Clinical Research in Cardiology VL - vol. 107 DO - https://doi.org/10.1007/s00392-018-1373-5 ER - TY - JOUR AU - Korjian, S. AU - Braunwald, Eugene AU - Daaboul, Y. AU - Mi, Michael AU - Bhatt, Deepak L. AU - Verheugt, F.W.A. AU - Plotnikov, A.N. AU - Gibson, C. Michael PY - 2018 UR - https://hdl.handle.net/2066/199534 TI - Usefulness of Rivaroxaban for Secondary Prevention of Acute Coronary Syndrome in Patients With History of Congestive Heart Failure (from the ATLAS-ACS-2 TIMI-51 Trial) EP - 1901 SN - 0002-9149 IS - iss. 11 SP - 1896 JF - American Journal of Cardiology VL - vol. 122 DO - https://doi.org/10.1016/j.amjcard.2018.08.034 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/199534/199534.pdf?sequence=1 ER - TY - JOUR AU - Gommans, D.H.F. AU - Cramer, G.E. AU - Bakker, Jeannette AU - Dieker, H.J. AU - Michels, Michelle AU - Fouraux, Michael A. AU - Marcelis, C.L.M. AU - Verheugt, F.W.A. AU - Timmermans, J. AU - Brouwer, M.A. AU - Kofflard, Marcel J.M. PY - 2018 UR - https://hdl.handle.net/2066/183873 TI - High T2-weighted signal intensity for risk prediction of sudden cardiac death in hypertrophic cardiomyopathy EP - 120 SN - 1569-5794 IS - iss. 1 SP - 113 JF - International Journal of Cardiovascular Imaging VL - vol. 34 DO - https://doi.org/10.1007/s10554-017-1252-6 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/183873/183873.pdf?sequence=1 ER - TY - JOUR AU - Kopin, D. AU - Jones, W.S. AU - Sherwood, M.W. AU - Wojdyla, D.M. AU - Wallentin, L. AU - Lewis, B.S. AU - Verheugt, F.W.A. AU - Vinereanu, D. AU - Bahit, M.C. AU - Halvorsen, S. AU - Huber, K. AU - Parkhomenko, A. AU - Granger, C.B. AU - Lopes, R.D. AU - Alexander, J.H. PY - 2018 UR - https://hdl.handle.net/2066/190525 AB - BACKGROUND: We assessed antiplatelet therapy use and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ARISTOTLE trial. METHODS: Patients were categorized based on the occurrence of PCI during follow-up (median 1.8 years); PCI details and outcomes post-PCI are reported. Of the 18,201 trial participants, 316 (1.7%) underwent PCI (152 in apixaban group, 164 in warfarin group). RESULTS: At the time of PCI, 84% (267) were on study drug (either apixaban or warfarin). Of these, 19% did not stop study drug during PCI, 49% stopped and restarted <5 days post-PCI, and 30% stopped and restarted >5 days post-PCI. At 30 days post-PCI, 35% of patients received dual -antiplatelet therapy (DAPT), 23% received aspirin only, and 13% received a P2Y12 inhibitor only; 29% received no antiplatelet therapy. Triple therapy (DAPT + oral anticoagulant [OAC]) was used in 21% of patients, 23% received OAC only, 15% received OAC plus aspirin, and 9% received OAC plus a P2Y12 inhibitor; 32% received antiplatelet agents without OAC. Post-PCI, patients assigned to apixaban versus warfarin had numerically similar rates of major bleeding (5.93 vs 6.73 events/100 patient-years; P = .95) and stroke (2.74 vs 1.84 events/100 patient-years; P = .62). CONCLUSIONS: PCI occurred infrequently during follow-up. Most patients on study drug at the time of PCI remained on study drug in the peri-PCI period; 19% continued the study drug without interruption. Antiplatelet therapy use post-PCI was variable, although most patients received DAPT. Additional data are needed to guide the use of antithrombotics in patients undergoing PCI. TI - Percutaneous coronary intervention and antiplatelet therapy in patients with atrial fibrillation receiving apixaban or warfarin: Insights from the ARISTOTLE trial EP - 141 SN - 0002-8703 SP - 133 JF - American Heart Journal VL - vol. 197 DO - https://doi.org/10.1016/j.ahj.2017.11.005 ER - TY - JOUR AU - Bassand, J.P. AU - Accetta, G. AU - Mahmeed, W. Al AU - Corbalan, R. AU - Eikelboom, J. AU - Fitzmaurice, D.A. AU - Fox, K.A. AU - Gao, H. AU - Goldhaber, S.Z. AU - Goto, S. AU - Haas, S. AU - Kayani, G. AU - Pieper, K. AU - Turpie, A.G.G. AU - Eickels, M. van AU - Verheugt, F.W.A. AU - Kakkar, A.K. PY - 2018 UR - https://hdl.handle.net/2066/190537 AB - BACKGROUND: The factors influencing three major outcomes-death, stroke/systemic embolism (SE), and major bleeding-have not been investigated in a large international cohort of unselected patients with newly diagnosed atrial fibrillation (AF). METHODS AND RESULTS: In 28,628 patients prospectively enrolled in the GARFIELD-AF registry with 2-year follow-up, we aimed at analysing: (1) the variables influencing outcomes; (2) the extent of implementation of guideline-recommended therapies in comorbidities that strongly affect outcomes. Median (IQR) age was 71.0 (63.0 to 78.0) years, 44.4% of patients were female, median (IQR) CHA2DS2-VASc score was 3.0 (2.0 to 4.0); 63.3% of patients were on anticoagulants (ACs) with or without antiplatelet (AP) therapy, 24.5% AP monotherapy, and 12.2% no antithrombotic therapy. At 2 years, rates (95% CI) of death, stroke/SE, and major bleeding were 3.84 (3.68; 4.02), 1.27 (1.18; 1.38), and 0.71 (0.64; 0.79) per 100 person-years. Age, history of stroke/SE, vascular disease (VascD), and chronic kidney disease (CKD) were associated with the risks of all three outcomes. Congestive heart failure (CHF) was associated with the risks of death and stroke/SE. Smoking, non-paroxysmal forms of AF, and history of bleeding were associated with the risk of death, female sex and heavy drinking with the risk of stroke/SE. Asian race was associated with lower risks of death and major bleeding versus other races. AC treatment was associated with 30% and 28% lower risks of death and stroke/SE, respectively, compared with no AC treatment. Rates of prescription of guideline-recommended drugs were suboptimal in patients with CHF, VascD, or CKD. CONCLUSIONS: Our data show that several variables are associated with the risk of one or more outcomes, in terms of death, stroke/SE, and major bleeding. Comprehensive management of AF should encompass, besides anticoagulation, improved implementation of guideline-recommended therapies for comorbidities strongly associated with outcomes, namely CHF, VascD, and CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01090362. TI - Risk factors for death, stroke, and bleeding in 28,628 patients from the GARFIELD-AF registry: Rationale for comprehensive management of atrial fibrillation SN - 1932-6203 IS - iss. 1 JF - PLoS One VL - vol. 13 DO - https://doi.org/10.1371/journal.pone.0191592 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/190537/190537.pdf?sequence=1 ER - TY - JOUR AU - Valgimigli, M. AU - Bueno, H. AU - Byrne, R.A. AU - Collet, J.P. AU - Costa, F. AU - Jeppsson, A. AU - Juni, P. AU - Kastrati, A. AU - Kolh, P. AU - Mauri, L. AU - Montalescot, G. AU - Neumann, F.J. AU - Petricevic, M. AU - Roffi, M. AU - Steg, P.G. AU - Windecker, S. AU - Zamorano, J.L. AU - Levine, G.N. AU - Verheugt, F.W.A. AU - Aboyans, V. PY - 2018 UR - https://hdl.handle.net/2066/190441 TI - 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS EP - 78 SN - 1010-7940 IS - iss. 1 SP - 34 JF - European Journal of Cardio-Thoracic Surgery VL - vol. 53 DO - https://doi.org/10.1093/ejcts/ezx334 ER - TY - JOUR AU - Valgimigli, M. AU - Bueno, H. AU - Byrne, R.A. AU - Collet, J.P. AU - Costa, F. AU - Jeppsson, A. AU - Juni, P. AU - Kastrati, A. AU - Kolh, P. AU - Mauri, L. AU - Montalescot, G. AU - Neumann, F.J. AU - Petricevic, M. AU - Roffi, M. AU - Steg, P.G. AU - Windecker, S. AU - Zamorano, J.L. AU - Levine, G.N. AU - Verheugt, F.W.A. AU - Aboyans, V. PY - 2018 UR - https://hdl.handle.net/2066/190452 TI - 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS) EP - 260 SN - 0195-668X IS - iss. 3 SP - 213 JF - European Heart Journal VL - vol. 39 DO - https://doi.org/10.1093/eurheartj/ehx419 ER - TY - JOUR AU - Kerneis, M. AU - Gibson, C.M. AU - Chi, G. AU - Mehran, R. AU - AlKhalfan, F. AU - Talib, U. AU - Pahlavani, S. AU - Mir, M. AU - Bode, C. AU - Halperin, J.L. AU - Nafee, T. AU - Peterson, E.D. AU - Verheugt, F.W.A. AU - Wildgoose, P. AU - Eickels, M. van AU - Lip, G.Y. AU - Fox, K.A. AU - Cohen, M. PY - 2018 UR - https://hdl.handle.net/2066/190509 AB - OBJECTIVES: This study sought to assess whether there were significant interactions of procedural access strategies and lesion characteristics with bleeding and ischemic events among atrial fibrillation (AF) patients anticoagulated with rivaroxaban or warfarin following a percutaneous coronary intervention. BACKGROUND: Among stented AF patients, the impact of procedural access strategies or lesion characteristics on antithrombotic safety and efficacy outcomes is unclear. METHODS: In the PIONEER AF-PCI (An Open-label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) trial, 2,124 patients were randomized to 3 groups and followed for 12 months: 1) rivaroxaban 15 mg once daily plus a P2Y12 inhibitor (n = 709); 2) rivaroxaban 2.5 mg twice a day plus dual antiplatelet therapy (DAPT) (n = 709); and 3) dose-adjusted warfarin plus DAPT (n = 706). Kaplan-Meier rates of clinically significant bleeding and major adverse cardiovascular events were compared between treatments stratified by subgroups of procedure type and lesion characteristics. RESULTS: Compared with warfarin, both rivaroxaban regimens consistently reduced clinically significant bleeding across subgroups of radial versus femoral arterial access and by vascular closure device use. Treatment effect of rivaroxaban on major adverse cardiovascular events did not vary when stratified by ischemia-driven revascularization, urgency of revascularization, location of culprit artery, presence of bifurcation lesion, presence of thrombus, type, and length of stent or number of stents (interaction p > 0.05 for all subgroups). CONCLUSIONS: Among stented AF patients requiring long-term oral anticoagulation, there was no effect modification by procedure or lesion characteristics of either clinically significant bleeding or major adverse cardiovascular events. Rivaroxaban-based therapy was superior to warfarin plus DAPT in bleeding outcomes regardless of the type of stent or arterial access during the index coronary revascularization. (A Study Exploring Two Strategies of Rivaroxaban [JNJ39039039; BAY-59-7939] and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention [PIONEER AF-PCI]; NCT01830543). TI - Effect of Procedure and Coronary Lesion Characteristics on Clinical Outcomes Among Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention: Insights From the PIONEER AF-PCI Trial EP - 634 SN - 1936-8798 IS - iss. 7 SP - 626 JF - Jacc. Cardiovascular Interventions VL - vol. 11 DO - https://doi.org/10.1016/j.jcin.2017.11.009 ER - TY - JOUR AU - Ferreira, J.P. AU - Duarte, K. AU - Montalescot, G. AU - Pitt, B. AU - Sa, E.L. de AU - Hamm, C.W. AU - Flather, M. AU - Verheugt, F.W. AU - Shi, H. AU - Turgonyi, E. AU - Orri, M. AU - Rossignol, P. AU - Vincent, J B AU - Zannad, F. PY - 2018 UR - https://hdl.handle.net/2066/190510 AB - OBJECTIVE: Aldosterone stimulates cardiac collagen synthesis. Circulating biomarkers of collagen turnover provide a useful tool for the assessment of cardiac remodeling in patients with an acute myocardial infarction (MI). METHODS: The REMINDER trial assessed the effect of eplerenone in patients with an acute ST-elevation Myocardial Infarction (STEMI) without known heart failure (HF), when initiated within 24 h of symptom onset. The primary outcome was almost totally (>90%) driven by natriuretic peptide (NP) thresholds after 1-month post-MI (it also included a composite of cardiovascular death or re-hospitalization or new onset HF or sustained ventricular tachycardia or fibrillation or LVEF /=1 investigator-determined stroke risk factor. We analysed 51 270 patients from 35 countries enrolled into five sequential cohorts between 2010 and 2016. Overall, 20.7% of patients received AP monotherapy, 52.1% AC monotherapy, and 14.1% AP + AC. Most AP monotherapy (82.5%) and AC monotherapy (86.8%) patients were CHA2DS2-VASc >/=2. Compared with patients on AC monotherapy, AP monotherapy patients were frequently Chinese (vs. Caucasian, odds ratio 2.73) and more likely to have persistent AF (1.32), history of coronary artery disease (2.41) or other vascular disease (1.67), bleeding (2.11), or dementia (1.81). The odds for AP monotherapy increased with 5 years of age increments for patients >/=75 years (1.24) but decreased with age increments for patients 55-75 years (0.86). Antiplatelet monotherapy patients were less likely to have paroxysmal (0.67) or permanent AF (0.57), history of embolism (0.56), or alcohol use (0.90). With each cohort, AP monotherapy declined (P<0.0001), especially non-indicated use. AP + AC and no antithrombotic therapy were unchanged. However, even in 2015 and 2016, about 50% of AP-treated patients had no indication except AF (71% were CHA2DS2-VASc >/=2). Conclusion: Prescribing AP monotherapy in newly diagnosed AF has declined, but even nowadays a substantial proportion of AP-treated patients with AF have no indication for AP. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362. TI - Characteristics of patients with atrial fibrillation prescribed antiplatelet monotherapy compared with those on anticoagulants: insights from the GARFIELD-AF registry EP - 473 SN - 0195-668X IS - iss. 6 SP - 464 JF - European Heart Journal VL - vol. 39 DO - https://doi.org/10.1093/eurheartj/ehx730 ER - TY - JOUR AU - Siller-Matula, J.M. AU - Pecen, L. AU - Patti, G. AU - Lucerna, M. AU - Kirchhof, P. AU - Lesiak, M. AU - Huber, K. AU - Verheugt, F.W.A. AU - Lang, I.M. AU - Renda, G. AU - Schnabel, R.B. AU - Wachter, R. AU - Kotecha, D. AU - Sellal, J.M. AU - Rohla, M. AU - Ricci, F. AU - Caterina, R. De PY - 2018 UR - https://hdl.handle.net/2066/193224 AB - BACKGROUND AND OBJECTIVES: To assess thromboembolic and bleeding risks in patients with heart failure (HF) and atrial fibrillation (AF) according to HF type. METHODS: We analyzed 6170 AF patients from the Prevention of thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF), and categorized patients into: HF with reduced left-ventricular ejection fraction (HFrEF; LVEF<40%); mid-range EF (HFmrEF; LVEF: 40-49%); lower preserved EF (HFLpEF; LVEF: 50-60%), higher preserved EF (HFHpEF; LVEF>60%), and no HF. Outcomes were ischemic stroke, major adverse cardiovascular and cerebral events (MACCE) and major bleeding occurring within 1-year. RESULTS: The annual incidence of stroke was linearly and inversely related to LVEF, increasing by 0.054% per each 1% of LVEF decrease (95% CI: 0.013%-0.096%; p=0.031). Patients with HFHpEF had the highest CHA2DS2-VASc score, but significantly lower stroke incidence than other HF groups (0.65%, compared to HFLpEF 1.30%; HFmrEF 1.71%; HFrEF 1.75%; trend p=0.014). The incidence of MACCE was also lower in HFHpEF (2.0%) compared to other HF groups (range: 3.8-4.4%; p=0.001). Age, HF type, and NYHA class were independent predictors of thromboembolic events. Conversely, major bleeding did not significantly differ between groups (p=0.168). CONCLUSION: Our study in predominantly anticoagulated patients with AF shows that, reduction in LVEF is associated with higher thromboembolic, but not higher bleeding risk. HFHpEF is a distinct and puzzling group, featuring the highest CHA2DS2-VASc score but the lowest residual risk of thromboembolic events, which warrants further investigation. TI - Heart failure subtypes and thromboembolic risk in patients with atrial fibrillation: The PREFER in AF - HF substudy EP - 147 SN - 0167-5273 SP - 141 JF - International Journal of Cardiology VL - vol. 265 DO - https://doi.org/10.1016/j.ijcard.2018.04.093 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2018 UR - https://hdl.handle.net/2066/193261 TI - Return of Oral Anticoagulation in Chronic Stable Coronary Disease EP - 1657 SN - 0009-7322 IS - iss. 16 SP - 1655 JF - Circulation VL - vol. 137 DO - https://doi.org/10.1161/CIRCULATIONAHA.117.032916 ER - TY - JOUR AU - Cohen, A.T. AU - Lip, G.Y. AU - Caterina, R. De AU - Heidbuchel, H. AU - Zamorano, J.L. AU - Agnelli, G. AU - Verheugt, F.W.A. AU - Camm, A.J. PY - 2018 UR - https://hdl.handle.net/2066/193268 AB - Atrial fibrillation (AF) and venous thromboembolism (VTE) are cardiovascular conditions significant in contemporary practice. In both, the use of anticoagulation with vitamin K antagonists (VKAs) has been traditionally used to prevent adverse events. However, VKA therapy is associated with challenges relating to dose maintenance, the need to monitor anticoagulation, and bleeding risks. The non-vitamin K oral anticoagulants (NOACs) are becoming accepted as a clear alternative to VKA therapy for both AF and VTE management. The aim of this paper was to review contemporary evidence on the safety of NOACs in both conditions. A comprehensive literature review was conducted to explore key safety issues and expert consensus was achieved from eight professionals specialised in AF and VTE care. Consensus-based statements were formulated where available evidence was weak or contradictory. The expert statements in this paper form a key overview of the safety of NOACs compared with VKA therapy, and the comparative safety of different NOACs. It is apparent that a detailed patient work-up is required in order to identify and manage individual risk factors for bleeding and thrombosis prior to NOAC therapy. Additional measures, such as dose reductions, may also be used to maintain the safety of NOACs in practice. TI - State of play and future direction with NOACs: An expert consensus EP - 21 SN - 1537-1891 SP - 9 JF - Vascular Pharmacology VL - vol. 106 DO - https://doi.org/10.1016/j.vph.2018.04.001 ER - TY - JOUR AU - Damen, S.A.J. AU - Cramer, G.E. AU - Dieker, H.J. AU - Gehlmann, H.R. AU - Aengevaeren, W.R.M. AU - Oude Ophuis, T.J.M. AU - Verheugt, F.W.A. AU - Brouwer, M.A. AU - Suryapranata, H. PY - 2018 UR - https://hdl.handle.net/2066/199050 TI - A multi-site coronary sampling study on CRP in non-STEMI: Novel insights into the inflammatory process in acute coronary syndromes EP - 123 SN - 0021-9150 SP - 117 JF - Atherosclerosis VL - vol. 278 DO - https://doi.org/10.1016/j.atherosclerosis.2018.09.024 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/199050/199050.pdf?sequence=1 ER - TY - JOUR AU - Campen, C. van AU - Verheugt, F.W.A. AU - Visser, F.C. PY - 2018 UR - https://hdl.handle.net/2066/196086 AB - Objectives: Using different techniques, reduction of cerebral blood flow (CBF) during orthostatic stress were demonstrated. One study reported flow reduction of the right internal carotid (ICA) and vertebral (VA) artery during orthostatic stress by Doppler imaging, with different effects on the 2 vessels. Global CBF changes, using this technique, have not been reported. Therefore, flow of the ICA, VA and global CBF were measured during head-up tilt testing. Methods: 33 healthy volunteers underwent tilt testing. At three time points (supine, half way and at the end of the test) Doppler imaging of the ICA and VA was performed, as well as PetCO2 measurements. Results: Global CBF was significantly reduced by 4.5+/-2.8% halfway the test and by 6.0+/-3.4% at the end. All 4 artery flows were significantly reduced during the tilt, without differences between them. Despite small changes in PetCO2 there was a significant relation between de CBF decrease and PetCO2 decrease (p<0.05). Conclusions: Orthostatic stress in HV results in a small but significant reduction of CBF by a homogenous reduction in the four cerebral vessels and is modulated by PetCO2 changes. Significance: CBF changes can be measured during tilt testing using Doppler VA and ICA imaging. TI - Cerebral blood flow changes during tilt table testing in healthy volunteers, as assessed by Doppler imaging of the carotid and vertebral arteries EP - 95 SN - 2467-981X SP - 91 JF - Clinical Neurophysiology Practice VL - vol. 3 DO - https://doi.org/10.1016/j.cnp.2018.02.004 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196086/196086.pdf?sequence=1 ER - TY - JOUR AU - Nikolsky, E. AU - Verheugt, F.W.A. PY - 2018 UR - https://hdl.handle.net/2066/196234 TI - Ischemia and Bleeding on the Horns of a Dilemma: Do Only Hard Endpoints Count? EP - 140 SN - 0735-1097 IS - iss. 2 SP - 137 JF - Journal of the American College of Cardiology VL - vol. 72 DO - https://doi.org/10.1016/j.jacc.2018.04.056 ER - TY - JOUR AU - Gommans, D.H.F. AU - Cramer, G.E. AU - Fouraux, M.A. AU - Bakker, J. den AU - Michels, M AU - Dieker, H.J. AU - Timmermans, J. AU - Marcelis, C.L.M. AU - Verheugt, F.W.A. AU - Boer, M.J. de AU - Kofflard, M.J.M. AU - Boer, R.A. de AU - Brouwer, M.A. PY - 2018 UR - https://hdl.handle.net/2066/196255 AB - In nonhigh risk patients with hypertrophic cardiomyopathy (HC), the presence of extensive late gadolinium enhancement (LGEext) at cardiovascular magnetic resonance (CMR) imaging has been proposed as a risk modifier in the decision process for implantable cardioverter defibrillator implantation. With a pretest risk of about 10%, a strategy that alters the likelihood of LGEext could markedly affect efficacious CMR imaging. Our aim was to study the potential of clinical variables and biomarkers to predict LGEext. In 98 HC patients without any clear indication for implantable cardioverter defibrillator implantation, we determined the discriminative values of a set of clinical variables and a panel of biomarkers (hs-cTnT, NTproBNP, GDF-15, and Gal-3, CICP) for LGEext, that is, LGE >/=15% of the left ventricular mass. LGEext was present in 10% (10/98) of patients. The clinical prediction model contained a history of nonsustained ventricular tachycardia, maximal wall thickness and reduced systolic function (c-statistic: 0.868, p <0.001). Of all biomarkers, only hs-cTnT was associated with LGEext, in addition to the improved clinical model of diagnostic accuracy (p=0.04). A biomarker-only strategy allowed the exclusion of LGEext in half of the cohort, in case of a hs-cTnT concentration less than the optimal cutoff (Youden index; 8 ng/L-sensitivity 100%, specificity 54%). In conclusion, in this nonhigh risk HC cohort, the pretest likelihood of LGEext can be altered using clinical variables and the addition of hs-cTnT. The promising findings with the use of hs-cTnT only call for new initiatives to study its impact on efficacious CMR imaging in a larger HC population, either with or without additional use of clinical variables. TI - Prediction of Extensive Myocardial Fibrosis in Nonhigh Risk Patients With Hypertrophic Cardiomyopathy EP - 489 SN - 0002-9149 IS - iss. 3 SP - 483 JF - American Journal of Cardiology VL - vol. 122 DO - https://doi.org/10.1016/j.amjcard.2018.04.020 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/196255/196255.pdf?sequence=1 ER - TY - JOUR AU - Chi, G. AU - Kerneis, M. AU - Kalayci, A. AU - Liu, Y AU - Mehran, R. AU - Bode, C. AU - Halperin, J.L. AU - Verheugt, F.W.A. AU - Wildgoose, P. AU - Eickels, M. van AU - Lip, G.Y. AU - Cohen, M. AU - Peterson, E.D. AU - Fox, K.A. AU - Gibson, C.M. PY - 2018 UR - https://hdl.handle.net/2066/196264 AB - BACKGROUND: The tradeoff in safety versus efficacy in substituting a non-vitamin K antagonist oral anticoagulant for a vitamin K antagonist (VKA) in the stented atrial fibrillation patient has not been quantitatively evaluated. METHODS: Based on summary data from the PIONEER AF-PCI and RE-DUAL PCI trials, 4 antithrombotic regimens were compared with VKA-based triple therapy: (1) rivaroxaban (riva) 15 mg daily + P2Y12 inhibitor, (2) riva 2.5 mg twice daily + P2Y12 inhibitor + aspirin, (3) dabigatran (dabi) 110 mg twice daily + P2Y12 inhibitor, and (4) dabi 150 mg twice daily + P2Y12 inhibitor. A bivariate model with a noninferiority margin of 1.38 was used to simultaneously assess safety and efficacy. The safety end point was major or clinically relevant nonmajor bleeding by International Society on Thrombosis and Haemostasis definitions. The efficacy end point was a thromboembolic event (myocardial infarction, stroke, or systemic embolism), death, or urgent revascularization. The bivariate outcome, a measure of risk difference in the net clinical outcome, was compared between antithrombotic regimens. RESULTS: All 4 non-vitamin K antagonist oral anticoagulant regimens were superior in bleeding and noninferior in efficacy compared with triple therapy with VKA. Riva 15 mg daily and 2.5 mg twice daily were associated with bivariate combined risk reductions of 5.6% (2.3%-8.8%) and 5.5% (2.1%-8.7%), respectively, and dabi 110 mg twice daily and 150 mg twice daily reduced the bivariate risk by 3.8% (0.5%-7.0%) and 6.3% (2.4%-9.8%), respectively. CONCLUSIONS: A bivariate analysis that simultaneously characterizes both risk and benefit demonstrates that riva- and dabi-based regimens were both favorable over VKA plus dual antiplatelet therapy among patients with atrial fibrillation undergoing PCI. TI - Safety and efficacy of non-vitamin K oral anticoagulant for atrial fibrillation patients after percutaneous coronary intervention: A bivariate analysis of the PIONEER AF-PCI and RE-DUAL PCI trial EP - 24 SN - 0002-8703 SP - 17 JF - American Heart Journal VL - vol. 203 DO - https://doi.org/10.1016/j.ahj.2018.06.003 ER - TY - JOUR AU - Chi, G. AU - Yee, M.K. AU - Kalayci, A. AU - Kerneis, M. AU - AlKhalfan, F. AU - Mehran, R. AU - Bode, C. AU - Halperin, J.L. AU - Verheugt, F.W.A. AU - Wildgoose, P. AU - Eickels, M. van AU - Lip, G.Y. AU - Cohen, M. AU - Peterson, E.D. AU - Fox, K.A. AU - Gibson, C.M. PY - 2018 UR - https://hdl.handle.net/2066/196178 AB - Among atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI), rivaroxaban with background antiplatelet therapy significantly reduced the first occurrence of bleeding compared to triple therapy with warfarin. This study hypothesized that total bleeding events, including those beyond the first event, would be reduced with rivaroxaban-based regimens. In the PIONEER AF-PCI trial, 2099 patients in the modified intention-to-treat population were randomized to three groups and followed for 12 months: (1) rivaroxaban 15 mg once daily plus a P2Y12 inhibitor (N = 696); (2) rivaroxaban 2.5 mg twice daily plus dual antiplatelet therapy (DAPT) (N = 706); and (3) dose-adjusted warfarin plus DAPT (N = 697). Descriptive statistics for the number of subjects who experienced one or more bleeding events were calculated. The total number of bleeding events was compared across treatment groups using the Wei, Lin, and Weissfeld method. A total of 514 and 439 events of clinically significant bleeding and bleeding requiring medical attention occurred throughout the study. Compared to triple therapy with warfarin, rivaroxaban-based regimen was associated with a reduction in total events of clinically significant bleeding (Group 1 vs. Group 3: HR 0.64 [95% CI 0.49-0.85], p < 0.001, NNT = 11; Group 2 vs. Group 3: HR 0.62 [95% CI 0.48-0.80], p < 0.001, NNT = 10). Similarly, rivaroxaban reduced the total bleeding events requiring medical attention (Group 1 vs. Group 3: HR 0.66 [95% CI 0.49-0.89], p < 0.001, NNT = 14; Group 2 vs. Group 3: HR 0.64 [95% CI 0.48-0.85], p = 0.002, NNT = 13). Rivaroxaban-based regimen reduced the total bleeding events compared with VKA-based triple therapy in stented AF patients. One clinically significant bleeding event could be prevented with rivaroxaban use for every 10-11 patients treated, and one bleeding requiring medical attention could be prevented with rivaroxaban for every 13-14 patients treated. These data provide evidence that total bleeding events, including those beyond the first event, are reduced with rivaroxaban-based antithrombotic regimens. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01830543 (PIONEER AF-PCI). TI - Total bleeding with rivaroxaban versus warfarin in patients with atrial fibrillation receiving antiplatelet therapy after percutaneous coronary intervention EP - 350 SN - 0929-5305 IS - iss. 3 SP - 346 JF - Journal of Thrombosis and Thrombolysis VL - vol. 46 DO - https://doi.org/10.1007/s11239-018-1703-5 ER - TY - JOUR AU - Steinberg, B.A. AU - Gao, H. AU - Shrader, P. AU - Pieper, K. AU - Thomas, L. AU - Camm, A.J. AU - Ezekowitz, M.D. AU - Fonarow, G.C. AU - Gersh, B.J. AU - Goldhaber, S. AU - Haas, S. AU - Hacke, W. AU - Kowey, P.R. AU - Ansell, J. AU - Mahaffey, K.W. AU - Naccarelli, G. AU - Reiffel, J.A. AU - Turpie, A. AU - Verheugt, F.W. AU - Piccini, J.P. AU - Kakkar, A. AU - Peterson, E.D. AU - Fox, K.A. PY - 2017 UR - https://hdl.handle.net/2066/182774 AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world. We aimed to provide comprehensive data on international patterns of AF stroke prevention treatment. METHODS: Demographics, comorbidities, and stroke risk of the patients in the GARFIELD-AF (n=51,270), ORBIT-AF I (n=10,132), and ORBIT-AF II (n=11,602) registries were compared (overall N=73,004 from 35 countries). Stroke prevention therapies were assessed among patients with new-onset AF (/=2 vs 91% and 85%) and lower bleeding risk (11% with HAS-BLED >/=3 vs 24% and 15%). Oral anticoagulant use was 46% and 57% for patients with a CHA2DS2-VASc=0 and 69% and 87% for CHA2DS2-VASc >/=2 in GARFIELD-AF and ORBIT-AF II, respectively, but with substantial geographic heterogeneity in use of oral anticoagulant (range: 31%-93% [GARFIELD-AF] and 66%-100% [ORBIT-AF II]). Among patients with new-onset AF, non-vitamin K antagonist oral anticoagulant use increased over time to 43% in 2016 for GARFIELD-AF and 71% for ORBIT-AF II, whereas use of antiplatelet monotherapy decreased from 36% to 17% (GARFIELD-AF) and 18% to 8% (ORBIT-AF I and II). CONCLUSIONS: Among new-onset AF patients, non-vitamin K antagonist oral anticoagulant use has increased and antiplatelet monotherapy has decreased. However, anticoagulation is used frequently in low-risk patients and inconsistently in those at high risk of stroke. Significant geographic variability in anticoagulation persists and represents an opportunity for improvement. TI - International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries EP - 140 SN - 0002-8703 SP - 132 JF - American Heart Journal VL - vol. 194 DO - https://doi.org/10.1016/j.ahj.2017.08.011 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/182774/182774.pdf?sequence=1 ER - TY - JOUR AU - Damen, S.A.J. AU - Brouwer, M.A. AU - Verheugt, F.W.A. PY - 2017 UR - https://hdl.handle.net/2066/182789 TI - Letter by Damen et al Regarding Article, "A Critical Appraisal of Aspirin in Secondary Prevention: Is Less More?" EP - e1036 SN - 0009-7322 IS - iss. 19 SP - e1035 JF - Circulation VL - vol. 135 DO - https://doi.org/10.1161/CIRCULATIONAHA.116.026985 ER - TY - JOUR AU - Hoedemaker, N.P.G. AU - Damman, P. AU - Woudstra, P. AU - Hirsch, A. AU - Windhausen, F. AU - Tijssen, J.G. AU - Winter, R.J. de AU - Verheugt, F.W.A. AU - et al. PY - 2017 UR - https://hdl.handle.net/2066/182879 AB - BACKGROUND: The ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes) trial compared early invasive strategy with a selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and an elevated cardiac troponin T. No long-term benefit of an early invasive strategy was found at 1 and 5 years. OBJECTIVES: The aim of this study was to determine the 10-year clinical outcomes of an early invasive strategy versus a selective invasive strategy in patients with NSTE-ACS and an elevated cardiac troponin T. METHODS: The ICTUS trial was a multicenter, randomized controlled clinical trial that included 1,200 patients with NSTE-ACS and an elevated cardiac troponin T. Enrollment was from July 2001 to August 2003. We collected 10-year follow-up of death, myocardial infarction (MI), and revascularization through the Dutch population registry, patient phone calls, general practitioners, and hospital records. The primary outcome was the 10-year composite of death or spontaneous MI. Additional outcomes included the composite of death or MI, death, MI (spontaneous and procedure-related), and revascularization. RESULTS: Ten-year death or spontaneous MI was not statistically different between the 2 groups (33.8% vs. 29.0%, hazard ratio [HR]: 1.12; 95% confidence interval [CI]: 0.97 to 1.46; p = 0.11). Revascularization occurred in 82.6% of the early invasive group and 60.5% in the selective invasive group. There were no differences in additional outcomes, except for a higher rate of death or MI in the early invasive group compared with the rates for the selective invasive group (37.6% vs. 30.5%; HR: 1.30; 95% CI: 1.07 to 1.58; p = 0.009), driven by a higher rate of procedure-related MI in the early invasive group (6.5% vs. 2.4%; HR: 2.82; 95% CI: 1.53 to 5.20; p = 0.001). CONCLUSIONS: In patients with NSTE-ACS and elevated cardiac troponin T levels, an early invasive strategy has no benefit over a selective invasive strategy in reducing the 10-year composite outcome of death or spontaneous MI, and a selective invasive strategy may be a viable option in selected patients. TI - Early Invasive Versus Selective Strategy for Non-ST-Segment Elevation Acute Coronary Syndrome: The ICTUS Trial EP - 1893 SN - 0735-1097 IS - iss. 15 SP - 1883 JF - Journal of the American College of Cardiology VL - vol. 69 PS - 11 p. DO - https://doi.org/10.1016/j.jacc.2017.02.023 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/182879/182879.pdf?sequence=1 ER - TY - JOUR AU - Niessner, A. AU - Tamargo, J. AU - Morais, J. AU - Koller, L. AU - Wassmann, S. AU - Husted, S.E. AU - Torp-Pedersen, C. AU - Kjeldsen, K. AU - Lewis, B.S. AU - Drexel, H. AU - Kaski, J.C. AU - Atar, D. AU - Storey, R.F. AU - Lip, G.Y. AU - Verheugt, F.W.A. AU - Agewall, S. PY - 2017 UR - https://hdl.handle.net/2066/182909 TI - Reversal strategies for non-vitamin K antagonist oral anticoagulants: a critical appraisal of available evidence and recommendations for clinical management-a joint position paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy and European Society of Cardiology Working Group on Thrombosis EP - 1716 SN - 0195-668X IS - iss. 22 SP - 1710 JF - European Heart Journal VL - vol. 38 DO - https://doi.org/10.1093/eurheartj/ehv676 ER - TY - JOUR AU - Huber, K. AU - Ducrocq, G. AU - Hamm, C.W. AU - Hof, A. van't AU - Lapostolle, F. AU - Coste, P. AU - Gordini, G. AU - Steinmetz, J. AU - Verheugt, F.W.A. AU - Adgey, J. AU - Nibbe, L. AU - Kanic, V. AU - Clemmensen, P. AU - Zeymer, U. AU - Bernstein, D. AU - Prats, J. AU - Deliargyris, E.N. AU - Gabriel Steg, P. PY - 2017 UR - https://hdl.handle.net/2066/182739 AB - Objective: To ascertain whether different oral P2Y12 inhibitors might affect rates of acute stent thrombosis and 30-day outcomes after primary percutaneous coronary intervention (pPCI). Methods: The European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) randomised trial compared prehospital bivalirudin with heparin with optional glycoprotein IIb/IIIa inhibitor treatment in patients with ST-segment elevation myocardial infarction triaged to pPCI. Choice of P2Y12 inhibitor was at the investigator's discretion. In a prespecified analysis, we compared event rates with clopidogrel and newer oral P2Y12 inhibitors (prasugrel, ticagrelor). Rates of the primary outcome (acute stent thrombosis) were examined as a function of the P2Y12 inhibitor used for loading and 30-day outcomes (including major adverse cardiac events) as a function of the P2Y12 inhibitor used for maintenance therapy. Logistic regression was used to adjust for differences in baseline characteristics. Results: Prasugrel or ticagrelor was given as the loading P2Y12 inhibitor in 49% of 2198 patients and as a maintenance therapy in 59%. No differences were observed in rates of acute stent thrombosis for clopidogrel versus newer P2Y12 inhibitors (adjusted OR 0.50, 95% CI 0.13 to 1.85). After adjustment, no difference was observed in 30-day outcomes according to maintenance therapy except for protocol major (p=0.029) or minor (p=0.025) bleeding and Thrombolysis In Myocardial Infarction minor bleeding (p=0.002), which were less frequent in patients on clopidogrel. Consistent results were observed in the bivalirudin and heparin arms. Conclusions: The choice of prasugrel or ticagrelor over clopidogrel was not associated with differences in acute stent thrombosis or 30-day ischaemic outcomes after pPCI. Trial registration number: NCT01087723. TI - Early clinical outcomes as a function of use of newer oral P2Y12 inhibitors versus clopidogrel in the EUROMAX trial SN - 2053-3624 IS - iss. 2 JF - Open Heart VL - vol. 4 DO - https://doi.org/10.1136/openhrt-2017-000677 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/182739/182739.pdf?sequence=1 ER - TY - JOUR AU - Halvorsen, S. AU - Storey, R.F. AU - Rocca, B. AU - Sibbing, D. AU - Grove, E.L. AU - Weiss, T.W. AU - Collet, J.P. AU - Andreotti, F. AU - Gulba, D.C. AU - Lip, G.Y. AU - Husted, S. AU - Vilahur, G. AU - Morais, J. AU - Verheugt, F.W.A. AU - Lanas, A. AU - Salman, R. Al-Shahi AU - Steg, P.G. AU - Huber, K. PY - 2017 UR - https://hdl.handle.net/2066/182623 TI - Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis EP - 1462 SN - 0195-668X IS - iss. 19 SP - 1455 JF - European Heart Journal VL - vol. 38 DO - https://doi.org/10.1093/eurheartj/ehw454 ER - TY - JOUR AU - Vugt, S.P.G. van AU - Brouwer, M.A. AU - Verheugt, F.W.A. PY - 2017 UR - https://hdl.handle.net/2066/182630 TI - Off-Label Use of Non-Vitamin K Antagonist Oral Anticoagulants EP - 2578 SN - 0735-1097 IS - iss. 20 SP - 2577 JF - Journal of the American College of Cardiology VL - vol. 69 DO - https://doi.org/10.1016/j.jacc.2017.01.073 ER - TY - JOUR AU - Huber, K. AU - Verheugt, F.W.A. PY - 2017 UR - https://hdl.handle.net/2066/169905 TI - Bivalirudin in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: uncertainties almost clarified EP - 1932 SN - 1774-024X IS - iss. 16 SP - 1930 JF - Eurointervention VL - vol. 12 DO - https://doi.org/10.4244/EIJV12I16A315 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2017 UR - https://hdl.handle.net/2066/176877 TI - Antiplatelet therapy with CABG: chaos in the Netherlands EP - 481 SN - 1568-5888 IS - iss. 9 SP - 481 JF - Netherlands Heart Journal VL - vol. 25 DO - https://doi.org/10.1007/s12471-017-1031-y L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/176877/176877.pdf?sequence=1 ER - TY - JOUR AU - Wehling, M. AU - Collins, R. AU - Gil, V.M. AU - Hanon, O. AU - Hardt, R. AU - Hoffmeister, M. AU - Monteiro, P. AU - Quinn, T.J. AU - Ropers, D. AU - Sergi, G. AU - Verheugt, F.W.A. PY - 2017 UR - https://hdl.handle.net/2066/176888 AB - BACKGROUND: Age appropriateness of anticoagulants for stroke prevention in atrial fibrillation is uncertain. OBJECTIVE: To review oral anticoagulants for the treatment of atrial fibrillation in older (age >65 years) people and to classify appropriate and inappropriate drugs based on efficacy, safety and tolerability using the Fit-fOR-The-Aged (FORTA) classification. METHODS: We performed a structured comprehensive review of controlled clinical trials and summaries of individual product characteristics to assess study and total patient numbers, quality of major outcome data and data of geriatric relevance. The resulting evidence was discussed in a round table with an interdisciplinary panel of ten European experts. Decisions on age appropriateness were made using a Delphi process. RESULTS: For the eight drugs included, 380 citations were identified. The primary outcome results were reported in 32 clinical trials with explicit and relevant data on older people. Though over 24,000 patients aged >75/80 years were studied for warfarin, data on geriatric syndromes were rare (two studies reporting on frailty/falls/mental status) and missing for all other compounds. Apixaban was rated FORTA-A (highly beneficial). Other non-vitamin K antagonist oral anticoagulants (including low/high-intensity dabigatran and high-intensity edoxaban) and warfarin were assigned to FORTA-B (beneficial). Phenprocoumon, acenocoumarol and fluindione were rated FORTA-C (questionable), mainly reflecting the absence of data. CONCLUSIONS: All non-vitamin K antagonist oral anticoagulants and warfarin were classified as beneficial or very beneficial in older persons (FORTA-A or -B), underlining the overall positive assessment of the risk/benefit ratio for these drugs. For other vitamin-K antagonists regionally used in Europe, the lack of evidence should challenge current practice. TI - Appropriateness of Oral Anticoagulants for the Long-Term Treatment of Atrial Fibrillation in Older People: Results of an Evidence-Based Review and International Consensus Validation Process (OAC-FORTA 2016) EP - 507 SN - 1170-229X IS - iss. 7 SP - 499 JF - Drugs & Aging VL - vol. 34 DO - https://doi.org/10.1007/s40266-017-0466-6 ER - TY - JOUR AU - Cuisset, T. AU - Verheugt, F.W.A. AU - Mauri, L. PY - 2017 UR - https://hdl.handle.net/2066/176956 AB - For relief of coronary obstruction, percutaneous coronary intervention has become a standard-of-care procedure over the past 40 years. Nonetheless, optimal outcomes after coronary stenting require careful attention to antithrombotic therapy. This review aims to summarise the current available evidence and discusses how to integrate scientific knowledge into clinical decisions. In recent years, improvement and modifications of drugs and devices have changed the field tremendously, and substantially benefitted patient outcomes. The key challenge of how to provide optimal protection against thrombotic events without excessive increases in bleeding risk has remained the same for decades. Alternative strategies with new drugs, both antiplatelet and anticoagulant agents, and new coronary stents will continue the journey to achieve this ultimate goal. TI - Update on antithrombotic therapy after percutaneous coronary revascularisation EP - 820 SN - 0140-6736 IS - iss. 10096 SP - 810 JF - The Lancet (London) VL - vol. 390 DO - https://doi.org/10.1016/S0140-6736(17)31936-0 ER - TY - JOUR AU - Diener, H.C. AU - Aisenberg, J. AU - Ansell, J. AU - Atar, D. AU - Breithardt, G. AU - Eikelboom, J. AU - Ezekowitz, M.D. AU - Granger, C.B. AU - Halperin, J.L. AU - Hohnloser, S.H. AU - Hylek, E.M. AU - Kirchhof, P. AU - Lane, D.A. AU - Verheugt, F.W.A. AU - Veltkamp, R. AU - Lip, G.Y. PY - 2017 UR - https://hdl.handle.net/2066/176976 AB - Patients with atrial fibrillation (AF) have a high risk of stroke and mortality, which can be considerably reduced by oral anticoagulants (OAC). Recently, four non-vitamin-K oral anticoagulants (NOACs) were compared with warfarin in large randomized trials for the prevention of stroke and systemic embolism. Today's clinician is faced with the difficult task of selecting a suitable OAC for a patient with a particular clinical profile or a particular pattern of risk factors and concomitant diseases. We reviewed analyses of subgroups of patients from trials of vitamin K antagonists vs. NOACs for stroke prevention in AF with the aim to identify patient groups who might benefit from a particular OAC more than from another. In the first of a two-part review, we discuss the choice of NOAC for stroke prevention in the following subgroups of patients with AF: (i) stable coronary artery disease or peripheral artery disease, including percutaneous coronary intervention with stenting and triple therapy; (ii) cardioversion, ablation and anti-arrhythmic drug therapy; (iii) mechanical valves and rheumatic valve disease, (iv) patients with time in therapeutic range of >70% on warfarin; (v) patients with a single stroke risk factor (CHA2DS2VASc score of 1 in males, 2 in females); and (vi) patients with a single first episode of paroxysmal AF. Although there are no major differences in terms of efficacy and safety between the NOACs for some clinical scenarios, in others we are able to suggest that particular drugs and/or doses be prioritized for anticoagulation. TI - Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 1 EP - 859 SN - 0195-668X IS - iss. 12 SP - 852 JF - European Heart Journal VL - vol. 38 DO - https://doi.org/10.1093/eurheartj/ehv643 ER - TY - JOUR AU - Diener, H.C. AU - Aisenberg, J. AU - Ansell, J. AU - Atar, D. AU - Breithardt, G. AU - Eikelboom, J. AU - Ezekowitz, M.D. AU - Granger, C.B. AU - Halperin, J.L. AU - Hohnloser, S.H. AU - Hylek, E.M. AU - Kirchhof, P. AU - Lane, D.A. AU - Verheugt, F.W.A. AU - Veltkamp, R. AU - Lip, G.Y. PY - 2017 UR - https://hdl.handle.net/2066/176977 AB - The choice of oral anticoagulant (OAC) for patients with atrial fibrillation (AF) may be influenced by individual clinical features or by patterns of risk factors and comorbidities. We reviewed analyses of subgroups of patients from trials of vitamin K antagonists vs. non-vitamin K oral anticoagulants (NOACs) for stroke prevention in AF with the aim to identify patient groups who might benefit from a particular OAC more than from another. In addition, we discuss the timing of initiation of anticoagulation. In the second of a two-part review, we discuss the use of NOAC for stroke prevention in the following subgroups of patients with AF: (vii) secondary stroke prevention in patients after stroke or transient ischaemic attack (TIA), (viii) patients with acute stroke requiring thrombolysis or thrombectomy, (ix) those initiating or restarting OAC treatment after stroke or TIA, (x) those with renal impairment on dialysis, (xi) the elderly, (xii) those at high risk of gastrointestinal bleeding, and (xiii) those with hypertension. In addition, we discuss adherence and compliance. Finally, we present a summary of treatment suggestions. In specific subgroups of patients with AF, evidence supports the use of particular NOACs and/or particular doses of anticoagulant. The appropriate choice of treatment for these subgroups will help to promote optimal clinical outcomes. TI - Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 2 EP - 868 SN - 0195-668X IS - iss. 12 SP - 860 JF - European Heart Journal VL - vol. 38 DO - https://doi.org/10.1093/eurheartj/ehw069 ER - TY - JOUR AU - Hu, P.T. AU - Lopes, R.D. AU - Stevens, S.R. AU - Wallentin, L. AU - Thomas, L. AU - Alexander, J.H. AU - Hanna, M. AU - Lewis, B.S. AU - Verheugt, F.W.A. AU - Granger, C.B. AU - Jones, W.S. PY - 2017 UR - https://hdl.handle.net/2066/169653 AB - BACKGROUND: We studied (1) the rates of stroke or systemic embolism and bleeding in patients with atrial fibrillation and peripheral artery disease (PAD) and (2) the efficacy and safety of apixaban versus warfarin in patients with atrial fibrillation with and without PAD. METHODS AND RESULTS: The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin for stroke/systemic embolism prevention; 884 (4.9%) patients had PAD at baseline. Patients with PAD had higher unadjusted rates of stroke and systemic embolism (hazard ratio [HR] 1.73, 95% CI 1.22-2.45; P=0.002) and major bleeding (HR 1.34, 95% CI 1.00-1.81; P=0.05), but after adjustment, no differences existed in rates of stroke and systemic embolism (HR 1.32, 95% CI 0.93-1.88; P=0.12) and major bleeding (HR 1.03, 95% CI 0.76-1.40; P=0.83) compared with patients without PAD. The risk of stroke or systemic embolism was similar in patients assigned to apixaban and warfarin with PAD (HR 0.63, 95% CI 0.32-1.25) and without PAD (HR 0.80, 95% CI 0.66-0.96; interaction P=0.52). Patients with PAD did not have a statistically significant reduction in major or clinically relevant nonmajor bleeding with apixaban compared with warfarin (HR 1.05, 95% CI 0.69-1.58), whereas those without PAD had a statistically significant reduction (HR 0.65, 95% CI 0.58-0.73; interaction P=0.03). CONCLUSIONS: Patients with PAD in ARISTOTLE had a higher crude risk of stroke or systemic embolism compared with patients without PAD that was not present after adjustment. The benefits of apixaban versus warfarin for stroke and systemic embolism were similar in patients with and without PAD. These findings highlight the need to optimize the treatment of patients with atrial fibrillation and PAD. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984. TI - Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation and Peripheral Artery Disease: Insights From the ARISTOTLE Trial SN - 2047-9980 IS - iss. 1 JF - Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease VL - vol. 6 DO - https://doi.org/10.1161/JAHA.116.004699 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/169653/169653.pdf?sequence=1 ER - TY - JOUR AU - Camm, A.J. AU - Accetta, G. AU - Ambrosio, G. AU - Atar, D. AU - Bassand, J.P. AU - Berge, E. van de AU - Cools, F. AU - Fitzmaurice, D.A. AU - Goldhaber, S.Z. AU - Goto, S. AU - Haas, S. AU - Kayani, G. AU - Koretsune, Y. AU - Mantovani, L.G. AU - Misselwitz, F. AU - Oh, S. AU - Turpie, A.G.G. AU - Verheugt, F.W.A. AU - Kakkar, A.K. PY - 2017 UR - https://hdl.handle.net/2066/169663 AB - OBJECTIVE: We studied evolving antithrombotic therapy patterns in patients with newly diagnosed non-valvular atrial fibrillation (AF) and >/=1 additional stroke risk factor between 2010 and 2015. METHODS: 39 670 patients were prospectively enrolled in four sequential cohorts in the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF): cohort C1 (2010-2011), n=5500; C2 (2011-2013), n=11 662; C3 (2013-2014), n=11 462; C4 (2014-2015), n=11 046. Baseline characteristics and antithrombotic therapy initiated at diagnosis were analysed by cohort. RESULTS: Baseline characteristics were similar across cohorts. Median CHA2DS2-VASc (cardiac failure, hypertension, age >/=75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65-74 and sex category (female)) score was 3 in all four cohorts. From C1 to C4, the proportion of patients on anticoagulant (AC) therapy increased by almost 15% (C1 57.4%; C4 71.1%). Use of vitamin K antagonist (VKA)+/-antiplatelet (AP) (C1 53.2%; C4 34.0%) and AP monotherapy (C1 30.2%; C4 16.6%) declined, while use of non-VKA oral ACs (NOACs)+/-AP increased (C1 4.2%; C4 37.0%). Most CHA2DS2-VASc >/=2 patients received AC, and this proportion increased over time, largely driven by NOAC prescribing. NOACs were more frequently prescribed than VKAs in men, the elderly, patients of Asian ethnicity, those with dementia, or those using non-steroidal anti-inflammatory drugs, and current smokers. VKA use was more common in patients with cardiac, vascular, or renal comorbidities. CONCLUSIONS: Since NOACs were introduced, there has been an increase in newly diagnosed patients with AF at risk of stroke receiving guideline-recommended therapy, predominantly driven by increased use of NOACs and reduced use of VKA+/-AP or AP alone. TRIAL REGISTRATION NUMBER: NCT01090362; Pre-results. TI - Evolving antithrombotic treatment patterns for patients with newly diagnosed atrial fibrillation EP - 314 SN - 1355-6037 IS - iss. 4 SP - 307 JF - Heart VL - vol. 103 DO - https://doi.org/10.1136/heartjnl-2016-309832 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/169663/169663.pdf?sequence=1 ER - TY - JOUR AU - Bahit, M.C. AU - Lopes, R.D. AU - Wojdyla, D.M. AU - Held, C. AU - Hanna, M. AU - Vinereanu, D. AU - Hylek, E.M. AU - Verheugt, F.W. AU - Goto, S. AU - Alexander, J.H. AU - Wallentin, L. AU - Granger, C.B. PY - 2017 UR - https://hdl.handle.net/2066/169768 AB - OBJECTIVE: We describe the incidence, location and management of non-major bleeding, and assess the association between non-major bleeding and clinical outcomes in patients with atrial fibrillation (AF) receiving anticoagulation therapy enrolled in Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE). METHODS: We included patients who received >/=1 dose of study drug (n=18 140). Non-major bleeding was defined as the first bleeding event considered to be clinically relevant non-major (CRNM) or minor bleeding, and not preceded by a major bleeding event. RESULTS: Non-major bleeding was three times more common than major bleeding (12.1% vs 3.8%). Like major bleeding, non-major bleeding was less frequent with apixaban (6.4 per 100 patient-years) than warfarin (9.4 per 100 patient-years) (adjusted HR 0.69, 95% CI 0.63 to 0.75). The most frequent sites of non-major bleeding were haematuria (16.4%), epistaxis (14.8%), gastrointestinal (13.3%), haematoma (11.5%) and bruising/ecchymosis (10.1%). Medical or surgical intervention was similar among patients with non-major bleeding on warfarin versus apixaban (24.7% vs 24.5%). A change in antithrombotic therapy (58.6% vs 50.0%) and permanent study drug discontinuation (5.1% (61) vs 3.6% (30), p=0.10) was numerically higher with warfarin than apixaban. CRNM bleeding was independently associated with an increased risk of overall death (adjusted HR 1.70, 95% CI 1.32 to 2.18) and subsequent major bleeding (adjusted HR 2.18, 95% CI 1.56 to 3.04). CONCLUSIONS: In ARISTOTLE, non-major bleeding was common and substantially less frequent with apixaban than with warfarin. CRNM bleeding was independently associated with a higher risk of death and subsequent major bleeding. Our results highlight the importance of any severity of bleeding in patients with AF treated with anticoagulation therapy and suggest that non-major bleeding, including minor bleeding, might not be minor. TRIAL REGISTRATION NUMBER: NCT00412984; post-results. TI - Non-major bleeding with apixaban versus warfarin in patients with atrial fibrillation EP - 628 SN - 1355-6037 IS - iss. 8 SP - 623 JF - Heart VL - vol. 103 DO - https://doi.org/10.1136/heartjnl-2016-309901 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/169768/169768.pdf?sequence=1 ER - TY - JOUR AU - Gommans, D.H.F. AU - Cramer, G.E. AU - Bakker, J. AU - Michels, M AU - Dieker, H.J. AU - Timmermans, J. AU - Fouraux, M.A. AU - Marcelis, C.L.M. AU - Verheugt, F.W.A. AU - Brouwer, M.A. AU - Kofflard, M.J.M. PY - 2017 UR - https://hdl.handle.net/2066/169685 AB - OBJECTIVE: Areas of high signal intensity (HighT2) on T2-weighted cardiovascular magnetic resonance (CMR) imaging have been demonstrated in hypertrophic cardiomyopathy (HCM). It has been hypothesised that HighT2 may indicate active tissue injury in HCM. In this context, we studied HighT2 in relation to cardiac troponin. METHODS: Outpatient HCM patients without a history of coronary artery disease underwent CMR imaging at 1.5 T using T2-weighted, cine and late gadolinium enhancement (LGE) imaging to assess HighT2, left ventricular (LV) function, LV mass and the presence and extent of LGE. Highly sensitive cardiac troponin T (hs-cTnT) was assessed as a marker of injury, with hs-cTnT >/=14 and >3 ng/L defined as an elevated and detectable troponin. RESULTS: HighT2 was present in 28% of patients (28/101). An elevated hs-cTnT was present in 54% of patients with HighT2 (15/28) compared with 14% of patients without HighT2 (10/73) (p<0.001). Hs-cTnT was detectable in 96% of patients with HighT2 (27/28) compared with 66% of patients without HighT2 (48/73) (p=0.002). In case of an undetectable hs-cTnT, HighT2 was only seen in 4% (1/26). In addition, the extent of HighT2 was related with increasing hs-cTnT concentrations (Spearman's rho: 0.42, p<0.001). CONCLUSIONS: In this CMR study of patients with HCM, we observed HighT2 in a quarter of patients, and demonstrated that HighT2 was associated with an elevated hs-cTnT. This observation, combined with the very high negative predictive value of an undetectable hs-cTnT for HighT2, provides supportive evidence for the hypothesis that HighT2 is indicative of recently sustained myocyte injury. TI - High T2-weighted signal intensity is associated with elevated troponin T in hypertrophic cardiomyopathy EP - 299 SN - 1355-6037 IS - iss. 4 SP - 293 JF - Heart VL - vol. 103 DO - https://doi.org/10.1136/heartjnl-2016-309900 ER - TY - JOUR AU - Berndt, N. AU - Vries, H. de AU - Lechner, L. AU - Acker, F. Van AU - Froelicher, E.S. AU - Verheugt, F.W. AU - Mudde, A. AU - Bolman, C. PY - 2017 UR - https://hdl.handle.net/2066/169686 AB - BACKGROUND: Without assistance, smokers being admitted to the hospital for coronary heart disease often return to regular smoking within a year. OBJECTIVE: This study assessed the 12-month effectiveness of a telephone and a face-to-face counselling intervention on smoking abstinence among cardiac patients. Differential effects for subgroups varying in their socioeconomic status and intention to quit smoking were also studied. METHODS: A randomised controlled trial was used. During hospital stay, smokers hospitalised for coronary heart disease were assigned to usual care (n = 245), telephone counselling (n = 223) or face-to-face counselling (n = 157). Eligible patients were allocated to an intervention counselling group and received nicotine patches. After 12 months, self-reported continued abstinence was assessed and biochemically verified in quitters. Effects on smoking abstinence were tested using multilevel logistic regression analyses applying the intention-to-treat approach. RESULTS: Compared with usual care, differential effects of telephone and face-to-face counselling on continued abstinence were found in patients with a low socioeconomic status and in patients with a low quit intention. For these patients, telephone counselling increased the likelihood of abstinence threefold (OR = 3.10, 95 % CI 1.32-7.31, p = 0.01), whereas face-to-face counselling increased this likelihood fivefold (OR = 5.30, 95 % CI 2.13-13.17, p < 0.001). Considering the total sample, the interventions did not result in stronger effects than usual care. CONCLUSION: Post-discharge telephone and face-to-face counselling interventions increased smoking abstinence rates at 12 months compared with usual care among cardiac patients of low socioeconomic status and low quit intentions. The present study indicates that patients of high socioeconomic status and high quit motivation require different cessation approaches. TI - High intensity smoking cessation interventions: Cardiac patients of low socioeconomic status and low intention to quit profit most EP - 32 SN - 1568-5888 IS - iss. 1 SP - 24 JF - Netherlands Heart Journal VL - vol. 25 DO - https://doi.org/10.1007/s12471-016-0906-7 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/169686/169686.pdf?sequence=1 ER - TY - JOUR AU - Gibson, C.M. AU - Pinto, D.S. AU - Chi, G. AU - Arbetter, D. AU - Yee, M. AU - Mehran, R. AU - Bode, C. AU - Halperin, J. AU - Verheugt, F.W.A. AU - Wildgoose, P. AU - Burton, P. AU - Eickels, M. van AU - Korjian, S. AU - Daaboul, Y. AU - Jain, P. AU - Lip, G.Y. AU - Cohen, M. AU - Peterson, E.D. AU - Fox, K.A. PY - 2017 UR - https://hdl.handle.net/2066/169804 AB - BACKGROUND: Patients with atrial fibrillation who undergo intracoronary stenting traditionally are treated with a vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT), yet this treatment leads to high risks of bleeding. We hypothesized that a regimen of rivaroxaban plus a P2Y12 inhibitor monotherapy or rivaroxaban plus DAPT could reduce bleeding and thereby have a favorable impact on all-cause mortality and the need for rehospitalization. METHODS: Stented subjects with nonvalvular atrial fibrillation (n=2124) were randomized 1:1:1 to administration of reduced-dose rivaroxaban 15 mg daily plus a P2Y12 inhibitor for 12 months (group 1); rivaroxaban 2.5 mg twice daily with stratification to a prespecified duration of DAPT of 1, 6, or 12 months (group 2); or the reference arm of dose-adjusted VKA daily with a similar DAPT stratification (group 3). The present post hoc analysis assessed the end point of all-cause mortality or recurrent hospitalization for an adverse event, which was further classified as the result of bleeding, a cardiovascular cause, or another cause blinded to treatment assignment. RESULTS: The risk of all-cause mortality or recurrent hospitalization was 34.9% in group 1 (hazard ratio=0.79; 95% confidence interval, 0.66-0.94; P=0.008 versus group 3; number needed to treat=15), 31.9% in group 2 (hazard ratio=0.75; 95% confidence interval, 0.62-0.90; P=0.002 versus group 3; number needed to treat=10), and 41.9% in group 3 (VKA+DAPT). Both all-cause death plus hospitalization potentially resulting from bleeding (group 1=8.6% [P=0.032 versus group 3], group 2=8.0% [P=0.012 versus group 3], and group 3=12.4%) and all-cause death plus rehospitalization potentially resulting from a cardiovascular cause (group 1=21.4% [P=0.001 versus group 3], group 2=21.7% [P=0.011 versus group 3], and group 3=29.3%) were reduced in the rivaroxaban arms compared with the VKA arm, but other forms of rehospitalization were not. CONCLUSIONS: Among patients with atrial fibrillation undergoing intracoronary stenting, administration of either rivaroxaban 15 mg daily plus P2Y12 inhibitor monotherapy or 2.5 mg rivaroxaban twice daily plus DAPT was associated with a reduced risk of all-cause mortality or recurrent hospitalization for adverse events compared with standard-of-care VKA plus DAPT. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01830543. TI - Recurrent Hospitalization Among Patients With Atrial Fibrillation Undergoing Intracoronary Stenting Treated With 2 Treatment Strategies of Rivaroxaban or a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy EP - 333 SN - 0009-7322 IS - iss. 4 SP - 323 JF - Circulation VL - vol. 135 DO - https://doi.org/10.1161/CIRCULATIONAHA.116.025783 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/169804/169804.pdf?sequence=1 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2017 UR - https://hdl.handle.net/2066/169887 AB - Antithrombotic therapy is essential in the prevention of periprocedural death and myocardial infarction during and after percutaneous coronary intervention. In the pathogenesis of acute coronary syndromes (ACS), both platelets and the coagulation cascade play an important role. Therefore, periprocedural antithrombotic therapy is even more important in ACS than in elective PCI. The most used agents are aspirin, platelet P2Y12 blockers, platelet glycoprotein IIb/IIIa blockers, and parenteral anticoagulants. The P2Y12 blockers must be continued at least 12 months. High-risk patients should be treated with glycoprotein IIb/IIIa receptor antagonists, especially those undergoing primary angioplasty for ST-elevation acute coronary syndrome. TI - Antithrombotic Therapy to Reduce Ischemic Events in Acute Coronary Syndromes Patients Undergoing Percutaneous Coronary Intervention EP - 140 SN - 2211-7458 IS - iss. 1 SP - 131 JF - Interventional Cardiology Clinics VL - vol. 6 DO - https://doi.org/10.1016/j.iccl.2016.08.009 ER - TY - JOUR AU - Oosterwerff, E.F. AU - Fagel, N.D. AU - Slagboom, T. AU - Tijssen, J.G. AU - Herrman, J.P. AU - Smits, P.C. AU - Suttorp, M.J. AU - Ronner, E. AU - Laarman, G.J. AU - Patterson, M.S. AU - Amoroso, G. AU - Vink, M.A. AU - Schaaf, R.J. van der AU - Verheugt, F.W. AU - Riezebos, R.K. PY - 2016 UR - https://hdl.handle.net/2066/172759 AB - BACKGROUND: The OPTIMA trial was a randomised multicentre trial exploring the influence of the timing of percutaneous coronary intervention (PCI) on patient outcomes in an intermediate to high risk non-ST-elevation acute coronary syndrome (NSTE-ACS) population. In order to decide the best treatment strategy for patients presenting with NSTE-ACS, long-term outcomes are essential. METHODS: Five-year follow-up data from 133 of the 142 patients could be retrieved (94 %). The primary endpoint was a composite of death and spontaneous myocardial infarction (MI). Spontaneous MI was defined as MI occurring more than 30 days after randomisation. Secondary endpoints were the individual outcomes of death, spontaneous MI or re-PCI. RESULTS: No significant difference with respect to the primary endpoint was observed (17.8 vs. 10.1 %; HR 1.55, 95 % CI: 0.73-4.22, p = 0.21). There was no significant difference in mortality rate. However, spontaneous MI was significantly more common in the group receiving immediate PCI (11.0 vs. 1.4 %; HR 4.46, 95 % CI: 1.21-16.50, p = 0.02). We did not find a significant difference between the groups with respect to re-PCI rate. CONCLUSION: There was no difference in the composite of death and spontaneous MI. The trial suggests an increased long-term risk of spontaneous MI for patients treated with immediate PCI. TI - Impact of percutaneous coronary intervention timing on 5-year outcome in patients with non-ST-segment elevation acute coronary syndromes. The 'wait a day' approach might be safer EP - 180 SN - 1568-5888 IS - iss. 3 SP - 173 JF - Netherlands Heart Journal VL - vol. 24 DO - https://doi.org/10.1007/s12471-016-0803-0 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/172759/172759.pdf?sequence=1 ER - TY - JOUR AU - Caterina, R. De AU - Husted, S. AU - Wallentin, L. AU - Andreotti, F. AU - Arnesen, H. AU - Bachmann, F. AU - Baigent, C. AU - Collet, J.P. AU - Halvorsen, S. AU - Huber, K. AU - Jespersen, J. AU - Kristensen, S.D. AU - Lip, G.Y. AU - Morais, J. AU - Rasmussen, L.H. AU - Ricci, F. AU - Sibbing, D. AU - Siegbahn, A. AU - Storey, R.F. AU - Berg, J ten AU - Verheugt, F.W.A. AU - Weitz, J.I. PY - 2016 UR - https://hdl.handle.net/2066/171096 AB - Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients, most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel. Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice. TI - Oral anticoagulants in coronary heart disease (Section IV). Position paper of the ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease EP - 711 SN - 0340-6245 IS - iss. 4 SP - 685 JF - Thrombosis and Haemostasis VL - vol. 115 DO - https://doi.org/10.1160/TH15-09-0703 ER - TY - JOUR AU - Husted, S. AU - Verheugt, F.W.A. AU - Comuth, W.J. PY - 2016 UR - https://hdl.handle.net/2066/171421 AB - The non-vitamin K antagonist oral anticoagulants (NOACs) are used for thromboembolic prophylaxis of patients with atrial fibrillation and in the treatment as well as secondary prophylaxis of patients with venous thromboembolism. Even though NOACs have a better safety profile than vitamin K antagonists (VKAs), there will still be bleeding complications on NOAC treatment. In some cases, stopping the NOAC and non-drug-related management such as manual compression and interventional endoscopy will be sufficient to stop the bleeding. In more serious bleeding events and before acute surgery, coagulation factor concentrates or NOAC-specific antidotes could be used. Coagulation factor concentrates can be used in patients with haemophilia and to reverse the effect of VKAs but, in NOAC-treated patients, results are inconsistent and these agents could potentially have pro-thrombotic effects. Specific antidotes for NOACs are expected to be on the market soon. Phase III clinical trials with a humanized antibody fragment directed against dabigatran (idarucizumab) and recombinant, modified factor Xa (andexanet alfa) are ongoing. A molecule (aripazine) with broad activity against various anticoagulants including NOACs is currently undergoing phase II trials. For use of these specific antidotes, it is desirable that measurements for coagulation activity with a short response delay are widely available for the different NOACs and further research in this field is needed. Furthermore, guidelines for antidote use, including general measures for the treatment of NOAC-related bleeding, should be available. TI - Reversal Strategies for NOACs: State of Development, Possible Clinical Applications and Future Perspectives EP - 13 SN - 0114-5916 IS - iss. 1 SP - 5 JF - Drug Safety VL - vol. 39 DO - http://dx.doi.org/10.1007/s40264-015-0357-x ER - TY - JOUR AU - Jaspers Focks, J. AU - Brouwer, M.A. AU - Wojdyla, D.M. AU - Thomas, L. AU - Lopes, R.D. AU - Washam, J.B. AU - Lanas, F. AU - Xavier, D. AU - Husted, S. AU - Wallentin, L. AU - Alexander, J.H. AU - Granger, C.B. AU - Verheugt, F.W.A. PY - 2016 UR - https://hdl.handle.net/2066/165742 AB - OBJECTIVE: To determine whether the treatment effect of apixaban versus warfarin differs with increasing numbers of concomitant drugs used by patients with atrial fibrillation. DESIGN: Post hoc analysis performed in 2015 of results from ARISTOTLE (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation)-a multicentre, double blind, double dummy trial that started in 2006 and ended in 2011. PARTICIPANTS: 18 201 ARISTOTLE trial participants. INTERVENTIONS: In the ARISTOTLE trial, patients were randomised to either 5 mg apixaban twice daily (n=9120) or warfarin (target international normalised ratio range 2.0-3.0; n=9081). In the post hoc analysis, patients were divided into groups according to the number of concomitant drug treatments used at baseline (0-5, 6-8, >/=9 drugs) with a median follow-up of 1.8 years. MAIN OUTCOME MEASURES: Clinical outcomes and treatment effects of apixaban versus warfarin (adjusted for age, sex, and country). RESULTS: Each patient used a median of six drugs (interquartile range 5-9); polypharmacy (>/=5 drugs) was seen in 13 932 (76.5%) patients. Greater numbers of concomitant drugs were used in older patients, women, and patients in the United States. The number of comorbidities increased across groups of increasing numbers of drugs (0-5, 6-8, >/=9 drugs), as did the proportions of patients treated with drugs that interact with warfarin or apixaban. Mortality also rose significantly with the number of drug treatments (P<0.001), as did rates of stroke or systemic embolism (1.29, 1.48, and 1.57 per 100 patient years, for 0-5, 6-8, and >/=9 drugs, respectively) and major bleeding (1.91, 2.46, and 3.88 per 100 patient years, respectively). Relative risk reductions in stroke or systemic embolism for apixaban versus warfarin were consistent, regardless of the number of concomitant drugs (Pinteraction=0.82). A smaller reduction in major bleeding was seen with apixaban versus warfarin with increasing numbers of concomitant drugs (Pinteraction=0.017). Patients with interacting (potentiating) drugs for warfarin or apixaban had similar outcomes and consistent treatment effects of apixaban versus warfarin. CONCLUSIONS: In the ARISTOTLE trial, three quarters of patients had polypharmacy; this subgroup had an increased comorbidity, more interacting drugs, increased mortality, and higher rates of thromboembolic and bleeding complications. In terms of a potential differential response to anticoagulation therapy in patients with atrial fibrillation and polypharmacy, apixaban was more effective than warfarin, and is at least just as safe.Trial registration ARISTOTLE trial, ClinicalTrials.gov NCT00412984. TI - Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial SN - 1756-1833 SP - i2868 JF - Bmj. British Medical Journal (Online) VL - vol. 353 DO - https://doi.org/10.1136/bmj.i2868 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/165742/165742.pdf?sequence=1 ER - TY - JOUR AU - Bonnes, J.L. AU - Brouwer, M.A. AU - Navarese, E.P. AU - Verhaert, D.V.M. AU - Verheugt, F.W. AU - Smeets, J.L. AU - Boer, M.J. de PY - 2016 UR - https://hdl.handle.net/2066/170930 AB - STUDY OBJECTIVE: Mechanical chest compression devices have been developed to facilitate continuous delivery of high-quality cardiopulmonary resuscitation (CPR). Despite promising hemodynamic data, evidence on clinical outcomes remains inconclusive. With the completion of 3 randomized controlled trials, we conduct a meta-analysis on the effect of in-field mechanical versus manual CPR on clinical outcomes after out-of-hospital cardiac arrest. METHODS: With a systematic search (PubMed, Web of Science, EMBASE, and the Cochrane Libraries), we identified all eligible studies (randomized controlled trials and nonrandomized studies) that compared a CPR strategy including an automated mechanical chest compression device with a strategy of manual CPR only. Outcome variables were survival to hospital admission, survival to discharge, and favorable neurologic outcome. RESULTS: Twenty studies (n=21,363) were analyzed: 5 randomized controlled trials and 15 nonrandomized studies, pooled separately. For survival to admission, the pooled estimate of the randomized controlled trials did not indicate a difference (odds ratio 0.94; 95% confidence interval 0.84 to 1.05; P=.24) between mechanical and manual CPR. In contrast, meta-analysis of nonrandomized studies demonstrated a benefit in favor of mechanical CPR (odds ratio 1.42; 95% confidence interval 1.21 to 1.67; P<.001). No interaction was found between the endorsed CPR guidelines (2000 versus 2005) and the CPR strategy (P=.27). Survival to discharge and neurologic outcome did not differ between strategies. CONCLUSION: Although there are lower-quality, observational data that suggest that mechanical CPR used at the rescuer's discretion could improve survival to hospital admission, the cumulative high-quality randomized evidence does not support a routine strategy of mechanical CPR to improve survival or neurologic outcome. These findings are irrespective of the endorsed CPR guidelines during the study periods. TI - Manual Cardiopulmonary Resuscitation Versus CPR Including a Mechanical Chest Compression Device in Out-of-Hospital Cardiac Arrest: A Comprehensive Meta-analysis From Randomized and Observational Studies EP - 360.e3 SN - 0196-0644 IS - iss. 3 SP - 349 JF - Annals of Emergency Medicine VL - vol. 67 DO - https://doi.org/10.1016/j.annemergmed.2015.09.023 ER - TY - JOUR AU - Gommans, D.H.F. AU - Bakker, J. AU - Cramer, G.E. AU - Verheugt, F.W.A. AU - Brouwer, M.A. AU - Kofflard, M.J.M. PY - 2016 UR - https://hdl.handle.net/2066/172762 AB - PURPOSE: The use of cardiac magnetic resonance (CMR) analysis has increased in patients with hypertrophic cardiomyopathy (HCM). Quantification of left ventricular (LV) measures will be affected by the inclusion or exclusion of the papillary muscles as part of the LV mass, but the magnitude of effect and potential consequences are unknown. METHODS: We performed Cine-CMR in (1) clinical HCM patients (n = 55) and (2) subclinical HCM mutation carriers without hypertrophy (n = 14). Absolute and relative differences in LV ejection fraction (EF) and mass were assessed between algorithms with and without inclusion of the papillary muscles. RESULTS: Papillary muscle mass in group 1 was 6.6 +/- 2.5 g/m(2) and inclusion of the papillary muscles resulted in significant relative increases in LVEF of 4.5 +/- 1.8 % and in LV mass of 8.7 +/- 2.6 %. For group 2 these figures were 4.0 +/- 0.9 g/m(2), 3.8 +/- 1.0 % and 9.5 +/- 1.8 %, respectively. With a coefficient of variation of 4 %, this 9 % difference in LV mass during CMR follow-up will be considered a change, while in fact the exact same mass may have been assessed according to two different algorithms. CONCLUSIONS: In clinical HCM patients, CMR quantification of important LV measures is significantly affected by inclusion or exclusion of the papillary muscles. In relative terms, the difference was similar in subjects without hypertrophy. This underscores a general need for a uniform approach in CMR image analysis. TI - Impact of the papillary muscles on cardiac magnetic resonance image analysis of important left ventricular parameters in hypertrophic cardiomyopathy EP - 331 SN - 1568-5888 IS - iss. 5 SP - 326 JF - Netherlands Heart Journal VL - vol. 24 DO - https://doi.org/10.1007/s12471-016-0805-y L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/172762/172762.pdf?sequence=1 ER - TY - JOUR AU - Begum, N. AU - Stephens, S. AU - Schoeman, O. AU - Fraschke, A. AU - Kirsch, B. AU - Briere, J.B. AU - Verheugt, F.W.A. AU - Hout, B.A. van PY - 2015 UR - https://hdl.handle.net/2066/152078 AB - BACKGROUND: Worldwide, coronary heart disease accounts for 7 million deaths each year. In Sweden, acute coronary syndrome (ACS) is a leading cause of hospitalization and is responsible for 1 in 4 deaths. OBJECTIVE: The aim of this analysis was to assess the cost-effectiveness of rivaroxaban 2.5 mg twice daily (BID) in combination with standard antiplatelet therapy (ST-APT) versus ST-APT alone, for the secondary prevention of ACS in adult patients with elevated cardiac biomarkers without a prior history of stroke/transient ischemic attack (TIA), from a Swedish societal perspective, based on clinical data from the global ATLAS ACS 2-TIMI 51 trial, literature-based quality of life data and costs sourced from Swedish national databases. METHODS: A Markov model was developed to capture rates of single and multiple myocardial infarction (MI), ischemic and hemorrhagic stroke, thrombolysis in myocardial infarction (TIMI) major, minor, and "requiring medical attention" bleeds, revascularization events, and associated costs and utilities in patients who were stabilized after an initial ACS event. Efficacy and safety data for the first 2 years came from the ATLAS ACS 2-TIMI 51 trial. Long-term probabilities were extrapolated using safety and effectiveness of acetylsalicylic acid data, which was estimated from published literature, assuming constant rates in time. Future cost and effects were discounted at 3.0%. Univariate and probabilistic sensitivity analyses were conducted. RESULTS: In the base case, the use of rivaroxaban 2.5 mg BID was associated with improvements in survival and quality-adjusted life years (QALYs), yielding an incremental cost per QALY of 71,246 Swedish Krona (SEK) (euro8045). The outcomes were robust to changes in inputs. The probabilistic sensitivity analysis demonstrated rivaroxaban 2.5 mg BID to be cost-effective in >99.9% of cases, assuming a willingness-to-pay threshold of SEK 500,000 (euro56,458). CONCLUSION: Compared with ST-APT alone, the use of rivaroxaban 2.5 mg BID in combination with ST-APT can be considered a cost-effective treatment option for ACS patients with elevated cardiac biomarkers without a prior history of stroke/TIA in Sweden. FUNDING: Bayer Pharma AG. TI - Cost-effectiveness Analysis of Rivaroxaban in the Secondary Prevention of Acute Coronary Syndromes in Sweden EP - 153 SN - 2193-8261 IS - iss. 2 SP - 131 JF - Cardiology and Therapy VL - vol. 4 DO - http://dx.doi.org/10.1007/s40119-015-0041-3 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/152078/152078.pdf?sequence=1 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2015 UR - https://hdl.handle.net/2066/154353 AB - The need to combine anticoagulant and antiplatelet therapy ('triple therapy') in patients with atrial fibrillation and coronary artery disease increases the risk of bleeding. As percutaneous intervention is now the dominant therapy for coronary disease, clinicians question how to manage the risk of stroke in patients with atrial fibrillation and a coronary stent that require dual antiplatelet therapy. In this review, the risk of stroke and coronary thrombosis in this difficult group of patients will be summarized using current recommendations and guidelines. The scarce randomized data on triple therapy are reviewed, and there will be a focus on currently running trials on this topic. TI - Triple therapy for percutaneous coronary intervention in atrial fibrillation: standard of care, or a nightmare soon to end? EP - 5 SN - 1538-7933 SP - S332 JF - Journal of Thrombosis and Haemostasis VL - vol. 13 Suppl 1 DO - http://dx.doi.org/10.1111/jth.12936 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2015 UR - https://hdl.handle.net/2066/154254 TI - The role of the cardiologist in the primary prevention of cardiovascular disease with aspirin EP - 124 SN - 0735-1097 IS - iss. 2 SP - 122 JF - Journal of the American College of Cardiology VL - vol. 65 DO - http://dx.doi.org/10.1016/j.jacc.2014.10.036 ER - TY - JOUR AU - Dewilde, W.J. AU - Janssen, P.W. AU - Kelder, J.C. AU - Verheugt, F.W.A. AU - Smet, B.J. de AU - Adriaenssens, T. AU - Vrolix, M. AU - Brueren, G.B. AU - Mieghem, C. Van AU - Cornelis, K AU - Vos, J. AU - Breet, N.J. AU - Berg, J.M. van den PY - 2015 UR - https://hdl.handle.net/2066/154375 AB - AIMS: To investigate the optimal periprocedural antithrombotic strategy in patients on long-term oral anticoagulation (OAC) who require percutaneous coronary intervention with stenting. METHODS AND Results : The WOEST study was a randomised controlled trial which recruited 573 patients on long-term OAC who underwent PCI. The periprocedural treatment strategy was left to the operator's discretion. To assess the safety and feasibility of uninterrupted oral anticoagulation (UAC) and bridging therapy (BT), bleeding complications and MACCE were assessed in patients treated according to UAC (n=241) and BT (n=322) regimen. After 30 days, as well as after one year, there were no significant differences in bleeding complications (HR 1.14, 95% CI: 0.77-1.69, p=0.51, and HR 1.26, 95% CI: 0.94-1.69, p=0.12, respectively) and MACCE. MACCE tended to be less frequent in the UAC group (respectively HR 0.48, 95% CI: 0.15-1.51, p=0.21, and HR 0.72, 95% CI: 0.46-1.14, p=0.16). Additionally, adjustment with a propensity score revealed no significant differences. Periprocedural INR was not associated with bleeding or MACCE. CONCLUSIONS: In the WOEST study, UAC was not associated with an increase of bleeding or MACCE compared to bridging therapy. This is the largest study up to now to support the current guidelines. The WOEST trial is registered with ClinicalTrials.gov, number NCT00769938. TI - Uninterrupted oral anticoagulation versus bridging in patients with long-term oral anticoagulation during percutaneous coronary intervention: subgroup analysis from the WOEST trial EP - 390 SN - 1774-024X IS - iss. 4 SP - 381 JF - Eurointervention VL - vol. 11 DO - http://dx.doi.org/10.4244/EIJY14M06_07 ER - TY - JOUR AU - Verheugt, F.W.A. AU - Granger, C.B. PY - 2015 UR - https://hdl.handle.net/2066/153550 AB - In patients with non-valvular atrial fibrillation, oral anticoagulation with vitamin K antagonists reduces the risk of stroke by more than 60%. But vitamin K antagonists have limitations, including causing serious bleeding such as intracranial haemorrhage and the need for anticoagulation monitoring. In part related to these limitations, they are used in only about half of patients who should be treated according to guideline recommendations. In the past decade, oral agents have been developed that directly block the activity of thrombin (factor IIa), as well as drugs that directly inhibit activated factor X (Xa), which is the first protein in the final common pathway to the activation of thrombin. These novel non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to be at least as good as warfarin for stroke prevention in atrial fibrillation and they have proved to have better safety profiles. Their net advantage is underscored by significantly lower all-cause mortality compared with warfarin in large clinical trials. Because of these features and their ease of use, they are recommended for stroke prevention in atrial fibrillation. They have also a fast onset and offset of action, but they currently lack specific antidotes. This paper addresses the role of anticoagulation for stroke prevention in atrial fibrillation in the era of NOACs, with a focus on special situations including management in the event of bleeding and around the time of procedures including cardioversion, catheter ablation, and device implantation. Also their use in patients with concomitant coronary artery disease, with advanced age, with chronic kidney disease, or with valvular heart disease will be discussed as well as the interaction of NOACs with other cardiac medication, and switching between anticoagulants. TI - Oral anticoagulants for stroke prevention in atrial fibrillation: current status, special situations, and unmet needs EP - 310 SN - 0140-6736 IS - iss. 9990 SP - 303 JF - The Lancet (London) VL - vol. 386 DO - http://dx.doi.org/10.1016/S0140-6736(15)60245-8 ER - TY - JOUR AU - Verheugt, F.W.A. AU - Granger, C.B. PY - 2015 UR - https://hdl.handle.net/2066/152391 TI - Intracerebral haemorrhage, atrial fibrillation, and anticoagulation - Authors' reply SN - 0140-6736 IS - iss. 10005 SP - 1737 JF - The Lancet (London) VL - vol. 386 DO - http://dx.doi.org/10.1016/S0140-6736(15)00696-0 ER - TY - JOUR AU - Gibson, C.M. AU - Mehran, R. AU - Bode, C. AU - Halperin, J. AU - Verheugt, F.W.A. AU - Wildgoose, P. AU - Eickels, M. van AU - Lip, G.Y. AU - Cohen, M. AU - Husted, S. AU - Peterson, E. AU - Fox, K. PY - 2015 UR - https://hdl.handle.net/2066/154078 AB - BACKGROUND: Guidelines recommendations regarding anticoagulant therapy after percutaneous coronary intervention (PCI) among patients with atrial fibrillation (AF) rely on retrospective, nonrandomized observational data. Currently, patients are treated with triple-therapy (dual antiplatelet therapy [DAPT] + oral anticoagulation therapy), but neither the duration of DAPT nor the level of anticoagulation has been studied in a randomized fashion. Recent studies also suggest dual pathway therapy with clopidogrel plus oral anticoagulation therapy may be superior, and other studies suggest that novel oral anticoagulants such as rivaroxaban may further improve patient outcomes. DESIGN: PIONEER AF-PCI (ClinicalTrials.gov NCT01830543) is an exploratory, open-label, randomized, multicenter clinical study assessing the safety of 2 rivaroxaban treatment strategies and 1 vitamin K antagonist (VKA) treatment strategy in subjects who have paroxysmal, persistent, or permanent nonvalvular AF and have undergone PCI with stent placement. Approximately 2,100 subjects will be randomized in a 1:1:1 ratio to receive either rivaroxaban 15 mg once daily plus clopidogrel 75 mg daily for 12 months (a WOEST trial-like strategy), or rivaroxaban 2.5 mg twice daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months, an ATLAS trial-like strategy), or dose-adjusted VKA once daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months, traditional triple therapy). All patients will be followed up for 12 months for the primary composite end point of Thrombolysis in Myocardial Infarction major bleeding, bleeding requiring medical attention, and minor bleeding (collectively, clinically significant bleeding). CONCLUSION: The PIONEER AF-PCI study is the first randomized comparison of VKA vs novel oral anticoagulant therapy in patients with NVAF receiving antiplatelet therapy after PCI to assess the relative risks of bleeding complications. TI - An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI) EP - 8.e5 SN - 0002-8703 IS - iss. 4 SP - 472 JF - American Heart Journal VL - vol. 169 DO - http://dx.doi.org/10.1016/j.ahj.2014.12.006 ER - TY - JOUR AU - Nicolau, J.C. AU - Bhatt, D.L. AU - Roe, M.T. AU - Lokhnygina, Y. AU - Neely, B. AU - Corbalan, R. AU - Leiva-Pons, J.L. AU - Martinez, F. AU - Goodman, S.G. AU - Winters, K.J. AU - Verheugt, F.W.A. AU - Armstrong, P.W. AU - White, H.D. AU - Fox, K.A. AU - Prabhakaran, D. AU - Ohman, E.M. PY - 2015 UR - https://hdl.handle.net/2066/154865 AB - Concomitant use of proton-pump inhibitors (PPIs) has been implicated in diminished antiplatelet response to clopidogrel and an increased risk of ischemic events, but primarily among patients undergoing percutaneous coronary intervention. We sought to examine the potential influence of interactions between PPIs and clopidogrel versus prasugrel on platelet reactivity and clinical outcomes after acute coronary syndromes (ACS) in patients managed medically without revascularization. METHODS: This analysis from the TRILOGY ACS trial focused upon the 7,243 ACS patients aged <75 years who were managed without revascularization, randomized to clopidogrel or prasugrel, and followed for a median of 17 months. Proton-pump inhibitor type and use were assessed at each study visit, and 2,049 of the patients in this cohort underwent serial platelet reactivity assessments. RESULTS: Proton-pump inhibitor use (23%) was similar between the clopidogrel and prasugrel groups at baseline and throughout the study. Median on-treatment platelet reactivity values were consistently lower with prasugrel versus clopidogrel irrespective of PPI use. For the primary end point (composite of cardiovascular death, myocardial infarction [MI], or stroke), PPI use modified the unadjusted treatment effect of prasugrel versus clopidogrel (interaction P = .02). After adjusting for differences in baseline characteristics, this treatment effect modification was attenuated for the composite end point (interaction P = .06) but was significant for the MI component end point (interaction P = .01). Similarly, among patients on a PPI, the frequency of MI was significantly lower with prasugrel versus clopidogrel (hazard ratio = 0.61; 95% CI 0.42-0.88). These findings were similar by PPI type (omeprazole and pantoprazole). CONCLUSIONS: Among ACS patients managed without revascularization, use of PPIs did not result in a differential antiplatelet response between prasugrel versus clopidogrel but was associated with a lower incidence of MI with prasugrel. These hypothesis-generating findings suggest that factors besides platelet reactivity may underlie the differential risk of MI observed by treatment assignment with PPI use. TI - Concomitant proton-pump inhibitor use, platelet activity, and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel and managed without revascularization: Insights from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial EP - 694.e3 SN - 0002-8703 IS - iss. 4 SP - 683 JF - American Heart Journal VL - vol. 170 DO - https://doi.org/10.1016/j.ahj.2015.05.017 ER - TY - JOUR AU - Hess, C.N. AU - James, S. AU - Lopes, R.D. AU - Wojdyla, D.M. AU - Neely, M.L. AU - Liaw, D. AU - Hagstrom, E. AU - Bhatt, D.L. AU - Husted, S. AU - Goodman, S.G. AU - Lewis, B.S. AU - Verheugt, F.W.A. AU - Caterina, R. De AU - Ogawa, H. AU - Wallentin, L. AU - Alexander, J.H. PY - 2015 UR - https://hdl.handle.net/2066/154488 AB - BACKGROUND: Bleeding limits anticoagulant treatment in patients with acute coronary syndromes (ACS). OBJECTIVES: We investigated whether background concomitant antiplatelet therapy influences the effects of apixaban after ACS. METHODS: This study examined high-risk ACS patients who were treated with aspirin or aspirin plus clopidogrel and who were randomized to apixaban 5 mg twice daily or placebo. In a post-hoc analysis, we assessed whether the effect of apixaban on efficacy and safety outcomes varied by the concomitant antiplatelet regimen by using simple Cox modeling and marginal structural models with propensity scores and antiplatelet therapy as a time-dependent covariate. RESULTS: At baseline, of 7,364 patients, 16.3% (n = 1,202) were on aspirin alone, and 79.0% (n = 5,814) were on aspirin plus clopidogrel. A total of 19.2% (n = 1,415) switched antiplatelet therapy during follow-up. No differential effect of apixaban versus placebo was observed for the composite endpoint of cardiovascular death, myocardial infarction, and ischemic stroke in patients taking aspirin (12.21 per 100 patient-years vs. 13.21 per 100 patient-years; adjusted hazard ratio [HR]: 0.91; 95% confidence interval [CI]: 0.62 to 1.32) or aspirin plus clopidogrel (13.22 vs. 14.24; adjusted HR: 0.95; 95% CI: 0.78 to 1.14; pinteraction = 0.84). Compared with placebo, apixaban increased Thrombolysis In Myocardial Infarction major bleeding in patients taking aspirin (1.48 vs. 0.25; adjusted HR: 6.62; 95% CI: 0.75 to 51.73) and in patients taking aspirin plus clopidogrel (2.58 vs. 1.02; adjusted HR: 2.44; 95% CI: 1.34 to 4.45; pinteraction = 0.41). Similar results were obtained with marginal structural models and in patients treated with and without percutaneous coronary intervention. CONCLUSIONS: Post-ACS treatment with apixaban versus placebo showed no efficacy, but it increased bleeding regardless of concomitant therapy with aspirin alone or aspirin plus clopidogrel. (Apixaban for Prevention of Acute Ischemic Events 2 [APPRAISE-2]; NCT00831441). TI - Apixaban Plus Mono Versus Dual Antiplatelet Therapy in Acute Coronary Syndromes: Insights From the APPRAISE-2 Trial EP - 787 SN - 0735-1097 IS - iss. 7 SP - 777 JF - Journal of the American College of Cardiology VL - vol. 66 DO - https://doi.org/10.1016/j.jacc.2015.06.027 ER - TY - JOUR AU - Granger, C.B. AU - Lopes, R.D. AU - Hanna, M. AU - Ansell, J. AU - Hylek, E.M. AU - Alexander, J.H. AU - Thomas, L. AU - Wang, J AU - Bahit, M.C. AU - Verheugt, F.W. AU - Lawrence, J. AU - Xavier, D. AU - Wallentin, L. PY - 2015 UR - https://hdl.handle.net/2066/154772 AB - BACKGROUND: We sought to assess the occurrence of events after blinded study drug discontinuation and transition to open-label vitamin K antagonist (VKA) in ARISTOTLE. METHODS: At the end of ARISTOTLE, blinded study drug was stopped, and open-label VKA was recommended. For patients completing the trial on blinded study drug, a 2-day bridging period with apixaban or apixaban placebo was recommended (while beginning open-label VKA). Outcomes were assessed during the 30 days after stopping blinded study drug. RESULTS: Of the 6,809 patients in the apixaban group and 6,588 in the warfarin group who completed the trial on study drug, there were 21 strokes or systemic emboli (4.02%/year) and 26 major bleeding (4.97%/year) events in the apixaban group (transitioning to VKA) and 5 strokes or systemic emboli (0.99%/year) and 10 major bleeding (1.97%/year) events in the warfarin group (continuing on VKA), with most of the imbalance between groups being after the first week. Similar results were seen in the first 30 days of the trial where warfarin-naive patients starting warfarin had a higher rate of stroke or systemic emboli (5.41%/year) than warfarin-experienced patients (1.42%/year), a pattern not seen when starting apixaban. No similar increase in events with apixaban versus warfarin was seen during temporary or permanent study drug discontinuation during the trial. CONCLUSIONS: The excess in thrombotic and bleeding events in the apixaban group after study drug discontinuation appears to be related to an increased risk associated with the initiation of a VKA rather than a direct effect of apixaban. Whether >/=2 days of apixaban bridging improves outcomes during VKA transition is unknown and deserves further evaluation. TI - Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial EP - 30 SN - 0002-8703 IS - iss. 1 SP - 25 JF - American Heart Journal VL - vol. 169 DO - https://doi.org/10.1016/j.ahj.2014.09.006 ER - TY - JOUR AU - Held, C. AU - Hylek, E.M. AU - Alexander, J.H. AU - Hanna, M. AU - Lopes, R.D. AU - Wojdyla, D.M. AU - Thomas, L. AU - Al-Khalidi, H. AU - Alings, M. AU - Xavier, D. AU - Ansell, J. AU - Goto, S. AU - Ruzyllo, W. AU - Rosenqvist, M. AU - Verheugt, F.W.A. AU - Zhu, J. AU - Granger, C.B. AU - Wallentin, L. PY - 2015 UR - https://hdl.handle.net/2066/154774 AB - AIM: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced the risk of stroke, major bleed, and death in patients with atrial fibrillation. In this ancillary study, we evaluated clinical consequences of major bleeds, as well as management and treatment effects of warfarin vs. apixaban. METHODS AND RESULTS: Major International Society on Thrombosis and Haemostasis bleeding was defined as overt bleeding accompanied by a decrease in haemoglobin (Hb) of >/=2 g/dL or transfusion of >/=2 units of packed red cells, occurring at a critical site or resulting in death. Time to event [death, ischaemic stroke, or myocardial infarction (MI)] was evaluated by Cox regression models. The excess risk associated with bleeding was evaluated by separate time-dependent indicators for intracranial (ICH) and non-intracranial haemorrhage. Major bleeding occurred in 848 individuals (4.7%), of whom 126 (14.9%) died within 30 days. Of 176 patients with an ICH, 76 (43.2%) died, and of the 695 patients with major non-ICH, 64 (9.2%) died within 30 days of the bleeding. The risk of death, ischaemic stroke, or MI was increased roughly 12-fold after a major non-ICH bleeding event within 30 days. Corresponding risk of death following an ICH was markedly increased, with HR 121.5 (95% CI 91.3-161.8) as was stroke or MI with HR 21.95 (95% CI 9.88-48.81), respectively. Among patients with major bleeds, 20.8% received vitamin K and/or related medications (fresh frozen plasma, coagulation factors, factor VIIa) to stop bleeding within 3 days, and 37% received blood transfusion. There was no interaction between apixaban and warfarin and major bleeding on the risk of death, stroke, or MI. CONCLUSION: Major bleeding was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following ICH, and this risk was similarly elevated regardless of treatment with apixaban or warfarin. These results underscore the importance of preventing bleeding in anti-coagulated patients. CLINICAL TRIALSGOV IDENTIFIER: NCT00412984. TI - Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial EP - 1272 SN - 0195-668X IS - iss. 20 SP - 1264 JF - European Heart Journal VL - vol. 36 DO - https://doi.org/10.1093/eurheartj/ehu463 ER - TY - JOUR AU - Andreotti, F. AU - Rocca, B. AU - Husted, S. AU - Ajjan, R.A. AU - Berg, J. van den AU - Cattaneo, M. AU - Collet, J.P. AU - Caterina, R. De AU - Fox, K.A. AU - Halvorsen, S. AU - Huber, K. AU - Hylek, E.M. AU - Lip, G.Y. AU - Montalescot, G. AU - Morais, J. AU - Patrono, C. AU - Verheugt, F.W.A. AU - Wallentin, L. AU - Weiss, T.W. AU - Storey, R.F. PY - 2015 UR - https://hdl.handle.net/2066/152750 TI - Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis EP - 3249 SN - 0195-668X IS - iss. 46 SP - 3238 JF - European Heart Journal VL - vol. 36 DO - https://doi.org/10.1093/eurheartj/ehv304 ER - TY - JOUR AU - Vranckx, P. AU - Leebeek, F.W. AU - Tijssen, J.G. AU - Koolen, J. AU - Stammen, F. AU - Herman, J.P. AU - Winter, R.J. de AU - van, T.H.A.W. AU - Backx, B. AU - Lindeboom, W. AU - Kim, S.Y. AU - Kirsch, B. AU - Eickels, M. van AU - Misselwitz, F. AU - Verheugt, F.W.A. PY - 2015 UR - https://hdl.handle.net/2066/153620 AB - Patients on rivaroxaban requiring percutaneous coronary intervention (PCI) represent a clinical conundrum. We aimed to investigate whether rivaroxaban, with or without an additional bolus of unfractionated heparin (UFH), effectively inhibits coagulation activation during PCI. Stable patients (n=108) undergoing elective PCI and on stable dual antiplatelet therapy were randomised (2:2:2:1) to a short treatment course of rivaroxaban 10 mg (n=30), rivaroxaban 20 mg (n=32), rivaroxaban 10 mg plus UFH (n=30) or standard peri-procedural UFH (n=16). Blood samples for markers of thrombin generation and coagulation activation were drawn prior to and at 0, 0.5, 2, 6-8 and 48 hours (h) after start of PCI. In patients treated with rivaroxaban (10 or 20 mg) and patients treated with rivaroxaban plus heparin, the levels of prothrombin fragment 1 + 2 at 2 h post-PCI were 0.16 [0.1] nmol/l (median) [interquartile range, IQR] and 0.17 [0.2] nmol/l, respectively. Thrombin-antithrombin complex values at 2 h post-PCI were 3.90 [6.8]microg/l and 3.90 [10.1] microg/l, respectively, remaining below the upper reference limit (URL) after PCI and stenting. This was comparable to the control group of UFH treatment alone. However, median values for thrombin-antithrombin complex passed above the URL with increasing tendency, starting at 2 h post-PCI in the UFH-alone arm but not in rivaroxaban-treated patients. In this exploratory trial, rivaroxaban effectively suppressed coagulation activation after elective PCI and stenting. TI - Peri-procedural use of rivaroxaban in elective percutaneous coronary intervention to treat stable coronary artery disease. The X-PLORER trial EP - 267 SN - 0340-6245 IS - iss. 2 SP - 258 JF - Thrombosis and Haemostasis VL - vol. 114 DO - https://doi.org/10.1160/TH15-01-0061 ER - TY - JOUR AU - Dewilde, W.J. AU - Janssen, P.W. AU - Verheugt, F.W.A. AU - Storey, R.F. AU - Adriaenssens, T. AU - Hansen, M.L. AU - Lamberts, M. AU - Berg, J.M. van den PY - 2015 UR - https://hdl.handle.net/2066/153862 TI - Reply: Triple Therapy for Atrial Fibrillation and ACS With or Without PCI: Don't Drop Aspirin Just Yet EP - 518 SN - 0735-1097 IS - iss. 5 SP - 516 JF - Journal of the American College of Cardiology VL - vol. 65 DO - https://doi.org/10.1016/j.jacc.2014.10.061 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2015 UR - https://hdl.handle.net/2066/154411 TI - Anticoagulation in patients with mechanical heart valves: follow the guidelines! EP - 110 SN - 1568-5888 IS - iss. 2 SP - 109 JF - Netherlands Heart Journal VL - vol. 23 DO - https://doi.org/10.1007/s12471-014-0642-9 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/154411/154411.pdf?sequence=1 ER - TY - JOUR AU - Lip, G.Y. AU - Rushton-Smith, S.K. AU - Goldhaber, S.Z. AU - Fitzmaurice, D.A. AU - Mantovani, L.G. AU - Goto, S. AU - Haas, S. AU - Bassand, J.P. AU - Camm, A.J. AU - Ambrosio, G. AU - Jansky, P. AU - Mahmeed, W. Al AU - Oh, S. AU - Eickels, M. van AU - Raatikainen, P. AU - Steffel, J. AU - Oto, A. AU - Kayani, G. AU - Accetta, G. AU - Kakkar, A.K. AU - Verheugt, F.W.A. AU - et al. PY - 2015 UR - https://hdl.handle.net/2066/155060 AB - BACKGROUND: Among patients with atrial fibrillation (AF), women are at higher risk of stroke than men. Using prospective cohort data from a large global population of patients with nonvalvular AF, we sought to identify any differences in the use of anticoagulants for stroke prevention in women and men. METHODS AND RESULTS: This was a prospective multicenter observational registry with 858 randomly selected sites in 30 countries. A total of 17 184 patients with newly diagnosed (/=1 additional investigator-defined stroke risk factor(s) were recruited (March 2010 to June 2013). The main outcome measure was the use of anticoagulants (vitamin K antagonists, factor Xa inhibitors, and direct thrombin inhibitors) for stroke prevention at AF diagnosis. Of 17 184 patients enrolled, 43.8% were women. More women than men were at moderate-to-high risk of stroke (CHADS2 score >/=2: 65.1% versus 54.7%). Rates of anticoagulant use were not different overall (60.9% of men versus 60.8% of women) and in patients with a CHADS2 score >/=2 (adjusted odds ratio for women versus men, 1.00; 95% confidence interval, 0.92-1.09). In patients at low risk (CHA2DS2-VASc of 0 in men and 1 in women), 41.8% of men and 41.1% of women received an anticoagulant. In patients at high risk (CHA2DS2-VASc score >/=2), 35.4% of men and 38.4% of women did not receive an anticoagulant. CONCLUSIONS: These contemporary global data show that anticoagulant use for stroke prevention is no different in men and women with nonvalvular AF. Thromboprophylaxis was, however, suboptimal in substantial proportions of men and women, with underuse in those at moderate-to-high risk of stroke and overuse in those at low risk. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362. TI - Does sex affect anticoagulant use for stroke prevention in nonvalvular atrial fibrillation? The prospective global anticoagulant registry in the FIELD-Atrial Fibrillation EP - 20 SN - 1941-7705 IS - iss. 2 Suppl 1 SP - S12 JF - Circulation-Cardiovascular Quality and Outcomes VL - vol. 8 DO - https://doi.org/10.1161/CIRCOUTCOMES.114.001556 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2014 UR - https://hdl.handle.net/2066/134043 AB - This article refers to 'Impact of aspirin and statins on longterm survival in patients with acute myocardial infarction complicated by heart failure: an analysis in 1746 patients' by C. Lewinter et al., published in this issue on page 95-102. TI - Evidence-based co-medication in heart failure: necessary or bystander? EP - 3 SN - 1388-9842 IS - iss. 1 SP - 1 JF - European Journal of Heart Failure VL - vol. 16 DO - http://dx.doi.org/10.1002/ejhf.46 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2014 UR - https://hdl.handle.net/2066/133903 TI - The elusive disconnection between mortality and early stent thrombosis: observations from the CHAMPION-PHOENIX trial EP - 9 SN - 0340-6245 IS - iss. 1 SP - 8 JF - Thrombosis and Haemostasis VL - vol. 111 DO - http://dx.doi.org/10.1160/TH13-10-0846 ER - TY - JOUR AU - Atar, D. AU - Bode, C. AU - Stuerzenbecher, A. AU - Verheugt, F.W.A. PY - 2014 UR - https://hdl.handle.net/2066/133827 AB - The impact of an acute coronary syndrome (ACS) event, such as an acute myocardial infarction (MI), is not limited to the acute management phase; patients face an elevated risk of residual atherothrombotic events that commonly requires chronic management for months or even years. Significant advances have been made in both the acute and chronic management of patients with acute MI over the past decade, resulting in improved prognoses. One of the hallmarks of modern treatment strategies is more aggressive antiplatelet treatment regimens. However, the risks of further ACS events, stroke and premature death remain elevated in these patients, and addressing this residual risk is challenging owing to interpatient variability, differences in management strategies between centres and countries, incomplete understanding of the specific pathophysiology of post-ACS thrombosis and limitations of current therapeutic approaches. The recent approval in Europe of the direct oral anticoagulant rivaroxaban for use in this setting in combination with clopidogrel and acetylsalicylic acid offers another strategy to consider in the management of these patients, and clinical strategies in this area continue to evolve. In this review, we chart the progress made over the past decade in reducing the burden of secondary thromboembolic events after acute MI and discuss the current position of and future perspectives on the inclusion of oral anticoagulants into care pathways in this setting. TI - Anticoagulants for secondary prevention after acute myocardial infarction: lessons from the past decade EP - 363 SN - 0767-3981 IS - iss. 4 SP - 353 JF - Fundamental & Clinical Pharmacology VL - vol. 28 DO - http://dx.doi.org/10.1111/fcp.12063 ER - TY - JOUR AU - Halvorsen, S. AU - Andreotti, F. AU - Berg, J.M. van den AU - Cattaneo, M. AU - Coccheri, S. AU - Marchioli, R. AU - Morais, J. AU - Verheugt, F.W.A. AU - Caterina, R. de PY - 2014 UR - https://hdl.handle.net/2066/133860 AB - Although the use of oral anticoagulants (vitamin K antagonists) has been abandoned in primary cardiovascular prevention due to lack of a favorable benefit-to-risk ratio, the indications for aspirin use in this setting continue to be a source of major debate, with major international guidelines providing conflicting recommendations. Here, we review the evidence in favor and against aspirin therapy in primary prevention based on the evidence accumulated so far, including recent data linking aspirin with cancer protection. While awaiting the results of several ongoing studies, we argue for a pragmatic approach to using low-dose aspirin in primary cardiovascular prevention and suggest its use in patients at high cardiovascular risk, defined as >/=2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding. TI - Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology working group on thrombosis EP - 327 SN - 0735-1097 IS - iss. 3 SP - 319 JF - Journal of the American College of Cardiology VL - vol. 64 DO - https://doi.org/10.1016/j.jacc.2014.03.049 ER - TY - JOUR AU - Hamon, M. AU - Bonello, L. AU - Marso, S. AU - Rao, S.V. AU - Valgimigli, M. AU - Verheugt, F.W.A. AU - Gershlick, A. AU - Wang, Y. AU - Prats, J. AU - Steg, G.P. AU - Deliargyris, E. PY - 2014 UR - http://repository.ubn.ru.nl/handle/2066/127585 AB - BACKGROUND: Several percutaneous coronary intervention (PCI) trials have established that the use of bivalirudin (BIV) is associated with improved patient outcomes and substantial hospital cost savings, relative to heparin (HEP)-based regimens+/-glycoprotein IIb/IIIa inhibitors (GPIs). Whether these benefits persist with the use of prasugrel, a new third-generation oral thienopyridine, has not been previously evaluated. METHODS: Using the Premier hospital database, 6986 patients treated with prasugrel who underwent elective, urgent, or primary PCI between quarter 3, 2009 and quarter 4, 2010 from 166 US hospitals were identified. These patients received either BIV (n=3377) or HEP+/-GPI (n=3609) as procedural anticoagulation. Outcomes of interest included bleeding, transfusions, death, and hospital length of stay (LOS). To control for patient and hospital-level characteristics, propensity score-matching (PSM) analyses were performed. RESULTS: Mortality, clinically apparent bleeding, clinically apparent bleeding requiring transfusion, any transfusions, and LOS were all lower in patients treated with BIV as compared with patients treated with HEP+/-GPI. After PSM, the rate of transfusion was significantly lower with BIV (odds ratio: 0.57, 95% confidence interval: 0.34-0.96), and the hospital LOS was significantly shorter in patients treated with BIV compared with those treated with HEP+/-GPI (0.9+/-2.0 vs 1.2+/-2.3 days, P<0.0001). CONCLUSIONS: In patients undergoing PCI and treated with prasugrel, the use of BIV rather than HEP+/-GPI is associated with significantly lower transfusion rate and LOS. These results suggest that the previously documented safety and cost-effectiveness benefits of BIV remain applicable when prasugrel is used. TI - Comparison of bivalirudin versus heparin(s) during percutaneous coronary interventions in patients receiving prasugrel: a propensity-matched study EP - 20 SN - 0160-9289 IS - iss. 1 SP - 14 JF - Clinical Cardiology VL - vol. 37 DO - https://doi.org/10.1002/clc.22208 ER - TY - JOUR AU - Gouya, G. AU - Arrich, J. AU - Wolzt, M. AU - Huber, K. AU - Verheugt, F.W.A. AU - Gurbel, P.A. AU - Pirker-Kees, A. AU - Siller-Matula, J.M. PY - 2014 UR - http://repository.ubn.ru.nl/handle/2066/127658 AB - BACKGROUND AND PURPOSE: The efficacy and safety of different antiplatelet regimes for prevention of stroke in patients at high risk were investigated in a systematic review and meta-analysis. METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Web of Science. Twenty-two studies comprising 173 371 patients were included. RESULTS: In the overall population, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in comparison to aspirin monotherapy reduced the relative risk of total stroke by 20% (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.73-0.88; P<0.0001; I(2)=28%) and of ischemic stroke or transient ischemic attack by 23% (RR, 0.77; 95% CI, 0.69-0.85; P<0.0001; I(2)=18%) without increasing the risk of intracranial hemorrhage. In the secondary prevention cohort, DAPT with aspirin and clopidogrel also reduced the relative risk of total stroke by 24% as compared with aspirin alone (RR, 0.76; 95% CI, 0.68-0.86; P<0.0001; I(2)=0%). DAPT with prasugrel or ticagrelor and aspirin versus DAPT with clopidogrel and aspirin was not associated with a risk reduction of stroke. CONCLUSIONS: DAPT with clopidogrel and aspirin compared with aspirin effectively reduces the risk of total and ischemic stroke in the overall cohort consisting of patients with cardiovascular disease without increase in intracranial hemorrhage, as well as decreases the risk of a recurrent total stroke in patients with a previous stroke/transient ischemic attack. Our meta-analysis suggests that DAPT including low-dose aspirin (75-100 mg) and clopidogrel (75 mg) should be further investigated as a strategy to reduce recurrent strokes. CLINICAL TRIAL REGISTRATION URL: http://www.crd.york.ac.uk/prospero. Unique identifier: CRD42011001596. TI - Antiplatelet treatment for prevention of cerebrovascular events in patients with vascular diseases: a systematic review and meta-analysis EP - 503 SN - 0039-2499 IS - iss. 2 SP - 492 JF - Stroke VL - vol. 45 DO - https://doi.org/10.1161/STROKEAHA.113.002590 ER - TY - JOUR AU - Alexander, J.H. AU - Lopes, R.D. AU - Thomas, L. AU - Alings, M. AU - Atar, D. AU - Aylward, P. AU - Goto, S. AU - Hanna, M. AU - Huber, K. AU - Husted, S. AU - Lewis, B.S. AU - McMurray, J.J. AU - Pais, P. AU - Pouleur, H. AU - Steg, P.G. AU - Verheugt, F.W.A. AU - Wojdyla, D.M. AU - Granger, C.B. AU - Wallentin, L. PY - 2014 UR - http://repository.ubn.ru.nl/handle/2066/127659 AB - AIMS: We assessed the effect of concomitant aspirin use on the efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation (AF). METHODS AND RESULTS: In ARISTOTLE, 18 201 patients were randomized to apixaban 5 mg twice daily or warfarin. Concomitant aspirin use was left to the discretion of the treating physician. In this predefined analysis, simple and marginal structured models were used to adjust for baseline and time-dependent confounders associated with aspirin use. Outcome measures included stroke or systemic embolism, ischaemic stroke, myocardial infarction, mortality, major bleeding, haemorrhagic stroke, major or clinically relevant non-major bleeding, and any bleeding. On Day 1, 4434 (24%) patients were taking aspirin. Irrespective of concomitant aspirin use, apixaban reduced stroke or systemic embolism [with aspirin: apixaban 1.12% vs. warfarin 1.91%, hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.39-0.85 vs. without aspirin: apixaban 1.11% vs. warfarin 1.32%, HR 0.84, 95% CI 0.66-1.07; P interaction = 0.10] and caused less major bleeding than warfarin (with aspirin: apixaban 3.10% vs. warfarin 3.92%, HR 0.77, 95% CI 0.60-0.99 vs. without aspirin: apixaban 1.82% vs. warfarin 2.78%, HR without aspirin 0.65, 95% CI 0.55-0.78; P interaction = 0.29). Similar results were seen in the subgroups of patients with and without arterial vascular disease. CONCLUSION: Apixaban had similar beneficial effects on stroke or systemic embolism and major bleeding compared with warfarin, irrespective of concomitant aspirin use. TI - Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial EP - 232 SN - 0195-668X IS - iss. 4 SP - 224 JF - European Heart Journal VL - vol. 35 DO - https://doi.org/10.1093/eurheartj/eht445 ER - TY - JOUR AU - Dewilde, W.J. AU - Janssen, P.W. AU - Verheugt, F.W.A. AU - Storey, R.F. AU - Adriaenssens, T. AU - Hansen, M.L. AU - Lamberts, M. AU - Berg, J.M. van den PY - 2014 UR - https://hdl.handle.net/2066/133911 AB - Chronic oral anticoagulant therapy is recommended (class I) in patients with mechanical heart valves and in patients with atrial fibrillation with a CHA2DS2-VASc (Congestive heart failure, Hypertension, Age >/=75 years, Diabetes mellitus, prior Stroke or transient ischemic attack or thromboembolism, Vascular disease, Age 65 to 74 years, Sex category) score >/=1. When these patients undergo percutaneous coronary intervention with stenting, treatment with aspirin and a P2Y12 receptor inhibitor also becomes indicated. Before 2014, guidelines recommended the use of triple therapy (vitamin K antagonists, aspirin, and clopidogrel) for these patients. However, major bleeding is increasingly recognized as the Achilles' heel of the triple therapy regimen. Lately, various studies have investigated this topic, including a prospective randomized trial, and the evidence for adding aspirin to the regimen of vitamin K antagonists and clopidogrel seems to be weakened. In this group of patients, the challenge is finding the optimal equilibrium to prevent thromboembolic events, such as stent thrombosis and thromboembolic stroke, without increasing bleeding risk. TI - Triple Therapy for Atrial Fibrillation and Percutaneous Coronary Intervention: A Contemporary Review EP - 1280 SN - 0735-1097 IS - iss. 12 SP - 1270 JF - Journal of the American College of Cardiology VL - vol. 64 DO - https://doi.org/10.1016/j.jacc.2014.06.1193 ER - TY - JOUR AU - Garcia, D. AU - Alexander, J.H. AU - Wallentin, L. AU - Wojdyla, D.M. AU - Thomas, L. AU - Hanna, M. AU - Al-Khatib, S.M. AU - Dorian, P. AU - Ansell, J. AU - Commerford, P. AU - Flaker, G. AU - Lanas, F. AU - Vinereanu, D. AU - Xavier, D. AU - Hylek, E.M. AU - Held, C. AU - Verheugt, F.W. AU - Granger, C.B. AU - Lopes, R.D. PY - 2014 UR - https://hdl.handle.net/2066/135959 AB - Using data from ARISTOTLE, we describe the periprocedural management of anticoagulation and rates of subsequent clinical outcomes among patients chronically anticoagulated with warfarin or apixaban. We recorded whether (and for how long) anticoagulant therapy was interrupted preprocedure, whether bridging therapy was used, and the proportion of patients who experienced important clinical outcomes during the 30 days postprocedure. Of 10 674 procedures performed during follow-up in 5924 patients, 9260 were included in this analysis. Anticoagulant treatment was not interrupted preprocedure 37.5% of the time. During the 30 days postprocedure, stroke or systemic embolism occurred after 16/4624 (0.35%) procedures among apixaban-treated patients and 26/4530 (0.57%) procedures among warfarin-treated patients (odds ratio [OR] 0.601; 95% confidence interval [CI] 0.322-1.120). Major bleeding occurred in 74/4560 (1.62%) procedures in the apixaban arm and 86/4454 (1.93%) in the warfarin arm (OR 0.846; 95% CI 0.614-1.166). The risk of death was similar with apixaban (54/4624 [1.17%]) and warfarin (49/4530 [1.08%]) (OR 1.082; 95% CI 0.733-1.598). Among patients in ARISTOTLE, the 30-day postprocedure stroke, death, and major bleeding rates were low and similar in apixaban- and warfarin-treated patients, regardless of whether anticoagulation was stopped beforehand. Our findings suggest that many patients on chronic anticoagulation can safely undergo procedures; some will not require a preprocedure interruption of anticoagulation. ARISTOTLE was registered at www.clinicaltrials.gov as #NCT00412984. TI - Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures EP - 3698 SN - 0006-4971 IS - iss. 25 SP - 3692 JF - Blood VL - vol. 124 DO - https://doi.org/10.1182/blood-2014-08-595496 ER - TY - JOUR AU - Dinh, T. AU - Baur, L.H. AU - Pisters, R. AU - Kamp, O. AU - Verheugt, F.W.A. AU - Smeets, J.L.R.M. AU - Cheriex, E.C. AU - Lindeboom, J.E. AU - Heesen, W.F. AU - Tieleman, R.G. AU - Prins, M.H. AU - Crijns, H.J.G.M. AU - et al. PY - 2014 UR - http://repository.ubn.ru.nl/handle/2066/127666 AB - OBJECTIVE: Current stroke risk schemes need improvement of predictive value in patients with atrial fibrillation. Transoesophageal echocardiography (TEE) may facilitate stroke risk assessment in such patients and guide antithrombotic treatment. METHODS: We randomised 238 patients with non-valvular atrial fibrillation and a moderate stroke risk to aspirin or adjusted vitamin K antagonist therapy after TEE had ruled out thrombogenic features in the atria and aorta. The primary outcome was a composite of stroke, major bleeding, peripheral embolism and all-cause mortality. RESULTS: Mean CHA2DS2-VASc score was 2.1+/-1.1. The incidences of the composite primary outcome at a mean follow-up of 1.6 years were 3.2% (2.02% per year) in the aspirin group compared to 6.1% (3.84% per year) in the vitamin K antagonists group with an absolute advantage of 2.9 percentage points. Aspirin was non-inferior to vitamin K antagonists (p<0.0001) because the upper limit of the 90% CI did not exceed the 7% absolute difference in event rate between the two treatment arms. CONCLUSIONS: This hypothesis-generating pilot trial has found that TEE may be used for refinement of stroke risk in paroxysmal atrial fibrillation patients. A larger trial is needed to confirm these data. (ClinicalTrials.gov number NTC00224757). TI - Aspirin versus vitamin K antagonist treatment guided by transoesophageal echocardiography in patients with atrial fibrillation: a pilot study EP - 568 SN - 1355-6037 IS - iss. 7 SP - 563 JF - Heart VL - vol. 100 DO - https://doi.org/10.1136/heartjnl-2013-305017 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2014 UR - https://hdl.handle.net/2066/133910 TI - Trials, registries and guidelines for non-ST-elevation acute coronary syndromes EP - 54 SN - 1568-5888 IS - iss. 2 SP - 52 JF - Netherlands Heart Journal VL - vol. 22 DO - https://doi.org/10.1007/s12471-013-0495-7 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/133910/133910.pdf?sequence=1 ER - TY - JOUR AU - Thompson, P.L. AU - Verheugt, F.W.A. PY - 2014 UR - https://hdl.handle.net/2066/133823 AB - PURPOSE: Atrial fibrillation (AF) and coronary heart disease (CHD) commonly occur together. Previous consensus guidelines were published before the wide availability of novel oral anticoagulants (NOACs) and newer P2Y12 antiplatelet agents. We examine recent evidence to guide management in 3 categories of patients with AF and CHD: patients with stable CHD, nonstented patients with recent acute coronary syndrome, and patients with a coronary stent requiring dual-antiplatelet therapy. METHODS: We conducted a literature search by evaluation of PubMed and other data sources including international meeting reports. We critically reviewed recent clinical trial and relevant registry evidence to update European and US consensus documents. FINDINGS: Oral anticoagulation with warfarin or NOACs is required to prevent embolic stroke in AF, and antiplatelet therapy is insufficient for this purpose. Antiplatelet therapy using monotherapy with aspirin is the standard of care in stable CHD. Dual-antiplatelet therapy with aspirin and clopidogrel or a new P2Y12 inhibitor (dual-antiplatelet therapy) is needed to reduce coronary events after an acute coronary syndrome or after percutaneous coronary intervention. Combinations of these agents increase the risk of bleeding, and limited clinical trial evidence suggests that withdrawal of aspirin may reduce bleeding without increasing coronary events. IMPLICATIONS: Available clinical trials and registries provide remarkably little evidence to guide difficult clinical decision making in patients with combined AF and CHD. In patients on triple antithrombotic therapy with vitamin K antagonists, aspirin, and clopidogrel, a single clinical trial indicates that withdrawal of aspirin may reduce bleeding risk without increasing the risk of coronary thrombosis. It is unclear whether this evidence applies to combinations of NOACs and newer P2Y12 inhibitors. Clinical trials of combinations of the newer antithrombotic agents are urgently needed to guide clinical care. TI - Managing antithrombotic therapy in patients with both atrial fibrillation and coronary heart disease EP - 1181 SN - 0149-2918 IS - iss. 9 SP - 1176 JF - Clinical Therapeutics VL - vol. 36 DO - https://doi.org/10.1016/j.clinthera.2014.08.010 ER - TY - JOUR AU - Verheugt, F.W. AU - Geersing, G.J. AU - Kappelle, L.J. PY - 2014 UR - https://hdl.handle.net/2066/136165 AB - - Platelet aggregation inhibitors reduce the risk of complications during and after acute coronary syndromes and after a TIA or stroke.- Acetylsalicylic acid plays a major role in secondary prevention; the combination of acetylsalicylic acid and a platelet ADP receptor antagonist, such as clopidogrel, may have added value.- In percutaneous coronary intervention, dual platelet inhibition appears to be effective in the prevention of stent thrombosis.- Long-term (> 1 year) use of dual platelet inhibition has an unfavourable risk-benefit profile, partly due to an increase in the number of bleeding events, particularly in the stomach.- The use of the combination of acetylsalicylic acid and clopidogrel may be helpful after a TIA or minor stroke, but further research is needed to identify the group of patients for whom this combination would be applicable.- This article provides an overview of the modern cardiological and neurological indications for platelet inhibition as well as the risk factors for severe bleeding events when using dual antiplatelet therapy. TI - [Added value of clopidogrel in cardiology and neurology] SN - 0028-2162 IS - iss. 0 SP - A7609 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 158 ER - TY - JOUR AU - Jaspers Focks, J. AU - Tielemans, M.M. AU - Rossum, L.G.M. van AU - Eikendal, T. AU - Brouwer, M.A. AU - Jansen, J.B.M.J. AU - Laheij, R.J.F. AU - Verheugt, F.W.A. AU - Oijen, M.G.H. van PY - 2014 UR - http://repository.ubn.ru.nl/handle/2066/127588 AB - BACKGROUND: Aspirin is associated with gastrointestinal side effects such as gastric ulcers, gastric bleeding and dyspepsia. High-dose effervescent calcium carbasalate (ECC), a buffered formulation of aspirin, is associated with reduced gastric toxicity compared with plain aspirin in healthy volunteers, but at lower cardiovascular doses no beneficial effects were observed. AIM: To compare the prevalence of self-reported gastrointestinal symptoms between low-dose plain aspirin and ECC. METHODS: A total of 51,869 questionnaires were sent to a representative sample of the Dutch adult general population in December 2008. Questions about demographics, gastrointestinal symptoms in general and specific symptoms, comorbidity, and medication use including bioequivalent doses of ECC (100 mg) and plain aspirin (80 mg) were stated. We investigated the prevalence of self-reported gastrointestinal symptoms on ECC compared with plain aspirin using univariate and multivariate logistic regression analyses. RESULTS: A total of 16,715 questionnaires (32 %) were returned and eligible for analysis. Of these, 911 (5 %) respondents reported the use of plain aspirin, 633 (4 %) ECC and 15,171 reported using neither form of aspirin (91 %). The prevalence of self-reported gastrointestinal symptoms in general was higher in respondents using ECC (27.5 %) compared with plain aspirin (26.3 %), but did not differ significantly with either univariate (OR 1.06, 95 %CI 0.84-1.33), or multivariate analysis (aOR 1.08, 95 %CI 0.83-1.41). Also, none of the specific types of symptoms differed between the two aspirin formulations. CONCLUSIONS: In this large cohort representative of the general Dutch population, low-dose ECC is not associated with a reduction in self-reported gastrointestinal symptoms compared with plain aspirin. TI - Gastrointestinal symptoms in low-dose aspirin users: a comparison between plain and buffered aspirin EP - 112 SN - 1568-5888 IS - iss. 3 SP - 107 JF - Netherlands Heart Journal VL - vol. 22 DO - https://doi.org/10.1007/s12471-014-0522-3 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/127588/127588.pdf?sequence=1 ER - TY - JOUR AU - Cramer, G.E. AU - Bakker, J. AU - Gommans, F. AU - Brouwer, M.A. AU - Kurvers, M. AU - Fouraux, M. AU - Verheugt, F.W.A. AU - Kofflard, M. PY - 2014 UR - https://hdl.handle.net/2066/133874 AB - Elevated cardiac troponin can be seen in patients with left ventricular (LV) hypertrophy and in asymptomatic subjects with a high a priori risk of cardiovascular disease (CVD). In hypertrophic cardiomyopathy (HC) troponin can be detected as well, but little is known about the contribution of LV mass, on the one hand, and the long-term risk of CVD, on the other. In an observational single-center study of 62 patients with HC, without a history of CVD, we assessed the Framingham Heart 10-year risk score (FH10yrs), LV mass index (LVMI) using magnetic resonance imaging, and highly sensitive cardiac troponin T (hs-cTnT). Hs-cTnT (>3 ng/L) was detectable in 74% of patients (46 of 62). Hs-cTnT was elevated in 26% (16 of 62) of patients (ninety-ninth percentile reference limit of 14 ng/L or more). From 3 to 14 ng/L, patients were older, more often had hypertension, and the FH10yrs was higher. Hs-cTnT correlated positively with LVMI (p <0.001) and maximal wall thickness (p <0.001). In addition, LVMI and hypertension were independently associated with increasing hs-cTnT concentrations in linear regression. Using multivariate binary logistic regression, both LVMI and FH10yrs were independently associated with detectable hs-cTnT levels. In contrast, only LVMI was associated with elevated hs-cTnT levels. In conclusion, hs-cTnT was detectable in 3 quarters and elevated in a quarter of our patients with HC. Although detectable hs-cTnT is associated with both LV mass and CVD risk, elevated hs-cTnT relates to LV mass only. This indicates that hypertrophy more than the risk of CVD seems the most important drive for hs-cTnT to occur in these patients. TI - Relation of highly sensitive cardiac troponin T in hypertrophic cardiomyopathy to left ventricular mass and cardiovascular risk EP - 1245 SN - 0002-9149 IS - iss. 7 SP - 1240 JF - American Journal of Cardiology VL - vol. 113 DO - https://doi.org/10.1016/j.amjcard.2013.12.033 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/125236 TI - Antithrombotic therapy during and after percutaneous coronary intervention in patients with atrial fibrillation EP - 2061 SN - 0009-7322 IS - iss. 18 SP - 2058 JF - Circulation VL - vol. 128 DO - http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002250 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/119133 AB - After acute coronary syndrome (ACS), long-term dual antiplatelet therapy with acetylsalicylic acid and a P2Y(12) platelet receptor antagonist is the standard of care for secondary prevention. Despite the introduction of more potent P2Y(12) receptor antagonists, the risk of a recurrent vascular event within 12 months remains at approximately 10%, indicating a need for improved secondary prevention strategies. A recent phase III trial found that addition of a third antiplatelet agent, vorapaxar, in patients with atherosclerosis might benefit those who have previously experienced a myocardial infarction, although a trial in patients with ACS found this strategy led to increased bleeding without significant efficacy improvement. Previously, data from patients with ACS given vitamin K antagonists in addition to acetylsalicylic acid demonstrated significant reductions in vascular events, but this was associated with an unacceptable bleeding risk. As expected, phase II trials of newer oral anticoagulants in addition to dual antiplatelet therapy also found increased bleeding risk, with only the direct factor Xa inhibitors apixaban and rivaroxaban continuing to phase III. The phase III trial of full-dose apixaban was stopped early for safety concerns, because the major bleeding rates were significantly increased with minimal improvement in efficacy. However, the phase III trial of low-dose rivaroxaban demonstrated a significantly reduced incidence of recurrent vascular events without an increased risk of fatal bleeding. In conclusion, these trials underline the potential importance of optimal dose selection in phase III studies and suggest that the long-term use of low-dose anticoagulation, together with dual antiplatelet therapy, might have a role in secondary prevention after ACS. TI - Low-dose anticoagulation for secondary prevention in acute coronary syndrome EP - 626 SN - 0002-9149 IS - iss. 4 SP - 618 JF - American Journal of Cardiology VL - vol. 111 DO - http://dx.doi.org/10.1016/j.amjcard.2012.10.046 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/119155 TI - New oral anticoagulants in atrial fibrillation forever? EP - 202 SN - 0009-7322 IS - iss. 3 SP - 200 JF - Circulation VL - vol. 128 DO - http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003825 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/119169 AB - Patients with atrial fibrillation (AF) have an increased stroke risk compared with those in sinus rhythm, although the absolute risk for individual patients is modulated by the presence of various additional risk factors. Patient selection for oral anticoagulation for stroke prevention is based on risks of stroke and bleeding. Although CHADS2 (congestive heart failure, hypertension, age >/=75 years, diabetes mellitus, stroke or transient ischemic attack) is the most widely used scheme for evaluating stroke risk in patients with AF, several other stroke risk factors are not included; therefore, many patients' stroke risk may be underestimated, contributing to the underuse of anticoagulants. Furthermore, a substantial proportion of patients are categorized as being at moderate risk (CHADS2 = 1), and there has been some ambiguity regarding optimum thromboprophylaxis in this group. The refinement of CHADS2 , CHA2 DS2 -VASc (Congestive heart failure, Hypertension, Age 75 years [2 points], Diabetes mellitus, Stroke or transient ischemic attack [2 points], Vascular disease, Age 65 to 74 years, Sex category [female]), considers additional risk factors. Its main advantage is its ability to identify patients truly at low risk of thromboembolism (CHA2 DS2 -VASc = 0), who are unlikely to benefit from antithrombotic therapy. For all others, an oral anticoagulant may be the preferred approach, simplifying clinical decision making. Implementation of CHA2 DS2 -VASc may also result in an increased proportion of patients receiving anticoagulation. The emergence of newer oral anticoagulants that can be given without routine coagulation monitoring, with improved benefit-risk profiles vs vitamin K antagonists, promises to simplify therapy for patients with AF at risk of stroke. This, coupled with advances in stroke risk stratification, is expected to improve patient outcomes and reduce the burden of AF-related stroke. TI - Advances in stroke prevention in atrial fibrillation: enhanced risk stratification combined with the newer oral anticoagulants EP - 322 SN - 0160-9289 IS - iss. 6 SP - 312 JF - Clinical Cardiology VL - vol. 36 DO - http://dx.doi.org/10.1002/clc.22122 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/119245 TI - Combined antiplatelet and novel oral anticoagulant therapy after acute coronary syndrome: is three a crowd? EP - 1620 SN - 0195-668X IS - iss. 22 SP - 1618 JF - European Heart Journal VL - vol. 34 DO - http://dx.doi.org/10.1093/eurheartj/eht075 ER - TY - JOUR AU - Gibson, C.M. AU - Chakrabarti, A.K. AU - Mega, J. AU - Bode, C. AU - Bassand, J.P. AU - Verheugt, F.W.A. AU - Bhatt, D.L. AU - Goto, S. AU - Cohen, M. AU - Mohanavelu, S. AU - Burton, P. AU - Stone, G. AU - Braunwald, E. AU - et al. PY - 2013 UR - https://hdl.handle.net/2066/119184 AB - OBJECTIVES: The aim of this study was to determine if rivaroxaban is associated with a reduction in stent thrombosis among patients with acute coronary syndromes (ACS) in the ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51) trial. BACKGROUND: Dual antiplatelet therapy (DAPT) has been the mainstay of efforts to prevent stent thrombosis. Because thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis. METHODS: The ATLAS-ACS 2 TIMI 51 study was a placebo-controlled trial that randomly assigned 15,526 patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. RESULTS: Among patients who had a stent placed before or at the time of the index event, rivaroxaban significantly reduced independently adjudicated Academic Research Consortium definite and probable stent thrombosis in the pooled (1.9% vs. 1.5%; hazard ratio [HR]: 0.65; p = 0.017) and the 2.5 mg twice-daily (1.9% vs. 1.5%; HR: 0.61; p = 0.023) treatment groups when compared with placebo, with a trend toward a reduction in the 5 mg twice-daily treatment group (1.9% vs. 1.5%; HR: 0.70; p = 0.089). Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT (HR: 0.68; 95% CI: 0.50 to 0.92, combined rivaroxaban group vs. placebo). Among stented patients who were treated with dual antiplatelet therapy, there was a mortality reduction among those treated with twice-daily rivaroxaban 2.5 mg (HR: 0.56; 95% CI: 0.35 to 0.89; p = 0.014). CONCLUSIONS: Among stented patients with ACS treated with DAPT, the administration of twice-daily rivaroxaban 2.5 mg was associated with a reduction in stent thrombosis and mortality. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965). TI - Reduction of stent thrombosis in patients with acute coronary syndromes treated with rivaroxaban in ATLAS-ACS 2 TIMI 51 EP - 290 SN - 0735-1097 IS - iss. 4 SP - 286 JF - Journal of the American College of Cardiology VL - vol. 62 DO - http://dx.doi.org/10.1016/j.jacc.2013.03.041 ER - TY - JOUR AU - Gershlick, A.H. AU - Banning, A.P. AU - Myat, A. AU - Verheugt, F.W.A. AU - Gersh, B.J. PY - 2013 UR - https://hdl.handle.net/2066/119186 AB - In the past ten years, primary percutaneous coronary intervention (PCI) has replaced thrombolysis as the revascularisation strategy for many patients presenting with ST-segment elevation myocardial infarction (STEMI). However, delivery of primary PCI within evidence-based timeframes is challenging, and health-care provision varies substantially worldwide. Consequently, even with the ideal circumstances of rapid initial diagnosis, long transfer delays to the catheter laboratory can occur. These delays are detrimental to outcomes for patients and can be exaggerated by variations in timing of patients' presentation and diagnosis. In this Series paper we summarise the value of immediate out-of-hospital thrombolysis for STEMI, and reconsider the potential therapeutic interface with a contemporary service for primary PCI. We review recent trial data, and explore opportunities for optimisation of STEMI outcomes with a pharmacoinvasive approach. TI - Reperfusion therapy for STEMI: is there still a role for thrombolysis in the era of primary percutaneous coronary intervention? EP - 632 SN - 0140-6736 IS - iss. 9892 SP - 624 JF - The Lancet (London) VL - vol. 382 DO - http://dx.doi.org/10.1016/S0140-6736(13)61454-3 ER - TY - JOUR AU - Dewilde, W.J. AU - Verheugt, F.W.A. AU - Berg, J.M. van den PY - 2013 UR - https://hdl.handle.net/2066/119202 TI - Antiplatelet therapy and anticoagulants - authors' reply SN - 0140-6736 IS - iss. 9886 SP - 25 JF - The Lancet (London) VL - vol. 382 ER - TY - JOUR AU - Dewilde, W.J. AU - Oirbans, T. AU - Verheugt, F.W.A. AU - Kelder, J.C. AU - Smet, B.J. de AU - Herrman, J.P. AU - Adriaenssens, T. AU - Vrolix, M. AU - Heestermans, A.A. AU - Vis, M.M. AU - Tijsen, J.G. AU - Hof, A.W. van 't AU - Berg, J.M. van den AU - et al. PY - 2013 UR - https://hdl.handle.net/2066/119218 AB - BACKGROUND: If percutaneous coronary intervention (PCI) is required in patients taking oral anticoagulants, antiplatelet therapy with aspirin and clopidogrel is indicated, but such triple therapy increases the risk of serious bleeding. We investigated the safety and efficacy of clopidogrel alone compared with clopidogrel plus aspirin. METHODS: We did an open-label, multicentre, randomised, controlled trial in 15 centres in Belgium and the Netherlands. From November, 2008, to November, 2011, adults receiving oral anticoagulants and undergoing PCI were assigned clopidogrel alone (double therapy) or clopidogrel plus aspirin (triple therapy). The primary outcome was any bleeding episode within 1 year of PCI, assessed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00769938. FINDINGS: 573 patients were enrolled and 1-year data were available for 279 (98.2%) patients assigned double therapy and 284 (98.3%) assigned triple therapy. Mean ages were 70.3 (SD 7.0) years and 69.5 (8.0) years, respectively. Bleeding episodes were seen in 54 (19.4%) patients receiving double therapy and in 126 (44.4%) receiving triple therapy (hazard ratio [HR] 0.36, 95% CI 0.26-0.50, p<0.0001). In the double-therapy group, six (2.2%) patients had multiple bleeding events, compared with 34 (12.0%) in the triple-therapy group. 11 (3.9%) patients receiving double therapy required at least one blood transfusion, compared with 27 (9.5%) patients in the triple-therapy group (odds ratio from Kaplan-Meier curve 0.39, 95% CI 0.17-0.84, p=0.011). INTERPRETATION: Use of clopiogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events. FUNDING: Antonius Ziekenhuis Foundation, Strect Foundation. TI - Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial EP - 1115 SN - 0140-6736 IS - iss. 9872 SP - 1107 JF - The Lancet (London) VL - vol. 381 DO - http://dx.doi.org/10.1016/S0140-6736(12)62177-1 ER - TY - JOUR AU - Riezebos, R.K. AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/126167 TI - Timing of angiography in non-ST elevation myocardial infarction EP - 1873 SN - 1355-6037 IS - iss. 24 SP - 1867 JF - Heart VL - vol. 99 DO - https://doi.org/10.1136/heartjnl-2012-302034 ER - TY - JOUR AU - Vranckx, P. AU - Verheugt, F.W.A. AU - Maat, M.P. de AU - Ulmans, V.A. AU - Regar, E. AU - Smits, P. AU - Berg, J.M. van den AU - Lindeboom, W. AU - Jones, R.L. AU - Friedman, J. AU - Reilly, P. AU - Leebeek, F.W. PY - 2013 UR - https://hdl.handle.net/2066/119279 AB - AIMS: Patients receiving long-term anticoagulant treatment with dabigatran may need to undergo a percutaneous coronary intervention (PCI). We studied markers of coagulation activation during elective PCI in patients using dabigatran in order to investigate whether coagulation activation upon balloon inflation and stenting is suppressed by dabigatran without additional heparin treatment. METHODS AND RESULTS: This phase IIa, exploratory, multicentre, randomised, open-label study included 50 stable patients having an elective PCI. Patients on standard dual antiplatelet therapy (DAPT) were randomised (2:2:1) to either pre-procedural dabigatran 110 mg BID (n=19) or 150 mg BID (n=21), as compared to standard intraprocedural unfractionated heparin (UFH) (n=10). Following PCI, a significant increase in the levels of prothrombin fragment 1+2 (F1+2) in the combined dabigatran group was observed compared to the level just before the start of PCI (159.1 [1.4] pmol/l; geometric mean [gSD]). Levels at 0.5, 1.0, 1.5 and 2 hrs after the start of PCI ranged from 193.5 (1.4) to 270.6 pmol/l (1.7); (p-value for paired analysis=0.015, 0.022, 0.2342, 0.0379, respectively). Also, thrombin-antithrombin (TAT) complexes were increased significantly in the combined dabigatran group compared to pre-PCI levels (4.2 [2.2] ug/l). Levels ranged from 5.2 (2.5) to 8.5 (2.3) (p=0.0497, 0.0343, 0.005 and 0.1628, respectively). In contrast, in the control group of patients treated with UFH, no increase was observed in F1+2 and TAT complexes during PCI. Five out of 40 (12.5%) patients required bail-out anticoagulation in the dabigatran group, of whom four experienced a procedural myocardial infarction (MI), versus one out of 10 in the UFH group, who had a stent thrombosis without MI prior to the study-PCI. One minor access-site bleeding occurred in the dabigatran group. CONCLUSIONS: Dabigatran treatment (110 mg or 150 mg BID) may not provide sufficient anticoagulation during PCI. EudraCT. No: 2007-007536-25. TI - A randomised study of dabigatran in elective percutaneous coronary intervention in stable coronary artery disease patients EP - 1060 SN - 1774-024X IS - iss. 9 SP - 1052 JF - Eurointervention VL - vol. 8 DO - https://doi.org/10.4244/EIJV8I9A162 ER - TY - JOUR AU - Riezebos, R.K. AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/119114 TI - ACP Journal Club. Cangrelor reduced ischemic PCI complications more than clopidogrel without increasing severe bleeding SN - 0003-4819 IS - iss. 12 SP - JC5 JF - Annals of Internal Medicine C.2 VL - vol. 158 DO - https://doi.org/10.7326/0003-4819-158-12-201306180-02005 ER - TY - JOUR AU - McElhaney, J.E. AU - Beran, J. AU - Devaster, J.M. AU - Esen, M. AU - Launay, O. AU - Leroux-Roels, G. AU - Ruiz-Palacios, G.M. AU - Essen, G.A. van AU - Caplanusi, A. AU - Claeys, C. AU - Durand, C. AU - Duval, X. AU - Idrissi, M. El AU - Falsey, A.R. AU - Feldman, G. AU - Frey, S.E. AU - Galtier, F. AU - Hwang, S.J. AU - Innis, B.L. AU - Kovac, M. AU - Kremsner, P. AU - McNeil, S. AU - Nowakowski, A. AU - Richardus, J.H. AU - Trofa, A. AU - Oostvogels, L. AU - Verheugt, F.W. AU - et al. PY - 2013 UR - https://hdl.handle.net/2066/119136 AB - BACKGROUND: We aimed to compare AS03-adjuvanted inactivated trivalent influenza vaccine (TIV) with non-adjuvanted TIV for seasonal influenza prevention in elderly people. METHODS: We did a randomised trial in 15 countries worldwide during the 2008-09 (year 1) and 2009-10 (year 2) influenza seasons. Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were randomly assigned (1:1) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV. Randomisation was done in an internet-based system, with a blocking scheme and stratification by age (65-74 years and 75 years or older). Participants were scheduled to receive one vaccine in each year, and remained in the same group in years 1 and 2. Unmasked personnel prepared and gave the vaccines, but participants and individuals assessing any study endpoint were masked. The coprimary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV (to be reported elsewhere). For the first objective, the primary endpoint was relative efficacy of the vaccines for prevention of influenza A (excluding A H1N1 pdm09) or B, or both, that was confirmed by PCR analysis in year 1 (lower limit of two-sided 95% CI had to be greater than zero to establish superiority). From Nov 15, to April 30, in both years, participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness. After onset of suspected cases, we obtained nasal and throat swabs to identify influenza RNA with real-time PCR. Efficacy analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT00753272. FINDINGS: We enrolled 43 802 participants, of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1. In the year 1 efficacy cohort, fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B, or both (274 [1.27%, 95% CI 1.12-1.43] of 21 573 vs 310 [1.44%, 1.29-1.61] of 21 482; relative efficacy 12.11%, 95% CI -3.40 to 25.29; superiority not established). Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A (224 [1.04%, 95% CI 0.91-1.18] vs 270 [1.26, 1.11-1.41]; relative efficacy 17.53%, 95% CI 1.55-30.92) and influenza A H3N2 (170 [0.79, 0.67-0.92] vs 205 [0.95, 0.83-1.09]; post-hoc analysis relative efficacy 22.0%, 95% CI 5.68-35.49). INTERPRETATION: AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV. Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints. FUNDING: GlaxoSmithKline Biologicals SA. TI - AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial EP - 496 SN - 1473-3099 IS - iss. 6 SP - 485 JF - Lancet Infectious Diseases VL - vol. 13 DO - https://doi.org/10.1016/S1473-3099(13)70046-X ER - TY - JOUR AU - Bhatt, D.L. AU - Stone, G.W. AU - Mahaffey, K.W. AU - Gibson, C.M. AU - Steg, P.G. AU - Hamm, C.W. AU - Price, M.J. AU - Leonardi, S. AU - Gallup, D. AU - Bramucci, E. AU - Radke, P.W. AU - Widimsky, P. AU - Tousek, F. AU - Tauth, J. AU - Spriggs, D. AU - McLaurin, B.T. AU - Angiolillo, D.J. AU - Genereux, P. AU - Liu, T. AU - Prats, J. AU - Todd, M. AU - Skerjanec, S. AU - White, H.D. AU - Harrington, R.A. AU - Verheugt, F.W. AU - et al. PY - 2013 UR - https://hdl.handle.net/2066/119266 AB - BACKGROUND: The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects. METHODS: In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours. RESULTS: The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups. CONCLUSIONS: Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.). TI - Effect of platelet inhibition with cangrelor during PCI on ischemic events EP - 1313 SN - 0028-4793 IS - iss. 14 SP - 1303 JF - The New England Journal of Medicine VL - vol. 368 DO - https://doi.org/10.1056/NEJMoa1300815 ER - TY - JOUR AU - Agewall, S. AU - Cattaneo, M. AU - Collet, J.P. AU - Andreotti, F. AU - Lip, G.Y. AU - Verheugt, F.W.A. AU - Huber, K. AU - Grove, E.L. AU - Morais, J. AU - Husted, S. AU - Wassmann, S. AU - Rosano, G. AU - Atar, D. AU - Pathak, A. AU - Kjeldsen, K. AU - Storey, R.F. AU - Pharmacology, E.S.C.W.G.o.C. AU - Drug, T. AU - Thrombosis, E.S.C.W.G.o. PY - 2013 UR - https://hdl.handle.net/2066/119274 TI - Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy EP - 13, 1713a-1713b SN - 0195-668X IS - iss. 23 SP - 1708 JF - European Heart Journal VL - vol. 34 DO - https://doi.org/10.1093/eurheartj/eht042 ER - TY - JOUR AU - Caterina, R. de AU - Husted, S. AU - Wallentin, L. AU - Andreotti, F. AU - Arnesen, H. AU - Bachmann, F. AU - Baigent, C. AU - Huber, K. AU - Jespersen, J. AU - Kristensen, S.D. AU - Lip, G.Y. AU - Morais, J. AU - Rasmussen, L.H. AU - Siegbahn, A. AU - Verheugt, F.W.A. AU - Weitz, J.I. PY - 2013 UR - https://hdl.handle.net/2066/119284 AB - Contrary to previous models based on plasma, coagulation processes are currently believed to be mostly cell surface-based, including three overlapping phases: initiation, when tissue factor-expressing cells and microparticles are exposed to plasma; amplification, whereby small amounts of thrombin induce platelet activation and aggregation, and promote activation of factors (F)V, FVIII and FXI on platelet surfaces; and propagation, in which the Xase (tenase) and prothrombinase complexes are formed, producing a burst of thrombin and the cleavage of fibrinogen to fibrin. Thrombin exerts a number of additional biological actions, including platelet activation, amplification and self-inhibition of coagulation, clot stabilisation and anti-fibrinolysis, in processes occurring in the proximity of vessel injury, tightly regulated by a series of inhibitory mechanisms. "Classical" anticoagulants, including heparin and vitamin K antagonists, typically target multiple coagulation steps. A number of new anticoagulants, already developed or under development, target specific steps in the process, inhibiting a single coagulation factor or mimicking natural coagulation inhibitors. TI - General mechanisms of coagulation and targets of anticoagulants (Section I). Position Paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease EP - 579 SN - 0340-6245 IS - iss. 4 SP - 569 JF - Thrombosis and Haemostasis VL - vol. 109 DO - https://doi.org/10.1160/TH12-10-0772 ER - TY - JOUR AU - Steg, G. AU - James, S.K. AU - Atar, D. AU - Badano, L.P. AU - Blomstrom-Lundqvist, C. AU - Borger, M.A. AU - Mario, C. de AU - Dickstein, K. AU - Ducrocq, G. AU - Fernandez-Aviles, F. AU - Gershlick, A.H. AU - Giannuzzi, P. AU - Halvorsen, S. AU - Huber, K. AU - Juni, P. AU - Kastrati, A. AU - Knuuti, J. AU - Lenzen, M.J. AU - Mahaffey, K.W. AU - Valgimigli, M. AU - Hof, A. van't AU - Widimsky, P. AU - Zahger, D. AU - Bax, J.J. AU - Baumgartner, H. AU - Ceconi, C. AU - Dean, V. AU - Deaton, C. AU - Fagard, R. AU - Funck-Brentano, C. AU - Hasdai, D. AU - Hoes, A. AU - Kirchhof, P. AU - Kolh, P. AU - McDonagh, T. AU - Moulin, C. AU - Popescu, B.A. AU - Reiner, Z. AU - Sectem, U. AU - Sirnes, P.A. AU - Tendera, M. AU - Torbicki, A. AU - Vahanian, A. AU - Windecker, S. AU - Astin, F. AU - Astrom, A.K. AU - Budaj, A. AU - Clemmensen, P. AU - Collet, J.P. AU - Fox, K.A. AU - Fuat, A. AU - Gustiene, O. AU - Hamm, C.W. AU - Kala, P. AU - Lancellotti, P. AU - Pietro Maggioni, A. AU - Merkely, B. AU - Neumann, F.J. AU - Piepoli, M. AU - Werf, F. van de AU - Verheugt, F.W. AU - Wallentin, L. PY - 2013 UR - https://hdl.handle.net/2066/119289 TI - Grupo de Trabajo para el manejo del infarto agudo de miocardio con elevación del segmento ST de la Sociedad Europea de Cardiología (ESC). EP - 53 e46 SN - 0300-8932 IS - iss. 1 SP - 53 e1 JF - Revista Espanõla de Cardiología VL - vol. 66 ER - TY - JOUR AU - Caterina, R. de AU - Husted, S. AU - Wallentin, L. AU - Andreotti, F. AU - Arnesen, H. AU - Bachmann, F. AU - Baigent, C. AU - Huber, K. AU - Jespersen, J. AU - Kristensen, S.D. AU - Lip, G.Y. AU - Morais, J. AU - Rasmussen, L.H. AU - Siegbahn, A. AU - Verheugt, F.W.A. AU - Weitz, J.I. PY - 2013 UR - https://hdl.handle.net/2066/119164 AB - Anticoagulants are a mainstay of cardiovascular therapy, and parenteral anticoagulants have widespread use in cardiology, especially in acute situations. Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparins, the synthetic pentasaccharides fondaparinux, idraparinux and idrabiotaparinux, and parenteral direct thrombin inhibitors. The several shortcomings of unfractionated heparin and of low-molecular-weight heparins have prompted the development of the other newer agents. Here we review the mechanisms of action, pharmacological properties and side effects of parenteral anticoagulants used in the management of coronary heart disease treated with or without percutaneous coronary interventions, cardioversion for atrial fibrillation, and prosthetic heart valves and valve repair. Using an evidence-based approach, we describe the results of completed clinical trials, highlight ongoing research with currently available agents, and recommend therapeutic options for specific heart diseases. TI - Parenteral anticoagulants in heart disease: current status and perspectives (Section II). Position paper of the ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease EP - 786 SN - 0340-6245 IS - iss. 5 SP - 769 JF - Thrombosis and Haemostasis VL - vol. 109 DO - https://doi.org/10.1160/TH12-06-0403 ER - TY - JOUR AU - Bahit, M.C. AU - Lopes, R.D. AU - Wojdyla, D.M. AU - Hohnloser, S.H. AU - Alexander, J.H. AU - Lewis, B.S. AU - Aylward, P.E. AU - Verheugt, F.W.A. AU - Keltai, M. AU - Diaz, R. AU - Hanna, M. AU - Granger, C.B. AU - Wallentin, L. PY - 2013 UR - https://hdl.handle.net/2066/125239 AB - BACKGROUND: A substantial portion of patients with atrial fibrillation (AF) also have coronary artery disease (CAD) and are at risk for coronary events. Warfarin is known to reduce these events, but increase the risk of bleeding. We assessed the effects of apixaban compared with warfarin in AF patients with and without prior CAD. METHODS AND RESULTS: In ARISTOTLE, 18,201 patients with AF were randomized to apixaban or warfarin. History of CAD was defined as documented CAD, prior myocardial infarction, and/or history of coronary revascularization. We analyzed baseline characteristics and clinical outcomes of patients with and without prior CAD and compared outcomes by randomized treatment using Cox models. A total of 6639 (36.5%) patients had prior CAD. These patients were more often male, more likely to have prior stroke, diabetes, and hypertension, and more often received aspirin at baseline (42.2% vs. 24.5%). The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism and death from any cause (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.71-1.27, P for interaction=0.12; HR 0.96, 95% CI 0.81-1.13, P for interaction=0.28). Rates of myocardial infarction were numerically lower with apixaban than warfarin among patients with and without prior CAD. The effect of apixaban on reducing major bleeding and intracranial hemorrhage was consistent in patients with and without CAD. CONCLUSIONS: In patients with AF, apixaban more often prevented stroke or systemic embolism and death and caused less bleeding than warfarin, regardless of the presence of prior CAD. Given the common occurrence of AF and CAD and the higher rates of cardiovascular events and death, our results indicate that apixaban may be a better treatment option than warfarin for these high-risk patients. TI - Apixaban in patients with atrial fibrillation and prior coronary artery disease: Insights from the ARISTOTLE trial EP - 220 SN - 0167-5273 IS - iss. 2 SP - 215 JF - International Journal of Cardiology VL - vol. 170 DO - https://doi.org/10.1016/j.ijcard.2013.10.062 ER - TY - JOUR AU - Steg, P.G. AU - Hof, A. van't AU - Hamm, C.W. AU - Clemmensen, P. AU - Lapostolle, F. AU - Coste, P. AU - Berg, J. van den AU - Grunsven, P. van AU - Eggink, G.J. AU - Nibbe, L. AU - Zeymer, U. AU - Orto, M. Campo dell' AU - Nef, H. AU - Steinmetz, J. AU - Soulat, L. AU - Huber, K. AU - Deliargyris, E.N. AU - Bernstein, D. AU - Schuette, D. AU - Prats, J. AU - Clayton, T. AU - Pocock, S. AU - Hamon, M. AU - Goldstein, P. AU - Verheugt, F.W.A. AU - et al. PY - 2013 UR - https://hdl.handle.net/2066/125328 AB - BACKGROUND: Bivalirudin, as compared with heparin and glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of bleeding and death in patients undergoing primary percutaneous coronary intervention (PCI). Whether these benefits persist in contemporary practice characterized by prehospital initiation of treatment, optional use of glycoprotein IIb/IIIa inhibitors and novel P2Y12 inhibitors, and radial-artery PCI access use is unknown. METHODS: We randomly assigned 2218 patients with ST-segment elevation myocardial infarction (STEMI) who were being transported for primary PCI to receive either bivalirudin or unfractionated or low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors (control group). The primary outcome at 30 days was a composite of death or major bleeding not associated with coronary-artery bypass grafting (CABG), and the principal secondary outcome was a composite of death, reinfarction, or non-CABG major bleeding. RESULTS: Bivalirudin, as compared with the control intervention, reduced the risk of the primary outcome (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) and the principal secondary outcome (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P=0.02). Bivalirudin also reduced the risk of major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001). The risk of acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk, 6.11; 95% CI, 1.37 to 27.24; P=0.007). There was no significant difference in rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups of patients. CONCLUSIONS: Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis. (Funded by the Medicines Company; EUROMAX ClinicalTrials.gov number, NCT01087723.). TI - Bivalirudin started during emergency transport for primary PCI EP - 2217 SN - 0028-4793 IS - iss. 23 SP - 2207 JF - The New England Journal of Medicine VL - vol. 369 DO - https://doi.org/10.1056/NEJMoa1311096 ER - TY - JOUR AU - Caterina, R. de AU - Husted, S. AU - Wallentin, L. AU - Andreotti, F. AU - Arnesen, H. AU - Bachmann, F. AU - Baigent, C. AU - Huber, K. AU - Jespersen, J. AU - Kristensen, S.D. AU - Lip, G.Y. AU - Morais, J. AU - Rasmussen, L.H. AU - Siegbahn, A. AU - Verheugt, F.W.A. AU - Weitz, J.I. PY - 2013 UR - https://hdl.handle.net/2066/126210 AB - Oral anticoagulants are a mainstay of cardiovascular therapy, and for over 60 years vitamin K antagonists (VKAs) were the only available agents for long-term use. VKAs interfere with the cyclic inter-conversion of vitamin K and its 2,3 epoxide, thus inhibiting gamma-carboxylation of glutamate residues at the amino-termini of vitamin K-dependent proteins, including the coagulation factors (F) II (prothrombin), VII, IX and X, as well as of the anticoagulant proteins C, S and Z. The overall effect of such interference is a dose-dependent anticoagulant effect, which has been therapeutically exploited in heart disease since the early 1950s. In this position paper, we review the mechanisms of action, pharmacological properties and side effects of VKAs, which are used in the management of cardiovascular diseases, including coronary heart disease (where their use is limited), stroke prevention in atrial fibrillation, heart valves and/or chronic heart failure. Using an evidence-based approach, we describe the results of completed clinical trials, highlight areas of uncertainty, and recommend therapeutic options for specific disorders. Although VKAs are being increasingly replaced in most patients with non-valvular atrial fibrillation by the new oral anticoagulants, which target either thrombin or FXa, the VKAs remain the agents of choice for patients with atrial fibrillation in the setting of rheumatic valvular disease and for those with mechanical heart valves. TI - Vitamin K antagonists in heart disease: Current status and perspectives (Section III). Position Paper of the ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease EP - 1107 SN - 0340-6245 IS - iss. 6 SP - 1087 JF - Thrombosis and Haemostasis VL - vol. 110 DO - https://doi.org/10.1160/TH13-06-0443 ER - TY - JOUR AU - Zannad, F. AU - Stough, W.G. AU - Regnault, V. AU - Gheorghiade, M. AU - Deliargyris, E. AU - Gibson, C.M. AU - Agewall, S. AU - Berkowitz, S.D. AU - Burton, P. AU - Calvo, G. AU - Goldstein, S. AU - Verheugt, F.W.A. AU - Koglin, J. AU - O'Connor, C.M. PY - 2013 UR - https://hdl.handle.net/2066/119127 AB - Thrombotic events (coronary thrombosis, venous thromboembolism, intraventricular thrombosis, intracranial and systemic thromboembolism) occur frequently in patients with heart failure. These events may be precipitated by several mechanisms including hypercoagulability through enhancement of procoagulant reactions, impairment of the protein C pathway, protease activated receptor (PAR) activation, adenosine-mediated thrombosis, or neurohormonal activation; stasis secondary to low cardiac output; and endothelial dysfunction from neurohormonal activation or systemic inflammation. Pathophysiologic evidence and analyses of retrospective data support the hypothesis that antithrombotic agents may improve outcomes in patients with heart failure. Warfarin has not been shown to reduce clinical events in patients with heart failure, although several of the completed randomized trials were underpowered, and the most recent was not placebo-controlled. Many unanswered questions remain that justify continued research in this area. This paper examines the conceptual framework, opportunities, and challenges of clinical investigative approaches with the newer anti-thrombotic agents in patients with heart failure. Critical questions are raised with regard to clinical trial designs that warrant consideration as the field progresses. TI - Is thrombosis a contributor to heart failure pathophysiology? Possible mechanisms, therapeutic opportunities, and clinical investigation challenges EP - 1782 SN - 0167-5273 IS - iss. 5 SP - 1772 JF - International Journal of Cardiology VL - vol. 167 DO - https://doi.org/10.1016/j.ijcard.2012.12.018 ER - TY - JOUR AU - Camm, A.J. AU - Lip, G.Y. AU - Caterina, R.D. AU - Savelieva, I. AU - Atar, D. AU - Hohnloser, S.H. AU - Hindricks, G. AU - Kirchhof, P. AU - Bax, J.J. AU - Baumgartner, H. AU - Ceconi, C. AU - Dean, V. AU - Deaton, C. AU - Fagard, R. AU - Funck-Brentano, C. AU - Hasdai, D. AU - Hoes, A. AU - Knuuti, J. AU - Kolh, P. AU - McDonagh, T. AU - Moulin, C. AU - Popescu, B.A. AU - Reiner, Z. AU - Sechtem, U. AU - Anton Sirnes, P. AU - Tendera, M. AU - Torbicki, A. AU - Vahanian, A. AU - Windecker, S. AU - Vardas, P. AU - Al-Attar, N. AU - Alfieri, O. AU - Angelini, A. AU - Blomstrom-Lundqvist, C. AU - Colonna, P. AU - Sutter, J. de AU - Ernst, S.M.P.G. AU - Goette, A. AU - Gorenek, B. AU - Hatala, R. AU - Heidbuchel, H. AU - Heldal, M. AU - Dalby Kristensen, S. AU - Heuzey, J.Y. AU - Mavrakis, H. AU - Mont, L. AU - Perrone Filardi, P. AU - Ponikowski, P. AU - Prendergast, B. AU - Rutten, F.H. AU - Schotten, U. AU - Gelder, I.C van AU - Verheugt, F.W. PY - 2013 UR - https://hdl.handle.net/2066/119158 TI - Actualización de las guías de la Sociedad Europea de Cardiología (ESC) para el manejo de la fibrilación auricular de 2010 Elaborada en colaboración con la Asociación Europea del Ritmo Cardiaco. EP - 54.e24 SN - 0300-8932 IS - iss. 1 SP - 54.e1 JF - Revista Espanõla de Cardiología VL - vol. 66 DO - https://doi.org/10.1016/j.recesp.2012.11.001 ER - TY - JOUR AU - Verheugt, F.W.A. AU - Clemmensen, P. AU - Mehran, R. AU - Agewall, S. AU - Pocock, S.J. AU - Goldstein, S. AU - Torp-Pedersen, C. AU - Simoons, M.L. AU - Borer, J.S. AU - Khder, Y.M. AU - Burton, P. AU - Deliargyris, E. AU - McMurray, J.J. AU - Berkowitz, S.D. AU - Stough, W.G. AU - Zannad, F. PY - 2013 UR - https://hdl.handle.net/2066/119213 TI - Antithrombotic outcome trials in acute coronary syndromes: seeking the optimal balance between safety and efficacy EP - 1629 SN - 0195-668X IS - iss. 22 SP - 1621 JF - European Heart Journal VL - vol. 34 DO - https://doi.org/10.1093/eurheartj/eht013 ER - TY - JOUR AU - Giugliano, R.P. AU - Ruff, C.T. AU - Braunwald, E. AU - Murphy, S.A. AU - Wiviott, S.D. AU - Halperin, J.L. AU - Waldo, A.L. AU - Ezekowitz, M.D. AU - Weitz, J.I. AU - Spinar, J. AU - Ruzyllo, W. AU - Ruda, M. AU - Koretsune, Y. AU - Betcher, J. AU - Shi, M. AU - Grip, L.T. AU - Patel, S.P. AU - Patel, I. AU - Hanyok, J.J. AU - Mercuri, M. AU - Antman, E.M. AU - Verheugt, F.W.A. AU - et al. PY - 2013 UR - https://hdl.handle.net/2066/125374 AB - BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). CONCLUSIONS: Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.). TI - Edoxaban versus warfarin in patients with atrial fibrillation EP - 2104 SN - 0028-4793 IS - iss. 22 SP - 2093 JF - The New England Journal of Medicine VL - vol. 369 DO - https://doi.org/10.1056/NEJMoa1310907 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/125374/125374.pdf?sequence=1 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/126143 AB - In patients with nonvalvular atrial fibrillation, oral anticoagulation with the vitamin K antagonists acenocoumarol, phenprocoumon and warfarin reduces the risk of stroke by more than 60 %, whereas single or double antiplatelet therapy is much less effective and sometimes associated with a similar bleeding risk as vitamin K antagonists. Besides bleeding, and intracranial haemorrhage in particular, INR monitoring remains the largest drawback of vitamin K antagonists. In the last decade oral agents have been developed that directly block the activity of thrombin (factor IIa), as well as drugs that directly inhibit activated factor X (Xa), which is the first compound in the final common pathway to the activation of thrombin. These agents have been approved for stroke prevention in atrial fibrillation and are now reimbursed under a national guideline for their safe use. They have advantages in that they do not need monitoring and have a fast onset and offset of action, but lack an established specific antidote. This survey addresses the role of modern anticoagulation for stroke prevention in atrial fibrillation. TI - The new oral anticoagulants in atrial fibrillation: an update EP - 484 SN - 1568-5888 IS - iss. 11 SP - 480 JF - Netherlands Heart Journal VL - vol. 21 DO - https://doi.org/10.1007/s12471-013-0473-0 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/126143/126143.pdf?sequence=1 ER - TY - BOOK AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/119752 PB - [S.l. : s.n.] TI - Plaatjes remmen is goed, ontstollen is beter PS - 13 p. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/119752/119752.pdf?sequence=1 ER - TY - JOUR AU - Kakkar, A.K. AU - Mueller, I. AU - Bassand, J.P. AU - Fitzmaurice, D.A. AU - Goldhaber, S.Z. AU - Goto, S. AU - Haas, S. AU - Hacke, W. AU - Lip, G.Y. AU - Mantovani, L.G. AU - Turpie, A.G.G. AU - Eickels, M. van AU - Misselwitz, F. AU - Rushton-Smith, S. AU - Kayani, G. AU - Wilkinson, P. AU - Verheugt, F.W.A. AU - et al. PY - 2013 UR - https://hdl.handle.net/2066/119188 AB - BACKGROUND: Limited data are available on the characteristics, clinical management, and outcomes of patients with atrial fibrillation at risk of stroke, from a worldwide perspective. The aim of this study was to describe the baseline characteristics and initial therapeutic management of patients with non-valvular atrial fibrillation across the spectrum of sites at which these patients are treated. METHODS AND FINDINGS: The Global Anticoagulant Registry in the FIELD (GARFIELD) is an observational study of patients newly diagnosed with non-valvular atrial fibrillation. Enrollment into Cohort 1 (of 5) took place between December 2009 and October 2011 at 540 sites in 19 countries in Europe, Asia-Pacific, Central/South America, and Canada. Investigator sites are representative of the distribution of atrial fibrillation care settings in each country. Cohort 1 comprised 10,614 adults (>/=18 years) diagnosed with non-valvular atrial fibrillation within the previous 6 weeks, with >/=1 investigator-defined stroke risk factor (not limited to those in existing risk-stratification schemes), and regardless of therapy. Data collected at baseline included demographics, medical history, care setting, nature of atrial fibrillation, and treatments initiated at diagnosis. The mean (SD) age of the population was 70.2 (11.2) years; 43.2% were women. Mean+/-SD CHADS2 score was 1.9+/-1.2, and 57.2% had a score >/=2. Mean CHA2DS2-VASc score was 3.2+/-1.6, and 8,957 (84.4%) had a score >/=2. Overall, 38.0% of patients with a CHADS2 score >/=2 did not receive anticoagulant therapy, whereas 42.5% of those at low risk (score 0) received anticoagulant therapy. CONCLUSIONS: These contemporary observational worldwide data on non-valvular atrial fibrillation, collected at the end of the vitamin K antagonist-only era, indicate that these drugs are frequently not being used according to stroke risk scores and guidelines, with overuse in patients at low risk and underuse in those at high risk of stroke. TRIAL REGISTRATION: ClinicalTrials.gov TRI08888. TI - Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry SN - 1932-6203 IS - iss. 5 JF - PLoS One VL - vol. 8 DO - https://doi.org/10.1371/journal.pone.0063479 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/119188/119188.pdf?sequence=1 ER - TY - JOUR AU - Jaspers Focks, J. AU - Brouwer, M.A. AU - Oijen, M.G.H. van AU - Lanas, A. AU - Bhatt, D.L. AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/119251 AB - BACKGROUND: Clopidogrel as an adjunct to aspirin has improved outcomes after acute coronary syndromes, but laboratory studies suggest a reduced antiplatelet effect when proton pump inhibitors (PPIs) are co-administered. Despite corroborating data from retrospective studies, new clinical data fuel the controversy on this issue. PURPOSE: Systematic review of the impact of the addition of PPIs to clopidogrel on platelet function and cardiovascular outcome. DATA SOURCES: PubMed, Web-of-Science, Cochrane Database and reference lists of related articles. STUDY SELECTION: Published articles on controlled studies addressing the addition of PPIs to clopidogrel. Platelet function studies describe patients as well as healthy volunteers. Clinical studies concern patients using clopidogrel for acute coronary syndromes or because of stent implantation for stable coronary disease. DATA EXTRACTION: Two investigators independently reviewed the identified articles for eligibility, and one author extracted the data. DATA SYNTHESIS: In 70% (7/10) of the laboratory studies examining healthy volunteers on clopidogrel, addition of PPIs resulted in a significant reduction in platelet inhibition. For patients, this was observed in 11/18 (61%) studies. The 33 clinical studies showed significant heterogeneity in observed outcomes, with risk ratios for major adverse cardiovascular events varying from 0.64 to 4.58 in the case of PPI use, which was randomly allocated in only two studies. Consequently, imbalances between prognosticators at baseline and PPI prescription bias markedly contributed to the variability in results. CONCLUSIONS: Despite indications of reduced antiplatelet activity ex vivo in the case of PPI administration in clopidogrel users, data on the clinical consequences are controversial. With the accumulating evidence from better designed, prospective clinical studies, an adverse effect of PPI use on clinical outcome in patients on clopidogrel cannot be substantiated. This review challenges the validity of conclusions based on quantitative analyses of predominantly non-randomised data. TI - Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review EP - 527 SN - 1355-6037 IS - iss. 8 SP - 520 JF - Heart VL - vol. 99 DO - https://doi.org/10.1136/heartjnl-2012-302371 ER - TY - JOUR AU - Brouwer, M.A. AU - Jaspers Focks, J. AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/119296 AB - Despite dual antiplatelet therapy (DAPT), one-year event rates after acute coronary syndrome (ACS) vary from 9-12%. The development of novel oral anticoagulants (NOAC) without a need for monitoring has initiated renewed interest for prolonged adjunctive anticoagulation. Importantly, the cornerstone of treatment after ACS consists of long-term DAPT. In that context, the NOACs have only been tested as adjunctive therapy. Of all new agents, only rivaroxaban -in a substantially lower dose than used for atrial fibrillation- has been demonstrated to improve outcome, albeit at the cost of bleeding. In selected cases, adjunctive therapy with dose-adjusted vitamin-K antagonists (international normalized ratio [INR] 2.0-3.0) can be considered as well. These two strategies of prolonged anticoagulation can be considered in case of 'high platelet reactivity', i.e. in patients at high risk of recurrent thrombotic events despite DAPT. Both during admission and after discharge for ACS, the use of NOACs in doses indicated for atrial fibrillation is strictly contra-indicated in patients on DAPT. In case of post-discharge anticoagulation therapy for atrial fibrillation, patients should preferably receive vitamin-K antagonists (INR 2.0-3.0), with discontinuation of one antiplatelet agent as soon as clinically justifiable. Importantly, the impact of prolonged anticoagulation (low-dose rivaroxaban, vitamin-K antagonists) as adjunctive to DAPT after ACS has not been addressed with the most potent antiplatelet agents (prasugrel, ticagrelor) and merits further study. Despite the potential indication of prolonged oral anticoagulation as adjunctive treatment, it remains to be established whether anticoagulation therapy could also be an alternative for either aspirin or thienopyridine treatment in selected ACS patients on DAPT. TI - High platelet reactivity--the challenge of prolonged anticoagulation therapy after ACS EP - 807 SN - 0340-6245 IS - iss. 5 SP - 799 JF - Thrombosis and Haemostasis VL - vol. 109 DO - https://doi.org/10.1160/TH12-08-0582 ER - TY - JOUR AU - Jaspers Focks, J. AU - Schaik, A. van AU - Clappers, N. AU - Dijk, E.G.J.A. van AU - Oijen, M.G.H. van AU - Verheugt, F.W.A. AU - Peters, W.H.M. PY - 2013 UR - https://hdl.handle.net/2066/125254 AB - Abstract Background: The aminothiols homocysteine and, to a lesser extent, cysteine have been associated with adverse cardiovascular outcome, whereas glutathione, as an antioxidant, may protect against atherosclerosis and thrombosis. Potentially, the combined assessment of these aminothiols may provide a more accurate association with future cardiovascular outcome. We evaluated the association between recurrent atherothrombotic events and the concentration of total plasma cysteine, homocysteine, and glutathione and their combination. Methods: Respective aminothiols were measured by high-performance liquid chromatography in blood plasma of consecutive first-day survivors admitted for an acute coronary syndrome between April 2002 and January 2004. The combined score was calculated using the combination of the individual aminothiols. The end point was the composite of cardiovascular death, myocardial infarction, and/or stroke. Results: A cohort of 375 consecutive patients (median age 66 years, 66% male) were followed for a median duration of 2.7 years. The end point occurred in 82 patients (22%). In univariate analyses, all aminothiols were significantly associated with the composite end point. After correction for possible confounders, only cysteine and glutathione remained significantly associated. The strongest association with the end point was observed for the combined score (adjusted hazard ratio, 1.40 per standard deviation increase; p=0.005). Conclusions: Although homocysteine is generally considered the aminothiol of interest with respect to cardiovascular disease, in our prospective study, only cysteine and glutathione appeared independently associated with recurrent atherothrombotic events. Moreover, we showed that an imbalance in the combination of aminothiols could be of more importance than investigating the individual metabolites. TI - Assessment of plasma aminothiol levels and the association with recurrent atherothrombotic events in patients hospitalized for an acute coronary syndrome: a prospective study EP - 2193 SN - 1434-6621 IS - iss. 11 SP - 2187 JF - Clinical Chemistry and Laboratory Medicine VL - vol. 51 DO - https://doi.org/10.1515/cclm-2013-0103 ER - TY - JOUR AU - Brouwer, M.A. AU - Jaspers Focks, J. AU - Verheugt, F.W. PY - 2013 UR - https://hdl.handle.net/2066/119156 TI - Novel antithrombotic challenges: head, heart, and guts EP - 1164 SN - 0016-5085 IS - iss. 5 SP - 1163 JF - Gastroenterology VL - vol. 145 DO - https://doi.org/10.1053/j.gastro.2013.09.043 ER - TY - JOUR AU - Cramer, G.E. AU - Brouwer, M.A. AU - Vader, H.L. AU - Boer, M.J. de AU - Pop, G.A.M. AU - Pop, V.J.M. AU - Verheugt, F.W.A. PY - 2013 UR - https://hdl.handle.net/2066/119298 AB - OBJECTIVE: To assess the association between baseline levels of highly sensitive cardiac troponin T (hs-cTnT) and long-term mortality in perimenopausal women of the general community using a gender specific 99th percentile reference limit. DESIGN: Nested case control. SETTING: The present study was conducted within the Eindhoven Perimenopausal Osteoporosis Study which is a large prospective cohort of 8503 community-derived women of the city of Eindhoven, The Netherlands. PARTICIPANTS: Cases were defined as Eindhoven Perimenopausal Osteoporosis Study participants who provided an adequate baseline blood sample and subsequently experienced death during follow-up between 1994 and 2003. In total, 123 cases were identified. For each case two matched controls were selected using age, body mass index and hypertension as matching factors. The gender specific 99th percentile reference limit determined in the 246 controls was 8.0 ng/l. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: Hs-cTnT was significantly higher in the cases: 3.0 ng/l versus 2.3 ng/l (p=0.04). After adjustment for matching and clinical risk factors, each 1 SD increase of the level of hs-cTnT was significantly associated with mortality (OR 1.3, 95% CI 1.1 to 1.7, p=0.018). With amino-terminal pro-B-type natriuretic peptide (NT-proBNP) in the multivariable model as a continuous variable the association of hs-cTnT with mortality was lost. With both hs-cTnT and NT-proBNP as dichotomous variables, the gender specific 99th percentile reference limit (8.0 ng/l) was associated with mortality, independent of NT-proBNP (OR 3.7, 95% CI 1.0 to 13.2, p=0.048). CONCLUSIONS: In this study of community-derived perimenopausal women, hs-cTnT was associated with long-term mortality, independent of clinical risk factors. With the use of easily applicable cut-off levels, the gender specific reference limit of hs-cTnT had a prognostic impact that was independent of NT-proBNP. TI - Highly sensitive cardiac troponin T and long-term mortality in a population of community-derived perimenopausal women: nested case-control study EP - 533 SN - 1355-6037 IS - iss. 8 SP - 528 JF - Heart VL - vol. 99 DO - https://doi.org/10.1136/heartjnl-2012-302829 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2012 UR - https://hdl.handle.net/2066/108936 TI - Outcomes of positive randomised controlled clinical trials: Double-blind or double vision? Editorial on Serebruany, Atar: 'Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials -Common patterns in TRITON, RECORD, and PLATO?' (Thromb Haemost 2012; 108.3). EP - 411 SN - 0340-6245 IS - iss. 3 SP - 410 JF - Thrombosis and Haemostasis VL - vol. 108 DO - http://dx.doi.org/10.1160/TH12-06-0435 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2012 UR - https://hdl.handle.net/2066/109514 AB - Vitamin K antagonists have been used as oral anticoagulants (OACs) for over five decades, yet their use in real-world practice is problematic primarily because of their narrow therapeutic window, exacerbated by extensive food and drug interactions, necessitating regular coagulation monitoring and dose adjustment. Around half of patients receiving warfarin are within the therapeutic range, exposing them to the dangers of under-anticoagulation (i.e. thrombosis formation) or over-anticoagulation (i.e. bleeding). A new generation of OACs with improved pharmacology promises to revolutionize antithrombotic management. Rivaroxaban, apixaban (both oral direct Factor Xa inhibitors) and dabigatran (a direct thrombin inhibitor) all exhibit predictable anticoagulant responses and few drug-drug interactions and do not require routine coagulation monitoring. TI - Anticoagulant management in the cardiovascular setting. EP - 15 SN - 0767-3981 IS - iss. 1 SP - 11 JF - Fundamental & Clinical Pharmacology VL - vol. 26 N1 - 1 februari 2012 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2012 UR - https://hdl.handle.net/2066/109569 AB - Patients with congestive heart failure have a significant risk of stroke due to thromboembolism from the dilated left ventricle. Two relatively small trials suggest that oral anticoagulation with vitamin-K antagonists may reduce this risk when compared with placebo, aspirin or clopidogrel. However, more studies are eagerly awaited. So far, physicians seeing patients with heart failure should decide who needs antithrombotic prophylaxis on a case-by-case basis, especially since most heart failure patients have significant comorbidity precluding the use of oral anticoagulant. TI - Antithrombotic therapy in heart failure. EP - 178 SN - 1568-5888 IS - iss. 4 SP - 176 JF - Netherlands Heart Journal VL - vol. 20 N1 - 1 april 2012 DO - http://dx.doi.org/10.1007/s12471-012-0250-5 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2012 UR - https://hdl.handle.net/2066/110062 TI - Triple antithrombotic therapy after coronary stenting in the elderly with atrial fibrillation: necessary or too hazardous? EP - 534 SN - 0002-8703 IS - iss. 4 SP - 531 JF - American Heart Journal VL - vol. 163 N1 - 1 april 2012 DO - http://dx.doi.org/10.1016/j.ahj.2012.01.018 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2012 UR - https://hdl.handle.net/2066/110383 TI - Beware of novel antiplatelet therapy in acute coronary syndrome patients with previous stroke. EP - 2823 SN - 0009-7322 IS - iss. 23 SP - 2821 JF - Circulation VL - vol. 125 DO - http://dx.doi.org/10.1161/CIRCULATIONAHA.112.111930 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2012 UR - https://hdl.handle.net/2066/110958 TI - Don't forget the intervention in very elderly persons with acute coronary syndromes EP - 918 SN - 1936-8798 IS - iss. 9 SP - 917 JF - Jacc. Cardiovascular Interventions VL - vol. 5 DO - http://dx.doi.org/10.1016/j.jcin.2012.07.003 ER - TY - JOUR AU - Camm, A.J. AU - Lip, G.Y. AU - Caterina, R. de AU - Savelieva, I. AU - Atar, D. AU - Hohnloser, S.H. AU - Hindricks, G. AU - Kirchhof, P. AU - Verheugt, F.W.A. AU - et al. PY - 2012 UR - https://hdl.handle.net/2066/108369 TI - 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association EP - 1413 SN - 1099-5129 IS - iss. 10 SP - 1385 JF - Europace VL - vol. 14 DO - http://dx.doi.org/10.1093/europace/eus305 ER - TY - JOUR AU - van Heerebeek, L. AU - Franssen, C.P. AU - Hamdani, N. AU - Verheugt, F.W.A. AU - Somsen, G.A. AU - Paulus, W.J. PY - 2012 UR - https://hdl.handle.net/2066/108710 AB - Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and is frequently associated with metabolic risk factors. Patients with HFpEF have only a slightly lower mortality than patients with HF and reduced EF. The pathophysiology of HFpEF is currently incompletely understood, which precludes specific therapy. Both HF phenotypes demonstrate distinct cardiac remodeling processes at the macroscopic, microscopic, and ultrastructural levels. Increased diastolic left-ventricular (LV) stiffness and impaired LV relaxation are important features of HFpEF, which can be explained by changes in the extracellular matrix and the cardiomyocytes. In HFpEF, elevated intrinsic cardiomyocyte stiffness contributes to high diastolic LV stiffness. Posttranslational changes in the sarcomeric protein titin, affecting titin isoform expression and phosphorylation, contribute to elevated cardiomyocyte stiffness. Increased nitrosative/oxidative stress, impaired nitric oxide bioavailability, and down-regulation of myocardial cyclic guanosine monophosphate and protein kinase G signaling could trigger posttranslational modifications of titin, thereby augmenting cardiomyocyte and LV diastolic stiffness. TI - Molecular and cellular basis for diastolic dysfunction EP - 302 SN - 1546-9549 IS - iss. 4 SP - 293 JF - Current Heart Failure Reports VL - vol. 9 ER - TY - JOUR AU - Heerebeek, L. van AU - Hamdani, N. AU - Falcao-Pires, I. AU - Leite-Moreira, A.F. AU - Begieneman, M.P. AU - Bronzwaer, J.G.F. AU - Velden, J. Van der AU - Stienen, G.J. AU - Laarman, G.J. AU - Somsen, A. AU - Verheugt, F.W.A. AU - Niessen, H.W.M. AU - Paulus, W.J. PY - 2012 UR - https://hdl.handle.net/2066/108567 AB - BACKGROUND: Prominent features of myocardial remodeling in heart failure with preserved ejection fraction (HFPEF) are high cardiomyocyte resting tension (F(passive)) and cardiomyocyte hypertrophy. In experimental models, both reacted favorably to raised protein kinase G (PKG) activity. The present study assessed myocardial PKG activity, its downstream effects on cardiomyocyte F(passive) and cardiomyocyte diameter, and its upstream control by cyclic guanosine monophosphate (cGMP), nitrosative/oxidative stress, and brain natriuretic peptide (BNP). To discern altered control of myocardial remodeling by PKG, HFPEF was compared with aortic stenosis and HF with reduced EF (HFREF). METHODS AND RESULTS: Patients with HFPEF (n=36), AS (n=67), and HFREF (n=43) were free of coronary artery disease. More HFPEF patients were obese (P<0.05) or had diabetes mellitus (P<0.05). Left ventricular myocardial biopsies were procured transvascularly in HFPEF and HFREF and perioperatively in aortic stenosis. F(passive) was measured in cardiomyocytes before and after PKG administration. Myocardial homogenates were used for assessment of PKG activity, cGMP concentration, proBNP-108 expression, and nitrotyrosine expression, a measure of nitrosative/oxidative stress. Additional quantitative immunohistochemical analysis was performed for PKG activity and nitrotyrosine expression. Lower PKG activity in HFPEF than in aortic stenosis (P<0.01) or HFREF (P<0.001) was associated with higher cardiomyocyte F(passive) (P<0.001) and related to lower cGMP concentration (P<0.001) and higher nitrosative/oxidative stress (P<0.05). Higher F(passive) in HFPEF was corrected by in vitro PKG administration. CONCLUSIONS: Low myocardial PKG activity in HFPEF was associated with raised cardiomyocyte F(passive) and was related to increased myocardial nitrosative/oxidative stress. The latter was probably induced by the high prevalence in HFPEF of metabolic comorbidities. Correction of myocardial PKG activity could be a target for specific HFPEF treatment. TI - Low myocardial protein kinase g activity in heart failure with preserved ejection fraction. EP - 839 SN - 0009-7322 IS - iss. 7 SP - 830 JF - Circulation VL - vol. 126 DO - https://doi.org/10.1161/CIRCULATIONAHA.111.076075 ER - TY - JOUR AU - Caterina, R. de AU - Husted, S. AU - Wallentin, L. AU - Andreotti, F. AU - Arnesen, H. AU - Bachmann, F. AU - Baigent, C. AU - Huber, K. AU - Jespersen, J. AU - Kristensen, S.D. AU - Lip, G.Y. AU - Morais, J. AU - Rasmussen, L.H. AU - Siegbahn, A. AU - Verheugt, F.W.A. AU - Weitz, J.I. PY - 2012 UR - https://hdl.handle.net/2066/108831 AB - Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fixed doses without coagulation monitoring. Here we review the pharmacology and the results of clinical trials with these new agents in stroke prevention in atrial fibrillation and secondary prevention after acute coronary syndromes, providing perspectives on their future incorporation into clinical practice. In phase III trials in atrial fibrillation, compared with warfarin, dabigatran etexilate 150 mg B.I.D. reduced the rates of stroke/systemic embolism without any difference in major bleeding; dabigatran etexilate 110 mg B.I.D. had similar efficacy with decreased bleeding; apixaban 5 mg B.I.D. reduced stroke, systemic embolism, and mortality as well as major bleeding; and rivaroxaban 20 mg Q.D. was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding. All these agents reduced intracranial hemorrhage. Edoxaban is currently being evaluated in a further large phase III trial. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischemia in patients with acute coronary syndromes who were mostly receiving dual antiplatelet therapy, with conflicting results on efficacy but consistent results for increased major bleeding. Overall, the new oral anticoagulants are poised to replace vitamin K antagonists for many patients with atrial fibrillation and may have a role after acute coronary syndromes. Although convenient to administer and manage, they present challenges that need to be addressed. TI - New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease position paper. EP - 1425 SN - 0735-1097 IS - iss. 16 SP - 1413 JF - Journal of the American College of Cardiology VL - vol. 59 DO - https://doi.org/10.1016/j.jacc.2012.02.008 ER - TY - JOUR AU - Berndt, N. AU - Bolman, C. AU - Mudde, A. AU - Verheugt, F.W. AU - Vries, H. de AU - Lechner, L. PY - 2012 UR - https://hdl.handle.net/2066/109419 AB - OBJECTIVES: We sought to identify risk groups among smoking cardiac patients from their social cognitive profiles, and to assess predictors of smoking abstinence shortly after discharge. METHODS: Smoking cardiac patients (n = 133) completed questionnaires at hospital admission and 1 month after discharge. Hierarchical cluster analysis was used to detect risk groups of smokers, based on baseline scores for smoking-related social cognitions. Regression analyses were used to identify predictors of the intention to abstain from smoking and smoking abstinence 1 month after discharge. RESULTS: Three groups of smokers were distinguished that differed significantly on the pros of nonsmoking, self-efficacy expectancies toward nonsmoking, social support, social modeling, and smoking behavior. Abstinence from smoking 1 month after discharge was predicted by group membership and a stronger intention to quit. A previous hospital admission because of a cardiac event significantly decreased the likelihood of abstinence. CONCLUSIONS: One third of cardiac patients are at high risk of continuing smoking after hospital discharge because of an unfavorable smoking and disease history and a poor social cognitive profile. Interventions for cardiac patients should address risk profiles to achieve long-term abstinence. The implications of nursing practices in smoking cessation treatments are discussed. TI - Risk groups and predictors of short-term abstinence from smoking in patients with coronary heart disease. EP - 343 SN - 0147-9563 IS - iss. 4 SP - 332 JF - Heart & Lung VL - vol. 41 DO - https://doi.org/10.1016/j.hrtlng.2012.03.001 ER - TY - JOUR AU - Mega, J.L. AU - Braunwald, E. AU - Wiviott, S.D. AU - Bassand, J.P. AU - Bhatt, D.L. AU - Bode, C. AU - Burton, P. AU - Cohen, M. AU - Cook-Bruns, N. AU - Fox, K.A. AU - Goto, S. AU - Murphy, S.A. AU - Plotnikov, A.N. AU - Schneider, D. AU - Sun, X. AU - Verheugt, F.W.A. AU - Gibson, C.M. PY - 2012 UR - https://hdl.handle.net/2066/109424 AB - BACKGROUND: Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. RESULTS: Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). CONCLUSIONS: In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.). TI - Rivaroxaban in patients with a recent acute coronary syndrome. EP - 19 SN - 0028-4793 IS - iss. 1 SP - 9 JF - The New England Journal of Medicine VL - vol. 366 DO - https://doi.org/10.1056/NEJMoa1112277 ER - TY - JOUR AU - Camm, A.J. AU - Lip, G.Y. AU - Caterina, R. de AU - Savelieva, I. AU - Atar, D. AU - Hohnloser, S.H. AU - Hindricks, G. AU - Kirchhof, P. AU - Bax, J.J. AU - Baumgartner, H. AU - Ceconi, C. AU - Dean, V. AU - Deaton, C. AU - Fagard, R. AU - Funck-Brentano, C. AU - Hasdai, D. AU - Hoes, A. AU - Knuuti, J. AU - Kolh, P. AU - McDonagh, T. AU - Moulin, C. AU - Popescu, B.A. AU - Reiner, Z. AU - Sechtem, U. AU - Sirnes, P.A. AU - Tendera, M. AU - Torbicki, A. AU - Vahanian, A. AU - Windecker, S. AU - Vardas, P. AU - Al-Attar, N. AU - Alfieri, O. AU - Angelini, A. AU - Blomstrom-Lundqvist, C. AU - Colonna, P. AU - De Sutter, J. AU - Ernst, S. AU - Goette, A. AU - Gorenek, B. AU - Hatala, R. AU - Heidbuchel, H. AU - Heldal, M. AU - Kristensen, S.D. AU - Le Heuzey, J.Y. AU - Mavrakis, H. AU - Mont, L. AU - Filardi, P.P. AU - Ponikowski, P. AU - Prendergast, B. AU - Rutten, F.H. AU - Schotten, U. AU - Van Gelder, I.C. AU - Verheugt, F.W.A. PY - 2012 UR - https://hdl.handle.net/2066/108258 TI - 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: An update of the 2010 ESC Guidelines for the management of atrial fibrillation * Developed with the special contribution of the European Heart Rhythm Association EP - 2747 SN - 0195-668X IS - iss. 21 SP - 2719 JF - European Heart Journal VL - vol. 33 DO - https://doi.org/10.1093/eurheartj/ehs253 ER - TY - JOUR AU - Werf, F. van de AU - Ardissino, D. AU - Bueno, H. AU - Collet, J.P. AU - Gershlick, A. AU - Kolh, P. AU - Kristensen, S.D. AU - Silber, S. AU - Verheugt, F.W. AU - Wojakowski, W. PY - 2012 UR - https://hdl.handle.net/2066/108481 AB - The management of acute coronary syndrome in Europe is covered by various European Society of Cardiology guidelines, which although valuable, are complex and may not always provide clear guidance in everyday clinical practice. Consequently, implementation of the guideline recommendations is frequently suboptimal. To complicate matters further, a wealth of new data from large trials examining novel anti-thrombotic agents will become or are already available, necessitating guideline updates. This article summarizes the gaps between current guideline-recommended treatment of acute coronary syndrome and daily practice as dictated by the evidence base, including recent trials. Reasons for the suboptimal implementation of the current European Society of Cardiology guidelines and possible solutions to making these more practice oriented are presented. TI - Acute coronary syndromes: considerations for improved acceptance and implementation of management guidelines. EP - 503 SN - 1477-9072 IS - iss. 4 SP - 489 JF - Expert Review of Cardiovascular Therapy VL - vol. 10 N1 - 1 april 2012 ER - TY - JOUR AU - Steg, P.G. AU - James, S.K. AU - Atar, D. AU - Badano, L.P. AU - Blomstrom-Lundqvist, C. AU - Borger, M.A. AU - Di Mario, C. AU - Dickstein, K. AU - Ducrocq, G. AU - Fernandez-Aviles, F. AU - Gershlick, A.H. AU - Giannuzzi, P. AU - Halvorsen, S. AU - Huber, K. AU - Juni, P. AU - Kastrati, A. AU - Knuuti, J. AU - Lenzen, M.J. AU - Mahaffey, K.W. AU - Valgimigli, M. AU - van 't Hof, A. AU - Widimsky, P. AU - Zahger, D. AU - Verheugt, F.W. AU - et al. PY - 2012 UR - https://hdl.handle.net/2066/111002 TI - ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation EP - 2619 SN - 0195-668X IS - iss. 20 SP - 2569 JF - European Heart Journal VL - vol. 33 DO - https://doi.org/10.1093/eurheartj/ehs215 ER - TY - JOUR AU - Camenzind, E. AU - Wijns, W. AU - Mauri, L. AU - Kurowski, V. AU - Parikh, K. AU - Gao, R. AU - Bode, C. AU - Greenwood, J.P. AU - Boersma, E. AU - Vranckx, P. AU - McFadden, E. AU - Serruys, P.W. AU - O'Neil, W.W. AU - Jorissen, B. AU - Leeuwen, F van AU - Steg, P.G. AU - Verheugt, F.W. AU - et al. PY - 2012 UR - https://hdl.handle.net/2066/109599 AB - BACKGROUND: We sought to compare the long-term safety of two devices with different antiproliferative properties: the Endeavor zotarolimus-eluting stent (E-ZES; Medtronic, Inc) and the Cypher sirolimus-eluting stent (C-SES; Cordis, Johnson & Johnson) in a broad group of patients and lesions. METHODS: Between May 21, 2007 and Dec 22, 2008, we recruited 8791 patients from 36 recruiting countries to participate in this open-label, multicentre, randomised, superiority trial. Eligible patients were those aged 18 years or older undergoing elective, unplanned, or emergency procedures in native coronary arteries. Patients were randomly assigned to either receive E-ZES and C-SES (ratio 1:1). Randomisation was stratified per centre with varying block sizes of four, six, or eight patients, and concealed with a central telephone-based or web-based allocation service. The primary outcome was definite or probable stent thrombosis at 3 years and was analysed by intention to treat. Patients and investigators were aware of treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT00476957. FINDINGS: PROTECT randomised 8791 patients, of whom 8709 provided consent to participate and were eligible: 4357 were allocated to the E-ZES group and 4352 patients to the C-SES group. At 3 years, rates of definite or probable stent thrombosis did not differ between groups (1.4% for E-ZES [predicted: 1.5%] vs 1.8% [predicted: 2.5%] for C-SES; hazard ratio [HR] 0.81, 95% CI 0.58-1.14, p=0.22). Dual antiplatelet therapy was used in 8402 (96%) patients at discharge, 7456 (88%) at 1 year, 3041 (37%) at 2 years, and 2364 (30%) at 3 years. INTERPRETATION: No evidence of superiority of E-ZES compared with C-SES in definite or probable stent thrombosis rates was noted at 3 years. Time analysis suggests a difference in definite or probable stent thrombosis between groups is emerging over time, and a longer follow-up is therefore needed given the clinical relevance of stent thrombosis. FUNDING: Medtronic, Inc. TI - Stent thrombosis and major clinical events at 3 years after zotarolimus-eluting or sirolimus-eluting coronary stent implantation: a randomised, multicentre, open-label, controlled trial EP - 1405 SN - 0140-6736 IS - iss. 9851 SP - 1396 JF - The Lancet (London) VL - vol. 380 DO - https://doi.org/10.1016/S0140-6736(12)61336-1 ER - TY - JOUR AU - Easton, J.D. AU - Lopes, R.D. AU - Bahit, M.C. AU - Wojdyla, D.M. AU - Granger, C.B. AU - Wallentin, L. AU - Alings, M. AU - Goto, S. AU - Lewis, B.S. AU - Rosenqvist, M. AU - Hanna, M. AU - Mohan, P. AU - Alexander, J.H. AU - Diener, H.C. AU - Verheugt, F.W. AU - et al. PY - 2012 UR - https://hdl.handle.net/2066/109625 AB - BACKGROUND: In the ARISTOTLE trial, the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation (AF). Patients with AF and previous stroke or transient ischaemic attack (TIA) have a high risk of stroke. We therefore aimed to assess the efficacy and safety of apixaban compared with warfarin in prespecified subgroups of patients with and without previous stroke or TIA. METHODS: Between Dec 19, 2006, and April 2, 2010, patients were enrolled in the ARISTOTLE trial at 1034 clinical sites in 39 countries. 18,201 patients with AF or atrial flutter were randomly assigned to receive apixaban 5 mg twice daily or warfarin (target international normalised ratio 2.0-3.0). The median duration of follow-up was 1.8 years (IQR 1.4-2.3). The primary efficacy outcome was stroke or systemic embolism, analysed by intention to treat. The primary safety outcome was major bleeding in the on-treatment population. All participants, investigators, and sponsors were masked to treatment assignments. In this subgroup analysis, we estimated event rates and used Cox models to compare outcomes in patients with and without previous stroke or TIA. The ARISTOTLE trial is registered with ClinicalTrials.gov, number NTC00412984. FINDINGS: Of the trial population, 3436 (19%) had a previous stroke or TIA. In the subgroup of patients with previous stroke or TIA, the rate of stroke or systemic embolism was 2.46 per 100 patient-years of follow-up in the apixaban group and 3.24 in the warfarin group (hazard ratio [HR] 0.76, 95% CI 0.56 to 1.03); in the subgroup of patients without previous stroke or TIA, the rate of stroke or systemic embolism was 1.01 per 100 patient-years of follow-up with apixaban and 1.23 with warfarin (HR 0.82, 95% CI 0.65 to 1.03; p for interaction=0.71). The absolute reduction in the rate of stroke and systemic embolism with apixaban versus warfarin was 0.77 per 100 patient-years of follow-up (95% CI -0.08 to 1.63) in patients with and 0.22 (-0.03 to 0.47) in those without previous stroke or TIA. The difference in major bleeding with apixaban compared with warfarin was 1.07 per 100 patient-years (95% CI 0.09-2.04) in patients with and 0.93 (0.54-1.32) in those without previous stroke or TIA. INTERPRETATION: The effects of apixaban versus warfarin were consistent in patients with AF with and without previous stroke or TIA. Owing to the higher risk of these outcomes in patients with previous stroke or TIA, the absolute benefits of apixaban might be greater in this population. FUNDING: Bristol-Myers Squibb and Pfizer. TI - Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. EP - 511 SN - 1474-4422 IS - iss. 6 SP - 503 JF - Lancet Neurology VL - vol. 11 N1 - 1 juni 2012 DO - https://doi.org/10.1016/S1474-4422(12)70092-3 ER - TY - JOUR AU - Hamon, M. AU - Rao, S.V. AU - Steg, G. AU - Valgimigli, M. AU - Verheugt, F.W. AU - Marso, S. AU - Gershlick, A. AU - Wang, Y. AU - Deliargyris, E. PY - 2012 UR - https://hdl.handle.net/2066/110406 AB - Aims: Fondaparinux is an indirect, Factor Xa inhibitor that requires co-administration of another anticoagulant with anti-Factor IIa activity for percutaneous coronary intervention (PCI) per guideline recommendations. In this setting, the use of bivalirudin, a direct Factor IIa inhibitor, is not well established. Methods and results: Using the Premier hospital database, we identified 971 patients who underwent elective or urgent PCI after receiving fondaparinux as the initial anticoagulant. They were treated with either bivalirudin +/- glycoprotein IIb/IIIa inhibitor (GPI) (Group A=618) or unfractionated heparin (UFH) +/- GPI (Group B=353) during PCI. A 2:1 propensity score matching (PSM) process was performed to control for patient and hospital level characteristics. The primary endpoints were to determine in-hospital death, bleeding and post-PCI length of stay (LOS) between treatment groups. After PSM, 512 matched patients were analysed (Group A=348 and Group B=174). In-hospital death was 1.4% in Group A vs. 2.9% in Group B (p=0.26). Clinically apparent bleeding occurred in 4.0% of Group A vs. 9.2% of Group B patients (p<0.02). Clinically apparent bleeding requiring transfusion was lower in Group A patients (0.6% vs. 2.9%; p=0.04). Post-PCI LOS was 1.9+/-3.8 days for Group A and 2.4+/-5.8 days for Group B (p=0.36). GPI use during PCI occurred in 9.2% of Group A vs. 44.8% of Group B patients (p<0.0001). Conclusions: After initial administration of fondaparinux, a bivalirudin-based strategy for PCI is associated with significantly reduced bleeding, with similar mortality and post-PCI LOS when compared with an UFH-based strategy. TI - Bivalirudin versus unfractionated heparin in percutaneous coronary interventions of patients having received initial fondaparinux treatment: a propensity matched study. EP - 492 SN - 1774-024X IS - iss. 4 SP - 486 JF - Eurointervention VL - vol. 8 DO - https://doi.org/10.4244/EIJV8I4A76 ER - TY - JOUR AU - Kakkar, A.K. AU - Mueller, I. AU - Bassand, J.P. AU - Fitzmaurice, D.A. AU - Goldhaber, S.Z. AU - Goto, S. AU - Haas, S. AU - Hacke, W. AU - Lip, G.Y. AU - Mantovani, L.G. AU - Verheugt, F.W.A. AU - Jamal, W. AU - Misselwitz, F. AU - Rushton-Smith, S. AU - Turpie, A.G.G. PY - 2012 UR - https://hdl.handle.net/2066/108402 AB - BACKGROUND: Atrial fibrillation (AF) is associated with high rates of morbidity and mortality. Patients with AF carry a fivefold increased risk of stroke and the risk of death from AF-related stroke is doubled. Current management is often inadequate, leaving patients at risk for a potentially fatal or disabling event. The purpose of the GARFIELD registry is to evaluate the management and outcomes of patients with newly diagnosed non-valvular AF at risk for stroke. DESIGN: The GARFIELD registry is an observational, multicenter, prospective study of patients with newly diagnosed AF and one or more additional risk factors for stroke. The aim is to enroll 55,000 patients at >1,000 centers in 50 countries. Enrollment will take place in five independent, sequential, prospective cohorts. An additional retrospective validation cohort of 5,000 patients with established AF and at least one additional risk factor for stroke will be conducted in parallel with cohort one. The study started in December 2009, with a planned recruitment period of 4 years and a minimum of 2-year follow-up for each patient. SUMMARY: The GARFIELD registry will provide valuable insights into the clinical management and related outcomes of AF patients throughout many regions of the world and across the spectrum of healthcare systems. By capturing data from unselected patients treated in everyday practice, the registry has the potential to identify best practices as well as deficiencies in available treatment options for specific patient populations and to describe how therapeutic strategies, patient care, and outcomes will evolve over time. TI - International longitudinal registry of patients with atrial fibrillation at risk of stroke: Global Anticoagulant Registry in the FIELD (GARFIELD). EP - 19.e1 SN - 0002-8703 IS - iss. 1 SP - 13 JF - American Heart Journal VL - vol. 163 N1 - 1 januari 2012 DO - https://doi.org/10.1016/j.ahj.2011.09.011 ER - TY - JOUR AU - Berndt, N. AU - Bolman, C. AU - Lechner, L. AU - Mudde, A. AU - Verheugt, F.W.A. AU - de Vries, H. PY - 2012 UR - https://hdl.handle.net/2066/111068 AB - BACKGROUND: There is no more effective intervention for secondary prevention of coronary heart disease than smoking cessation. Yet, evidence about the (cost-)effectiveness of smoking cessation treatment methods for cardiac inpatients that also suit nursing practice is scarce. This protocol describes the design of a study on the (cost-)effectiveness of two intensive smoking cessation interventions for hospitalised cardiac patients as well as first results on the inclusion rates and the characteristics of the study population. METHODS/DESIGN: An experimental study design is used in eight cardiac wards of hospitals throughout the Netherlands to assess the (cost-)effectiveness of two intensive smoking cessation counselling methods both combined with nicotine replacement therapy. Randomization is conducted at the ward level (cross-over). Baseline and follow-up measurements after six and 12 months are obtained. Upon admission to the cardiac ward, nurses assess patients' smoking behaviour, ensure a quit advice and subsequently refer patients for either telephone counselling or face-to-face counselling. The counselling interventions have a comparable structure and content but differ in provider and delivery method, and in duration. Both counselling interventions are compared with a control group receiving no additional treatment beyond the usual care. Between December 2009 and June 2011, 245 cardiac patients who smoked prior to hospitalisation were included in the usual care group, 223 in the telephone counselling group and 157 in the face-to-face counselling group. Patients are predominantly male and have a mean age of 57 years. Acute coronary syndrome is the most frequently reported admission diagnosis. The ultimate goal of the study is to assess the effects of the interventions on smoking abstinence and their cost-effectiveness. Telephone counselling is expected to be more (cost-)effective in highly motivated patients and patients with high SES, whereas face-to-face counselling is expected to be more (cost-)effective in less motivated patients and patients with low SES. DISCUSSION: This study examines two intensive smoking cessation interventions for cardiac patients using a multi-centre trial with eight cardiac wards. Although not all eligible patients could be included and the distribution of patients is skewed in the different groups, the results will be able to provide valuable insight into effects and costs of counselling interventions varying in delivery mode and intensity, also concerning subgroups. TRIAL REGISTRATION: Dutch Trial Register NTR2144. TI - Effectiveness of two intensive treatment methods for smoking cessation and relapse prevention in patients with coronary heart disease: study protocol and baseline description SN - 1471-2261 JF - BMC Cardiovascular Disorders VL - vol. 12 DO - https://doi.org/10.1186/1471-2261-12-33 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/111068/111068.pdf?sequence=1 ER - TY - JOUR AU - Loon, R.B. van AU - Veen, G. AU - Baur, L.H. AU - Kamp, O. AU - Bronzwaer, J.G.F. AU - Twisk, J.W.R. AU - Verheugt, F.W.A. AU - Rossum, A.C. van PY - 2012 UR - https://hdl.handle.net/2066/108268 AB - BACKGROUND: Patients with ST-elevation myocardial infarction (STEMI) not treated with primary or rescue percutaneous coronary intervention (PCI) are at risk for recurrent ischemia, especially when viability in the infarct-area is present. Therefore, an invasive strategy with PCI of the infarct-related coronary artery in patients with viability would reduce the occurrence of a composite end point of death, reinfarction, or unstable angina (UA). METHODS: Patients admitted with an (sub)acute myocardial infarction, who were not treated by primary or rescue PCI, and who were stable during the first 48 hours after the acute event, were screened for the study. Eventually, we randomly assigned 216 patients with viability (demonstrated with low-dose dobutamine echocardiography) to an invasive or a conservative strategy. In the invasive strategy stenting of the infarct-related coronary artery was intended with abciximab as adjunct treatment. Seventy-five (75) patients without viability served as registry group. The primary endpoint was the composite of death from any cause, recurrent myocardial infarction (MI) and unstable angina at one year. As secondary endpoint the need for (repeat) revascularization procedures and anginal status were recorded. RESULTS: The primary combined endpoint of death, recurrent MI and unstable angina was 7.5% (8/106) in the invasive group and 17.3% (19/110) in the conservative group (Hazard ratio 0.42; 95% confidence interval [CI] 0.18-0.96; p = 0.032). During follow up revascularization-procedures were performed in 6.6% (7/106) in the invasive group and 31.8% (35/110) in the conservative group (Hazard ratio 0.18; 95% CI 0.13-0.43; p < 0.0001). A low rate of recurrent ischemia was found in the non-viable group (5.4%) in comparison to the viable-conservative group (14.5%). (Hazard-ratio 0.35; 95% CI 0.17-1.00; p = 0.051). CONCLUSION: We demonstrated that after acute MI (treated with thrombolysis or without reperfusion therapy) patients with viability in the infarct-area benefit from a strategy of early in-hospital stenting of the infarct-related coronary artery. This treatment results in a long-term uneventful clinical course. The study confirmed the low risk of recurrent ischemia in patients without viability. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00149591. TI - Improved clinical outcome after invasive management of patients with recent myocardial infarction and proven myocardial viability: primary results of a randomized controlled trial (VIAMI-trial). SN - 1745-6215 JF - Trials VL - vol. 13 DO - https://doi.org/10.1186/1745-6215-13-1 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/108268/108268.pdf?sequence=1 ER - TY - JOUR AU - Roe, M.T. AU - Armstrong, P.W. AU - Fox, K.A. AU - White, H.D. AU - Prabhakaran, D. AU - Goodman, S.G. AU - Cornel, J.H. AU - Bhatt, D.L. AU - Clemmensen, P. AU - Martinez, F. AU - Ardissino, D. AU - Nicolau, J.C. AU - Boden, W.E. AU - Gurbel, P.A. AU - Ruzyllo, W. AU - Dalby, A.J. AU - McGuire, D.K. AU - Leiva-Pons, J.L. AU - Parkhomenko, A. AU - Gottlieb, S. AU - Topacio, G.O. AU - Hamm, C. AU - Pavlides, G. AU - Goudev, A.R. AU - Oto, A. AU - Tseng, C.D. AU - Merkely, B. AU - Gasparovic, V. AU - Corbalan, R. AU - Cinteza, M. AU - McLendon, R.C. AU - Winters, K.J. AU - Brown, E.B. AU - Lokhnygina, Y. AU - Aylward, P.E. AU - Huber, K. AU - Hochman, J.S. AU - Ohman, E.M. AU - Verheugt, F.W.A. AU - et al. PY - 2012 UR - https://hdl.handle.net/2066/109106 AB - BACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS: Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.). TI - Prasugrel versus clopidogrel for acute coronary syndromes without revascularization EP - 1309 SN - 0028-4793 IS - iss. 14 SP - 1297 JF - The New England Journal of Medicine VL - vol. 367 DO - https://doi.org/10.1056/NEJMoa1205512 ER - TY - JOUR AU - Tricoci, P. AU - Huang, Z. AU - Held, C. AU - Moliterno, D.J. AU - Armstrong, P.W. AU - Werf, F. van de AU - White, H.D. AU - Aylward, P.E. AU - Wallentin, L. AU - Chen, E. AU - Lokhnygina, Y. AU - Pei, J. AU - Leonardi, S. AU - Rorick, T.L. AU - Kilian, A.M. AU - Jennings, L.H. AU - Ambrosio, G. AU - Bode, C. AU - Cequier, A. AU - Cornel, J.H. AU - Diaz, R. AU - Erkan, A. AU - Huber, K. AU - Hudson, M.P. AU - Jiang, L. AU - Jukema, J.W. AU - Lewis, B.S. AU - Lincoff, A.M. AU - Montalescot, G. AU - Nicolau, J.C. AU - Ogawa, H. AU - Pfisterer, M. AU - Prieto, J.C. AU - Ruzyllo, W. AU - Sinnaeve, P.R. AU - Storey, R.F. AU - Valgimigli, M. AU - Whellan, D.J. AU - Widimsky, P. AU - Strony, J. AU - Harrington, R.A. AU - Mahaffey, K.W. AU - Verheugt, F.W. AU - et al. PY - 2012 UR - https://hdl.handle.net/2066/109982 AB - BACKGROUND: Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.). TI - Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. EP - 33 SN - 0028-4793 IS - iss. 1 SP - 20 JF - The New England Journal of Medicine VL - vol. 366 DO - https://doi.org/10.1056/NEJMoa1109719 ER - TY - JOUR AU - Riezebos, R.K. AU - Verheugt, F.W.A. AU - Laarman, G.J. AU - Tijssen, J.G.P. PY - 2012 UR - https://hdl.handle.net/2066/109713 AB - The clinical course of an acute coronary syndrome can vary from relatively benign to potentially fatal. The biomarkers of myocardial necrosis relate to the amount of myocardial damage and are closely linked to a patient's prognosis. They are measured to help guide management decisions. Recent interest in myocardial neurohumoral mechanisms has identified the natriuretic peptides as strong prognostic biomarkers following an ischemic event. During an acute event they provide information regarding the area of myocardium at risk. The biomarkers of inflammation, such as C-reactive protein, are related to both the development of atherosclerosis and the risk of acute ischemic events. The mechanism characterizing the pathophysiology of the syndrome is represented by these cardiac biomarkers. Assessing combinations of pathobiologically diverse biomarkers may provide a better risk evaluation method and further dictate subsequent therapy. TI - The Biochemical Aspects of a Non-ST-Segment Elevation Acute Coronary Syndrome EP - 6 SN - 1530-6550 IS - iss. 2-3 SP - e70 JF - Reviews in Cardiovascular Medicine VL - vol. 13 DO - https://doi.org/10.3909/ricm0607 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/109713/109713.pdf?sequence=1 ER - TY - JOUR AU - Verheugt, F.W.A. AU - Bolte, A.C. PY - 2011 UR - https://hdl.handle.net/2066/98457 AB - BACKGROUND: The aim of this review is to discuss the role of aspirin for various conditions in women. METHODS: A nonsystematic review of articles published on PubMed((R)) that examines the role of aspirin in women. RESULTS: Aspirin is associated with a significant reduction of stroke risk in women, which may be linked to age. However, despite this evidence, underutilization of aspirin in eligible women is reported. In women of reproductive age, it may also have a role to play in reducing early-onset preeclampsia and intrauterine growth restriction, and in the prevention of recurrent miscarriage in women with antiphospholipid antibodies; it may also reduce cardiovascular risk in associated systemic conditions such as lupus. Aspirin may reduce colorectal cancer risk in women, but its role in breast cancer warrants further data from controlled trials. CONCLUSIONS: The risk-benefit threshold for aspirin use in women has been established for several conditions. Reasons why women are less likely to be prescribed aspirin have not been established, but the overall underuse of aspirin in women needs to be addressed. TI - The role of aspirin in women's health EP - 166 SN - 1179-1411 SP - 151 JF - International Journal of Women'S Health VL - vol. 3 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98457/98457.pdf?sequence=1 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2011 UR - https://hdl.handle.net/2066/96090 TI - Medicamenteuze behandeling van stabiele angina pectoris. EP - 108 SN - 0304-4629 SP - 97 JF - Geneesmiddelenbulletin VL - vol. 45 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2011 UR - https://hdl.handle.net/2066/96485 TI - Triple antithrombotic therapy after coronary stenting: why expert opinion is necessary EP - 412 SN - 1941-7640 IS - iss. 5 SP - 410 JF - Circulation-Cardiovascular Interventions VL - vol. 4 DO - http://dx.doi.org/10.1161/CIRCINTERVENTIONS.111.965210 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2011 UR - https://hdl.handle.net/2066/98544 AB - Cerebral infarction is the most serious complication of atrial fibrillation. Coumarin derivatives (vitamin K antagonists) counteract systemic thromboembolism and reduce the risk of stroke by more than 60%, but carry a risk of serious bleeding. Antiplatelet therapy and subcutaneous low-molecular-weight heparin are as yet not sufficiently effective and are associated with a bleeding risk similar to vitamin K antagonists. Vitamin K antagonists require intensive INR monitoring to ensure efficacy and safety. In the past decade, oral agents have been developed that directly inhibit the activity of thrombin (factor IIa) and of activated factor X (Xa), which is the first compound in the final common pathway of the coagulation cascade. These do require INR monitoring and have rapid onset and offset of action. The first results with thrombin blockers, such as dabigatran, look promising in efficacy and safety and Xa inhibitors are currently under investigation in atrial fibrillation in 3 large clinical trials. Long-term safety of the new agents in patients with atrial fibrillation has not yet been determined. TI - [New antithrombotics for atrial fibrillation]. EP - A2143 SN - 0028-2162 SP - A2143 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 155 ER - TY - JOUR AU - Rubboli, A. AU - Becattini, C. AU - Verheugt, F.W.A. PY - 2011 UR - https://hdl.handle.net/2066/98000 AB - Bleeding is the most important complication of oral anticoagulation (OAC) with vitamin K-antagonists. Whilst bleeding is unavoidably related to OAC, it may have a great impact on the prognosis of treated subjects by leading to discontinuation of treatment, permanent disability or death. The yearly incidence of bleeding during OAC is 2%-5% for major bleeding, 0.5%-1% for fatal bleeding, and 0.2%-0.4% for intracranial bleeding. While OAC interruption and/or antagonism, as well as administration of coagulation factors, represent the necessary measures for the management of bleeding, proper stratification of the individual risk of bleeding prior to start OAC is of paramount importance. Several factors, including advanced age, female gender, poor control and higher intensity of OAC, associated diseases and medications, as well as genetic factors, have been proven to be associated with an increased risk of bleeding. Most of these factors have been included in the development of bleeding prediction scores, which should now be used by clinicians when prescribing and monitoring OAC. Owing to the many limitations of OAC, including a narrow therapeutic window, cumbersome management, and wide inter- and intra-individual variability, novel oral anticoagulants, such as factor Xa inhibitors and direct thrombin inhibitors, have been recently developed. These agents can be given in fixed doses, have little interaction with foods and drugs, and do not require regular monitoring of anticoagulation. While the novel oral anticoagulants show promise for effective thromboprophylaxis in atrial fibrillation and venous thromboembolism, definitive data on their safety and efficacy are awaited. TI - Incidence, clinical impact and risk of bleeding during oral anticoagulation therapy. EP - 358 SN - 1949-8462 IS - iss. 11 SP - 351 JF - World Journal of Cardiology VL - vol. 3 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98000/98000.pdf?sequence=1 ER - TY - JOUR AU - Riezebos, R.K. AU - Laarman, G.J. AU - Tijssen, J.G.P. AU - Verheugt, F.W.A. PY - 2011 UR - https://hdl.handle.net/2066/97457 AB - BACKGROUND: N-terminal proB-type natriuretic peptide (NT-proBNP) is a marker of biomechanical strain, secreted by cardiomyocytes in response to ischemia. As necrosis occurs after prolonged ischemia, a rise in NT-proBNP concentration could precede a rise in markers of necrosis. METHODS: The aim of the study was to evaluate whether NT-proBNP is able to identify those patients with an evolving myocardial infarction (MI) with high-risk non-ST-elevation acute coronary syndromes (NSTE-ACS). Data were analyzed from a prospective cohort of 103 high-risk NSTE-ACS patients admitted within 6 h after onset of pain and treated with an early invasive strategy. NT-proBNP samples, obtained immediately upon admission, were related to the presence of an in hospital MI. The optimal cut-off value for NT-proBNP was determined using receiver-operating characteristics (ROC) curve analysis. RESULTS: Analyses was performed separately for creatinine kinase MB-mass (CKMB) and troponin T (TnT) based MI definitions. In both cases, a NT-proBNP concentration above 40 pmol/L (339 ng/L) at admission proved to be independently associated with the presence of MI. The diagnostic odds ratio (OR) for CKMB-MI was 4.9 (confidence interval 2.0-11.9, p<0.001). The diagnostic OR for TnT-MI was 4.9 (1.8-14.4, p=0.003). Adjusting for differences in baseline variables did not weaken the diagnostic OR. In addition, elevated NT-proBNP concentrations were related to unfavour-able demographic, physical and biochemical parameters. CONCLUSIONS: With a dichotomous cut-off value, a single elevated NT-proBNP (>40 pmol/L) at admission provides independent information about the presence of MI in high-risk NSTE-ACS patients. TI - The value of N-terminal proB-type natriuretic peptide for early identification of myocardial infarction in patients with high-risk non-ST-elevation acute coronary syndromes EP - 1365 SN - 1434-6621 IS - iss. 8 SP - 1359 JF - Clinical Chemistry and Laboratory Medicine VL - vol. 49 DO - https://doi.org/10.1515/CCLM.2011.213 ER - TY - JOUR AU - Steg, P.G. AU - Huber, K. AU - Andreotti, F. AU - Arnesen, H. AU - Atar, D. AU - Badimon, L. AU - Bassand, J.P. AU - De Caterina, R. AU - Eikelboom, J.A. AU - Gulba, D. AU - Hamon, M. AU - Helft, G. AU - Fox, K.A. AU - Kristensen, S.D. AU - Rao, S.V. AU - Verheugt, F.W.A. AU - Widimsky, P. AU - Zeymer, U. AU - Collet, J.P. PY - 2011 UR - https://hdl.handle.net/2066/97680 AB - Bleeding has recently emerged as an important outcome in the management of acute coronary syndromes (ACS), which is relatively frequent compared with ischaemic outcomes and has important implications in terms of prognosis, outcomes, and costs. In particular, there is evidence that patients experiencing major bleeding in the acute phase are at higher risk for death in the following months, although the causal nature of this relation is still debated. This position paper aims to summarize current knowledge regarding the epidemiology of bleeding in ACS and percutaneous coronary intervention, including measurement and definitions of bleeding, with emphasis on the recent consensus Bleeding Academic Research Consortium (BARC) definitions. It also provides an European perspective on management strategies to minimize the rate, extent, and consequences of bleeding. Finally, the research implications of bleeding (measuring and reporting bleeding in trials, the importance of bleeding as an outcome measure, and bleeding as a subject for future research) are also discussed. TI - Bleeding in acute coronary syndromes and percutaneous coronary interventions: position paper by the Working Group on Thrombosis of the European Society of Cardiology EP - 1864 SN - 0195-668X IS - iss. 15 SP - 1854 JF - European Heart Journal VL - vol. 32 DO - https://doi.org/10.1093/eurheartj/ehr204 ER - TY - JOUR AU - Verheugt, F.W.A. AU - Steinhubl, S.R. AU - Hamon, M. AU - Darius, H. AU - Steg, P.G. AU - Valgimigli, M. AU - Marso, S.P. AU - Rao, S.V. AU - Gershlick, A.H. AU - Lincoff, A.M. AU - Mehran, R. AU - Stone, G.W. PY - 2011 UR - https://hdl.handle.net/2066/98001 AB - OBJECTIVES: The aim of this study was to evaluate the relative frequency of access and nonaccess site bleeding, the association of these events with 1-year mortality, and the impact of randomized antithrombotic therapy. BACKGROUND: Post-percutaneous coronary intervention (PCI) bleeding has been strongly associated with subsequent mortality. The extent to which access versus nonaccess site bleeding contributes to this poor prognosis and the role of antithrombotic therapies remains poorly understood. METHODS: The incidence and impact of Thrombolysis In Myocardial Infarction (TIMI) major/minor 30-day bleeding and randomized antithrombotic therapy were examined in a combined dataset from the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events), Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY), and HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trials in 17,393 PCI patients. RESULTS: The TIMI major/minor bleeding occurred in 5.3% of patients, 61.4% of which (3.3%) were nonaccess site bleeds. After multivariable adjustment, TIMI bleeding was associated with an increased risk of 1-year mortality (hazard ratio [HR]: 3.17, 95% confidence interval [CI]: 2.51 to 4.00, p < 0.0001). The HR of a nonaccess site bleed was approximately 2-fold that of an access site bleed: HR: 3.94, 95% CI: 3.07 to 5.15, p < 0.0001 versus HR: 1.82, 95% CI: 1.17 to 2.83, p = 0.008, respectively. Randomization to bivalirudin versus heparin + a glycoprotein IIb/IIIa inhibitor resulted in 38% and 43% relative reductions in TIMI major/minor and TIMI major bleeding, respectively (p < 0.0001 for both), with significant reductions in both access and nonaccess site bleeding. CONCLUSIONS: Nonaccess site bleeding after PCI is common, representing approximately two-thirds of all TIMI bleeding events, and is associated with a 4-fold increase in 1-year mortality. Use of bivalirudin rather than heparin + a glycoprotein IIb/IIIa inhibitor significantly decreases both nonaccess site as well as access site bleeding events by approximately 40%. TI - Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention EP - 197 SN - 1936-8798 IS - iss. 2 SP - 191 JF - Jacc. Cardiovascular Interventions VL - vol. 4 DO - https://doi.org/10.1016/j.jcin.2010.10.011 ER - TY - JOUR AU - Gibson, C.M. AU - Mega, J.L. AU - Burton, P. AU - Goto, S. AU - Verheugt, F.W.A. AU - Bode, C. AU - Plotnikov, A. AU - Sun, X. AU - Cook-Bruns, N. AU - Braunwald, E. PY - 2011 UR - https://hdl.handle.net/2066/96262 AB - BACKGROUND: Although therapy with aspirin or aspirin plus a thienopyridine reduces the incidence of long-term adverse cardiovascular events among patients with acute coronary syndrome (ACS), there remains a significant residual risk of cardiovascular death, recurrent myocardial infarction (MI), and stroke. In a phase 2 trial (ClinicalTrials.gov NCT00402597) in which the addition of the factor Xa inhibitor rivaroxaban was compared with placebo, among ACS patients receiving either aspirin alone or dual-antiplatelet therapy with aspirin and a thienopyridine, the end point of death, MI, or stroke compared with placebo was reduced (87/2331 [3.9%] vs 62/1160 [5.5%]; hazard ratio 0.69, [95% CI 0.50-0.96], P = .027). Two candidate doses of rivaroxaban were selected for further evaluation in a pivotal phase 3. DESIGN: The second ATLAS-ACS 2 TIMI 51 Trial is an international, randomized, double-blind, event-driven (n = 983) phase 3 trial involving more than 15,570 patients hospitalized with ACS (ClinicalTrials.gov NCT00809965). All patients are treated with a background of standard therapy including low-dose aspirin, and patients are stratified by the administration of a thienopyridine (clopidogrel or ticlopidine; stratum 2) or not (stratum 1). Within each stratum, patients are randomly assigned in a 1:1:1 ratio to receive rivaroxaban 2.5 mg twice daily, or rivaroxaban 5 mg twice daily, or placebo twice daily. The primary efficacy end point is the composite of cardiovascular death, MI, or stroke. The primary safety end point is thrombolysis in MI major bleeding not associated with coronary artery bypass graft surgery. SUMMARY: The ATLAS-ACS 2 TIMI 51 is testing the hypothesis that anticoagulation with the oral factor Xa inhibitor rivaroxaban reduces cardiovascular death, MI, and stroke among patients with ACS treated with guideline-based therapies for ACS. TI - Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis in myocardial infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome. EP - 821.e6 SN - 0002-8703 IS - iss. 5 SP - 815 JF - American Heart Journal VL - vol. 161 N1 - 1 mei 2011 DO - https://doi.org/10.1016/j.ahj.2011.01.026 ER - TY - JOUR AU - Harmsze, A.M. AU - Boer, A. de AU - Boot, H. AU - Deneer, V.H. AU - Heringa, M. AU - Mol, P.G. AU - Schalekamp, T. AU - Verduijn, M.M. AU - Verheugt, F.W.A. AU - Comte, M. le PY - 2011 UR - https://hdl.handle.net/2066/96544 AB - The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. TI - [Interaction between clopidogrel and proton pump inhibitors] EP - A2442 SN - 0028-2162 IS - iss. 28 SP - A2442 JF - Nederlands Tijdschrift voor Geneeskunde VL - vol. 155 ER - TY - JOUR AU - Granger, C.B. AU - Alexander, J.H. AU - McMurray, J.J. AU - Lopes, R.D. AU - Hylek, E.M. AU - Hanna, M. AU - Al-Khalidi, H.R. AU - Ansell, J. AU - Atar, D. AU - Avezum, A. AU - Bahit, M.C. AU - Diaz, R. AU - Easton, J.D. AU - Ezekowitz, J.A. AU - Flaker, G. AU - Garcia, D. AU - Geraldes, M. AU - Gersh, B.J. AU - Golitsyn, S. AU - Goto, S. AU - Hermosillo, A.G. AU - Hohnloser, S.H. AU - Horowitz, J. AU - Mohan, P. AU - Jansky, P. AU - Lewis, B.S. AU - Lopez-Sendon, J.L. AU - Pais, P. AU - Parkhomenko, A. AU - Verheugt, F.W.A. AU - Zhu, J. AU - Wallentin, L. PY - 2011 UR - https://hdl.handle.net/2066/96642 AB - BACKGROUND: Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS: In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS: The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). CONCLUSIONS: In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.). TI - Apixaban versus warfarin in patients with atrial fibrillation EP - 992 SN - 0028-4793 IS - iss. 11 SP - 981 JF - The New England Journal of Medicine VL - vol. 365 DO - https://doi.org/10.1056/NEJMoa1107039 ER - TY - JOUR AU - Patrono, C. AU - Andreotti, F. AU - Arnesen, H. AU - Badimon, L. AU - Baigent, C. AU - Collet, J.P. AU - Caterina, R. de AU - Gulba, D. AU - Huber, K. AU - Husted, S. AU - Kristensen, S.D. AU - Morais, J. AU - Neumann, F.J. AU - Rasmussen, L. AU - Siegbahn, A. AU - Steg, P.G. AU - Storey, E. AU - Werf, F. van de AU - Verheugt, F.W.A. PY - 2011 UR - https://hdl.handle.net/2066/97902 TI - Expert consensus document on the use of antiplatelet agents: 2010 update. EP - 2932 SN - 0195-668X SP - 2922 JF - European Heart Journal VL - vol. 32 DO - https://doi.org/10.1093/eurheartj/ehr373 ER - TY - JOUR AU - Zwart, B. de AU - Werkum, J.W. van AU - Heestermans, A.A. AU - Kelder, J.C. AU - Zomer, A.C. AU - Hof, A.W. van 't AU - Verheugt, F.W.A. AU - Berg, J.M. ten PY - 2011 UR - https://hdl.handle.net/2066/96484 AB - AIMS: The aim of this study was to determine the role of potential triggers of stent thrombosis. METHODS AND RESULTS: Patients (n = 437) with "definite" ST were recruited consecutively in the setting of a large multicentre observational cohort study. Patients were interviewed with validated questionnaires to identify one of the following triggers: i) timing of onset of ST, ii) performance of vigorous ( >/= 6 MET) physical activity in the two hours preceding ST, iii) presence of emotional stress (experiencing a serious life event in the 14 days preceding the ST or feelings of anger in the 12 hours of ST) and iv) presence of a documented active infection at the time of ST. A total of 363 patients (83.1%) were able to supply adequate information. A significant trigger was identified in 83 patients (22.9%). Analysis of the different categories according to timing of ST revealed a higher prevalence of triggers with an increasing time-interval between index PCI and ST. Analysis of circadian variation showed a steep peak incidence from 7 am-12 pm. CONCLUSIONS: Triggering mechanisms such as time of the day, physical exertion, emotional stress and infection may play an important role in a considerable number of patients presenting with ST, in particular in patients with (very) late ST. TI - Triggering mechanisms of stent thrombosis EP - 728 SN - 1774-024X IS - iss. 6 SP - 722 JF - Eurointervention VL - vol. 6 DO - https://doi.org/10.4244/EIJV6I6A122 ER - TY - JOUR AU - Korte, W. AU - Cattaneo, M. AU - Chassot, P.G. AU - Eichinger, S. AU - Heymann, C. von AU - Hofmann, N. AU - Rickli, H. AU - Spannagl, M. AU - Ziegler, B. AU - Verheugt, F.W.A. AU - Huber, K. PY - 2011 UR - https://hdl.handle.net/2066/96188 AB - An increasing number of patients suffering from cardiovascular disease, especially coronary artery disease (CAD), are treated with aspirin and/or clopidogrel for the prevention of major adverse events. Unfortunately, there are no specific, widely accepted recommendations for the perioperative management of patients receiving antiplatelet therapy. Therefore, members of the Perioperative Haemostasis Group of the Society on Thrombosis and Haemostasis Research (GTH), the Perioperative Coagulation Group of the Austrian Society for Anesthesiology, Reanimation and Intensive Care (OGARI) and the Working Group Thrombosis of the European Society of Cardiology (ESC) have created this consensus position paper to provide clear recommendations on the perioperative use of anti-platelet agents (specifically with semi-urgent and urgent surgery), strongly supporting a multidisciplinary approach to optimize the treatment of individual patients with coronary artery disease who need major cardiac and non-cardiac surgery. With planned surgery, drug eluting stents (DES) should not be used unless surgery can be delayed for >/=12 months after DES implantation. If surgery cannot be delayed, surgical revascularisation, bare-metal stents or pure balloon angioplasty should be considered. During ongoing antiplatelet therapy, elective surgery should be delayed for the recommended duration of treatment. In patients with semi-urgent surgery, the decision to prematurely stop one or both antiplatelet agents (at least 5 days pre-operatively) has to be taken after multidisciplinary consultation, evaluating the individual thrombotic and bleeding risk. Urgently needed surgery has to take place under full antiplatelet therapy despite the increased bleeding risk. A multidisciplinary approach for optimal antithrombotic and haemostatic patient management is thus mandatory. TI - Peri-operative management of antiplatelet therapy in patients with coronary artery disease: joint position paper by members of the working group on Perioperative Haemostasis of the Society on Thrombosis and Haemostasis Research (GTH), the working group on Perioperative Coagulation of the Austrian Society for Anesthesiology, Resuscitation and Intensive Care (OGARI) and the Working Group Thrombosis of the European Society for Cardiology (ESC). EP - 749 SN - 0340-6245 IS - iss. 5 SP - 743 JF - Thrombosis and Haemostasis VL - vol. 105 N1 - 1 mei 2011 DO - https://doi.org/10.1160/TH10-04-0217 ER - TY - JOUR AU - Riezebos, R.K. AU - Tijssen, J.G.P. AU - Verheugt, F.W.A. AU - Laarman, G.J. PY - 2011 UR - https://hdl.handle.net/2066/97210 AB - The presentation of patients with suspected non ST-elevation acute coronary syndromes is quite diverse. Therefore, the diagnostic workup and choice of treatment may vary accordingly. Major issues regarding the evaluation are the likelihood of the diagnosis and the risk for adverse events. These factors should guide the choice of diagnostic test. Patients with increased risk for ischemic events and patients with recurrent ischemia are most likely to benefit from revascularization. In addition, when percutaneous coronary intervention is considered, evidence suggests that sufficient time should be allowed for pharmacologic stabilization, reducing the possibility of periprocedurally inflicted myocardial infarction. However, postponement of intervention may lead to an increase of new spontaneous events, and high-risk patients should apply for revascularization soon after pharmacologic stabilization. The extent of revascularization performed by percutaneous coronary intervention depends predominantly on patient characteristics and anatomy but should be limited to flow-obstructive lesions. In conclusion, patients presenting with non-ST elevation acute coronary syndromes constitute a very diverse population; diagnostic workup, treatment, and the timing of a possible intervention should be tailored individually. TI - Percutaneous coronary intervention for non ST-elevation acute coronary syndromes: which, when and how? EP - 515 SN - 0002-9149 IS - iss. 4 SP - 509 JF - American Journal of Cardiology VL - vol. 107 DO - https://doi.org/10.1016/j.amjcard.2010.10.016 ER - TY - JOUR AU - Bueno, H. AU - Armstrong, P.W. AU - Buxton, M.J. AU - Danchin, N. AU - Lubsen, J. AU - Roland, E. AU - Verheugt, F.W.A. AU - Zalewski, A. AU - Jackson, N. AU - Komajda, M. AU - Steg, P.G. PY - 2011 UR - https://hdl.handle.net/2066/97431 TI - The future of clinical trials in secondary prevention after acute coronary syndromes EP - 1589 SN - 0195-668X IS - iss. 13 SP - 1583 JF - European Heart Journal VL - vol. 32 DO - https://doi.org/10.1093/eurheartj/ehq388 ER - TY - JOUR AU - Dinh, T. AU - Baur, L.H. AU - Pisters, R. AU - Kamp, O. AU - Verheugt, F.W.A. AU - Smeets, J.L.R.M. AU - Cheriex, E.C. AU - Tieleman, R.G. AU - Prins, M.H. AU - Crijns, H.J.G.M. PY - 2011 UR - https://hdl.handle.net/2066/97916 AB - BACKGROUND: Antithrombotic management in atrial fibrillation (AF) is currently based on clinical characteristics, despite evidence of potential fine-tuning with transoesophageal echocardiography (TEE). This open, randomised, multicentre study addresses the hypothesis that a comprehensive strategy of TEE-based aspirin treatment in AF patients is feasible and safe. METHODS: Between 2005 and 2009, ten large hospitals in the Netherlands enrolled AF patients with a moderate risk of stroke. Patients without thrombogenic TEE characteristics were randomised to aspirin or vitamin K antagonists (VKA). The primary objective is to show that TEE-based aspirin treatment is safe compared with VKA therapy. The secondary objective tests feasibility of TEE as a tool to detect echocardiographic features of high stroke risk. This report compares randomised to non-randomised patients and describes the feasibility of a TEE-based approach. RESULTS: In total, 310 patients were included. Sixty-nine patients were not randomised because of non-visualisation (n = 6) or TEE risk factors (n = 63). Compared with non-randomised patients, randomised patients (n = 241) were younger (65 +/- 11 vs. 69 +/- 9 years, p = 0.004), had less coronary artery disease (9 vs. 20%, p = 0.018), previous TIA (1.7 vs. 7.2%, p = 0.029), AF during TEE (25 vs. 54%, p < 0.001), mitral incompetence (55 vs. 70%, p = 0.038), VKA use (69 vs. 82%, p = 0.032), had a lower mean CHADS(2) score (1.2 +/- 0.6 vs. 1.6 +/- 1.0, p = 0.004), and left ventricular ejection fraction (59 +/- 8 vs. 56 +/- 8%, p = 0.016). CONCLUSIONS: This study shows that a TEE-based approach for fine-tuning stroke risk in AF patients with a moderate risk for stroke is feasible. Follow-up data will address the safety of this TEE-based approach. TI - Feasibility of TEE-guided stroke risk assessment in atrial fibrillation-background, aims, design and baseline data of the TIARA pilot study EP - 222 SN - 1568-5888 IS - iss. 5 SP - 214 JF - Netherlands Heart Journal VL - vol. 19 DO - https://doi.org/10.1007/s12471-011-0095-3 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/97916/97916.pdf?sequence=1 ER - TY - JOUR AU - Butterworth, A.S. AU - Braund, P.S. AU - Hardwick, R.J. AU - Saleheen, D. AU - Peden, J.F. AU - Soranzo, N. AU - Chambers, J.C. AU - Kleber, M.E. AU - Keating, B. AU - Qasim, A. AU - Klopp, N. AU - Erdmann, J. AU - Basart, H. AU - Baumert, J.H. AU - Bezzina, C.R. AU - Boehm, B.O. AU - Brocheton, J. AU - Bugert, P. AU - Cambien, F. AU - Collins, R. AU - Couper, D. AU - Jong, J.S. de AU - Diemert, P. AU - Ejebe, K. AU - Elbers, C.C. AU - Elliott, P. AU - Fornage, M. AU - Frossard, P. AU - Garner, S. AU - Hunt, S.E. AU - Kastelein, J.J. AU - Klungel, O.H. AU - Kluter, H. AU - Koch, K. AU - Konig, I.R. AU - Kooner, A.S. AU - Liu, K. AU - McPherson, R. AU - Musameh, M.D. AU - Musani, S. AU - Papanicolaou, G. AU - Peters, A. AU - Peters, B.J. AU - Potter, S. AU - Psaty, B.M. AU - Rasheed, A. AU - Scott, J. AU - Seedorf, U. AU - Sehmi, J.S. AU - Sotoodehnia, N. AU - Stark, K. AU - Stephens, J. AU - Schoot, C.E. van der AU - Schouw, Y.T. van der AU - Harst, P. van der AU - Vasan, R.S. AU - Wilde, A.A. AU - Willenborg, C. AU - Winkelmann, B.R. AU - Zaidi, M. AU - Zhang, W. AU - Ziegler, A. AU - Koenig, W. AU - Matz, W. AU - Trip, M.D. AU - Reilly, M.P. AU - Kathiresan, S. AU - Schunkert, H. AU - Hamsten, A. AU - Hall, A.S. AU - Kooner, J.S. AU - Thompson, S.G. AU - Thompson, J.R. AU - Watkins, H. AU - Danesh, J. AU - Barnes, T. AU - Rafelt, S. AU - Codd, V. AU - Bruinsma, N. AU - Dekker, L.R. AU - Henriques, J.P. AU - Koch, K.T. AU - Winter, R.J. de AU - Alings, M. AU - Allaart, C.F. AU - Gorgels, A.P. AU - Verheugt, F.W.A. AU - Mueller, M. AU - Meisinger, C. AU - DerOhannessian, S. AU - Mehta, N.N. AU - Ferguson, J. AU - Hakonarson, H. AU - Matthai, W. AU - Wilensky, R. AU - Hopewell, J.C. AU - Parish, S. AU - Linksted, P. AU - Notman, J. AU - Gonzalez, H. AU - Young, A. AU - Ostley, T. AU - Munday, A. AU - Goodwin, N. AU - Verdon, V. AU - Shah, S. AU - Edwards, C. AU - Mathews, C. AU - Gunter, R. AU - Benham, J. AU - Davies, C. AU - Cobb, M. AU - Cobb, L. AU - Crowther, J. AU - Richards, A. AU - Silver, M. AU - Tochlin, S. AU - Mozley, S. AU - Clark, S. AU - Radley, M. AU - Kourellias, K. AU - Olsson, P. AU - Barlera, S. AU - Tognoni, G. AU - Rust, S. AU - Assmann, G. AU - Heath, S. AU - Zelenika, D. AU - Gut, I. AU - Green, F. AU - Farrall, M. AU - Goel, A. AU - Ongen, H. AU - Franzosi, M.G. AU - Lathrop, M. AU - Clarke, R. AU - Aly, A. AU - Anner, K. AU - Bjorklund, K. AU - Blomgren, G. AU - Cederschiold, B. AU - Danell-Toverud, K. AU - Eriksson, P. AU - Grundstedt, U. AU - Heinonen, M. AU - Hellenius, M.L. AU - Hooft, F. van 't AU - Husman, K. AU - Lagercrantz, J. AU - Larsson, A. AU - Larsson, M. AU - Mossfeldt, M. AU - Malarstig, A. AU - Olsson, G. AU - Sabater-Lleal, M. AU - Sennblad, B. AU - Silveira, A. AU - Strawbridge, R. AU - Soderholm, B. AU - Ohrvik, J. AU - Zaman, K.S. AU - Mallick, N.H. AU - Azhar, M. AU - Samad, A. AU - Ishaq, M. AU - Shah, N. AU - Samuel, M. AU - Kathiresan, S.C. AU - Assimes, T.L. AU - Holm, H. AU - Preuss, M. AU - Stewart, A.F. AU - Barbalic, M. AU - Gieger, C. AU - Absher, D. AU - Aherrahrou, Z. AU - Allayee, H. AU - Altshuler, D. AU - Anand, S. AU - Andersen, K. AU - Anderson, J.L. AU - Ardissino, D. AU - Ball, S.G. AU - Balmforth, A.J. AU - Barnes, T.A. AU - Becker, L.C. AU - Becker, D.M. AU - Berger, K. AU - Bis, J.C. AU - Boekholdt, S.M. AU - Boerwinkle, E. AU - Brown, M.J. AU - Burnett, M.S. AU - Buysschaert, I. AU - Carlquist, J.F. AU - Chen, L. AU - Davies, R.W. AU - Dedoussis, G. AU - Dehghan, A. AU - Demissie, S. AU - Devaney, J. AU - Do, R. AU - Doering, A. AU - El Mokhtari, N.E. AU - Ellis, S.G. AU - Elosua, R. AU - Engert, J.C. AU - Epstein, S. AU - Faire, U. de AU - Fischer, M. AU - Folsom, A.R. AU - Freyer, J. AU - Gigante, B. AU - Girelli, D. AU - Gretarsdottir, S. AU - Gudnason, V. AU - Gulcher, J.R. AU - Tennstedt, S. AU - Halperin, E. AU - Hammond, N. AU - Hazen, S.L. AU - Hofman, A. AU - Horne, B.D. AU - Illig, T. AU - Iribarren, C. AU - Jones, G.T. AU - Jukema, J.W. AU - Kaiser, M.A. AU - Kaplan, L.M. AU - Khaw, K.T. AU - Knowles, J.W. AU - Kolovou, G. AU - Kong, A. AU - Laaksonen, R. AU - Lambrechts, D. AU - Leander, K. AU - Li, M. AU - Lieb, W. AU - Lettre, G. AU - Loley, C. AU - Lotery, A.J. AU - Mannucci, P.M. AU - Martinelli, N. AU - McKeown, P.P. AU - Meitinger, T. AU - Melander, O. AU - Merlini, P.A. AU - Mooser, V. AU - Morgan, T. AU - Muhleisen T.W., . AU - Muhlestein, J.B. AU - Musunuru, K. AU - Nahrstaedt, J. AU - Nothen, Markus AU - Olivieri, O. AU - Peyvandi, F. AU - Patel, R.S. AU - Patterson, C.C. AU - Qu, L. AU - Quyyumi, A.A. AU - Rader, D.J. AU - Rallidis, L.S. AU - Rice, C. AU - Roosendaal, F.R. AU - Rubin, D. AU - Salomaa, V. AU - Sampietro, M.L. AU - Sandhu, M.S. AU - Schadt, E. AU - Schafer, A. AU - Schillert, A. AU - Schreiber, S. AU - Schrezenmeir, J. AU - Schwartz, S.M. AU - Siscovick, D.S. AU - Sivananthan, M. AU - Sivapalaratnam, S. AU - Smith, A.V. AU - Smith, T.B. AU - Snoep, J.D. AU - Spertus, J.A. AU - Stefansson, K. AU - Stirrups, K. AU - Stoll, M. AU - Tang, W.H. AU - Thorgeirsson, G. AU - Thorleifsson, G. AU - Tomaszewski, M. AU - Uitterlinden, A.G. AU - Rij, A.M. van AU - Voight, B.F. AU - Wareham, N.J. AU - AWells, G. AU - Wichmann, H.E. AU - Witteman, J.C. AU - Wright, B.J. AU - Ye, S. AU - Cupples, L.A. AU - Quertermous, T. AU - Marz, W. AU - Blankenberg, S. AU - Thorsteinsdottir, U. AU - Roberts, R. AU - O'Donnell, C.J. AU - Onland-Moret, N.C. AU - Setten, J. van AU - Bakker, P.I. de AU - Verschuren, W.M. AU - Boer, J.M. AU - Wijmenga, C. AU - Hofker, M.H. AU - Maitland-van der Zee, A.H. AU - Boer, A. de AU - Grobbee, D.E. AU - Attwood, T. AU - Belz, S. AU - Cooper, J. AU - Crisp-Hihn, A. AU - Deloukas, P. AU - Foad, N. AU - Goodall, A.H. AU - Gracey, J. AU - Gray, E. AU - Gwilliams, R. AU - Heimerl, S. AU - Hengstenberg, C. AU - Jolley, J. AU - Krishnan, U. AU - Lloyd-Jones, H. AU - Lugauer, I. AU - Lundmark, P. AU - Maouche, S. AU - Moore, J.S. AU - Muir, D. AU - Murray, E. AU - Nelson, C.P. AU - Neudert, J. AU - Niblett, D. AU - O'Leary, K. AU - Ouwehand, W.H. AU - Pollard, H. AU - Rankin, A. AU - Rice, C.M. AU - Sager, H. AU - Samani, N.J. AU - Sambrook, J. AU - Schmitz, G. AU - Scholz, M. AU - Schroeder, L. AU - Syvannen, A.C. AU - Wallace, C. PY - 2011 UR - https://hdl.handle.net/2066/98050 AB - Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in approximately 2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5x10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other approximately 4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes. TI - Large-scale gene-centric analysis identifies novel variants for coronary artery disease EP - e1002260 SN - 1553-7404 IS - iss. 9 SP - e1002260 JF - Plos Genetics VL - vol. 7 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98050/98050.pdf?sequence=1 ER - TY - JOUR AU - Gomes, M.E.R. AU - El Messaoudi, S. AU - Lenders, J.W.M. AU - Bellersen, L. AU - Verheugt, F.W.A. AU - Smits, P. AU - Tack, C.J.J. PY - 2011 UR - https://hdl.handle.net/2066/97959 AB - WHAT IS KNOWN AND OBJECTIVE: The increased central sympathetic activity typically associated with chronic heart failure (CHF) is probably mediated by formation of reactive oxygen species (ROS) in the brain. Our objective was to undertake a trial to test our hypothesis that administration of the well-known antioxidant and ROS scavenger ascorbic acid, would reverse or reduce the sympathetic overactivity in CHF patients. METHODS: In a prospective, randomized, placebo-controlled, double-blind, cross-over trial, 11 CHF patients were treated with ascorbic acid 2 g/day or placebo for 3 days. At the end of each treatment period, sympathetic nervous system activity was measured by microneurography for direct muscle sympathetic nerve activity (MSNA) recording, analysis of heart rate variability (HRV) and measurement of plasma norepinephrine concentrations. RESULTS: During ascorbic acid administration, plasma vitamin C levels were higher than during placebo (74.9 +/- 6.0 mumol/L vs. 54.8 +/- 4.6 mumol/L, P = 0.03). Ascorbic acid had no effect on sympathetic activity: MSNA (ascorbic acid: 66.8 +/- 3.3 vs. placebo 66.9 +/- 3.2 bursts/100 beats, P = 0.98). In addition, HRV and plasma norepinephrine levels did not differ. WHAT IS NEW AND CONCLUSION: Short-term administration of the antioxidant ascorbic acid in CHF patients does not reverse the increased sympathetic activity as measured by microneurography, HRV and plasma norepinephrine levels. The use of higher oral dosages seems not feasible due to accompanying side effects. TI - High dose ascorbic acid does not reverse central sympathetic overactivity in chronic heart failure EP - 552 SN - 0269-4727 IS - iss. 5 SP - 546 JF - Journal of Clinical Pharmacy and Therapeutics VL - vol. 36 DO - https://doi.org/10.1111/j.1365-2710.2010.01205.x ER - TY - JOUR AU - Alexander, J.H. AU - Lopes, R.D. AU - James, S. AU - Kilaru, R. AU - He, Y. AU - Mohan, P. AU - Bhatt, D.L. AU - Goodman, S. AU - Verheugt, F.W.A. AU - Flather, M. AU - Huber, K. AU - Liaw, D. AU - Husted, S.E. AU - Lopez-Sendon, J. AU - De Caterina, R. AU - Jansky, P. AU - Darius, H. AU - Vinereanu, D. AU - Cornel, J.H. AU - Cools, F. AU - Atar, D. AU - Leiva-Pons, J.L. AU - Keltai, M. AU - Ogawa, H. AU - Pais, P. AU - Parkhomenko, A. AU - Ruzyllo, W. AU - Diaz, R. AU - White, H. AU - Ruda, M. AU - Geraldes, M. AU - Lawrence, J. AU - Harrington, R.A. AU - Wallentin, L. PY - 2011 UR - https://hdl.handle.net/2066/95648 AB - BACKGROUND: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. RESULTS: The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. CONCLUSIONS: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.). TI - Apixaban with antiplatelet therapy after acute coronary syndrome EP - 708 SN - 0028-4793 IS - iss. 8 SP - 699 JF - The New England Journal of Medicine VL - vol. 365 DO - https://doi.org/10.1056/NEJMoa1105819 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/95648/95648.pdf?sequence=1 ER - TY - JOUR AU - Kuilenburg, J. van AU - Lappegard, K.T. AU - Sexton, J. AU - Plesiewicz, I. AU - Lap, P. AU - Bouwels, L. AU - Sprong, T. AU - Mollnes, T.E. AU - Verheugt, F.W.A. AU - Heerde, W.L. van AU - Pop, G.A.M. PY - 2011 UR - https://hdl.handle.net/2066/98208 AB - BACKGROUND: It has been demonstrated that the occurrence of ischemic stroke is more prevalent in AF patients, when increased levels of inflammatory markers are present. OBJECTIVE: The aim of this study was to evaluate the effect of intensive cholesterol lowering therapy on inflammatory markers and evidence of thrombotic in elderly AF patients treated with OAC. METHODS: 34 elderly patients (69-85 yrs) were randomized to double blind treatment with atorvastatin 40 mg plus ezetimibe 10 mg (n = 17) or double placebo (n = 17) for one year. All were anticoagulated with warfarin (target INR 2.5-3.5). Every 3 months inflammatory markers and parameters for evaluation of haemostatic and fibrinolytic activity were measured. RESULTS: Anti-inflammatory effects in the treatment arm were reflected by a significant decrease from baseline in hs-CRP, FGF, G-CSF, GM-CSF, IL-1ra, IL-9, IL-13, IL-17 and interferon-gamma (P < .05). There was no significant decrease in the control group. Endogenous thrombin potential was still present and active but decreased during treatment (P = .0005) compared to the placebo group. After 12 months treatment, a significant correlation was found between changes in endogenous thrombin potential and hs-CRP, interferon-gamma and G-CSF, respectively. No hemorrhagic complications occurred. CONCLUSION: Intensive cholesterol lowering significantly reduced inflammation and was accompanied by reduced thrombin generation. Larger clinical studies should determine which inflammatory markers are most specific and sensitive for estimating the inflammatory burden in these patients and at which corresponding thrombin activity level it is beneficial and safe to add intensive cholesterol lowering therapy even if normal cholesterol levels are present. TI - Persisting thrombin activity in elderly patients with atrial fibrillation on oral anticoagulation is decreased by anti-inflammatory therapy with intensive cholesterol-lowering treatment EP - 280 SN - 1933-2874 IS - iss. 4 SP - 273 JF - Journal of Clinical Lipidology VL - vol. 5 DO - https://doi.org/10.1016/j.jacl.2011.05.003 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2010 UR - https://hdl.handle.net/2066/87534 TI - Update on antithrombotic therapy. EP - 79 SN - 0914-5087 SP - 77 JF - Journal of Cardiology VL - vol. 17 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2010 UR - https://hdl.handle.net/2066/87669 AB - PURPOSE OF REVIEW: Despite its limited efficacy in opening occluded coronary arteries in ST-elevation myocardial infarction, fibrinolysis remains the major reperfusion strategy used worldwide. Apart from bleeding, early reocclusion of the culprit artery is a common complication of the therapy and usually leads to a worse prognosis. RECENT FINDINGS: During the last 7 years routine percutaneous coronary intervention after fibrinolysis has been shown to improve early and long-term outcome in six large randomized trials. SUMMARY: The optimal time window to perform percutaneous coronary intervention is between 3 and 24 h after fibrinolysis. TI - Timing of angiography after fibrinolysis for ST-elevation acute myocardial infarction. EP - 304 SN - 0268-4705 IS - iss. 4 SP - 302 JF - Current Opinion in Cardiology VL - vol. 25 N1 - 1 juli 2010 DO - http://dx.doi.org/10.1097/HCO.0b013e328338bc92 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2010 UR - https://hdl.handle.net/2066/89324 TI - Safety of dual antiplatelet therapy in daily cardiology practice. EP - 229 SN - 1568-5888 IS - iss. 5 SP - 228 JF - Netherlands Heart Journal VL - vol. 18 N1 - 1 mei 2010 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2010 UR - https://hdl.handle.net/2066/89703 TI - Newsflash Thrombosis 2010. EP - 4 SN - 0914-5087 SP - 1 JF - Journal of Cardiology VL - vol. 17 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2010 UR - https://hdl.handle.net/2066/87773 AB - In patients with nonvalvular atrial fibrillation oral anticoagulation with the vitamin K antagonists acenocoumarol, phenprocoumon and warfarin reduces the risk of stroke by more than 60%, whereas single or double antiplatelet therapy is much less effective and sometimes associated with a similar bleeding risk as vitamin K antagonists. Besides bleeding, INR monitoring and high interindividual variability remain the largest drawbacks of vitamin K antagonists. In the last decade oral agents have been developed that directly block the activity of thrombin (factor IIa), as well as drugs that directly inhibit activated factor X (Xa), which is the first protein in the final common pathway to the activation of thrombin. These agents have huge advantages in that they do not need monitoring and have a fast onset and offset of action. This survey addresses the role of classical and modern anticoagulation in stroke prevention in atrial fibrillation. (Neth Heart J 2010;18:314-8.). TI - The new oral anticoagulants. EP - 318 SN - 1568-5888 IS - iss. 6 SP - 314 JF - Netherlands Heart Journal VL - vol. 18 N1 - 1 juni 2010 ER - TY - JOUR AU - Bogaard, K. AU - Koper, M.A. AU - Verheugt, F.W.A. PY - 2010 UR - https://hdl.handle.net/2066/88306 TI - Hotline sessions of the 32nd European Congress of Cardiology. EP - 2704 SN - 0195-668X IS - iss. 22 SP - 2701 JF - European Heart Journal VL - vol. 31 N1 - 1 november 2010 ER - TY - JOUR AU - Dieker, H.J. AU - Liem, S.S. AU - El Aidi, H. AU - Grunsven, P. van AU - Aengevaeren, W.R.M. AU - Brouwer, M.A. AU - Verheugt, F.W.A. PY - 2010 UR - https://hdl.handle.net/2066/89689 AB - OBJECTIVES: We sought to study the impact of direct referral to an intervention center after pre-hospital diagnosis of ST-segment elevation myocardial infarction (STEMI) on treatment intervals and outcome. BACKGROUND: Primary angioplasty has become the preferred reperfusion strategy in STEMI. Ambulance diagnosis and direct referral to an intervention center is an attractive treatment option that has not been studied extensively. METHODS: Consecutive pre-hospital patients with STEMI, who were referred to our intervention center for primary angioplasty between 2005 and 2007, were studied. After pre-hospital diagnosis, patients were either directly transported to our center or referred through a nonintervention center. The catheterization laboratory was activated before transport to the intervention center. RESULTS: Of the 581 patients referred, 454 (78%) came with direct transport and 127 (22%) through a nonintervention center. Direct transport was associated with a higher proportion of patients treated within the 90-min time window of the STEMI guidelines: 82% versus 23% (p < 0.01). Patients directly transported had a significantly shorter median symptom-to-balloon time of 149 min (Interquartile range: 118 to 197 min) versus 219 min (interquartile range: 178 to 315 min), p < 0.01, a higher post-procedural Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 rate (92% vs. 84%; p = 0.03), and a lower 1-year mortality rate (7% vs. 13%; p = 0.03). Direct transport to the intervention center was independently associated with the symptom-to-balloon time, which in turn was an independent predictor of post-procedural TIMI flow grade 3, a strong prognosticator of outcome. CONCLUSIONS: After ambulance-based diagnosis of STEMI, direct transport to an intervention center with pre-hospital notification of the catheterization laboratory more than triples the proportion of patients treated within the time window of the guidelines. Time to balloon was an independent predictor of post-procedural TIMI flow grade 3, which underscores the need to reduce treatment delays. TI - Pre-hospital triage for primary angioplasty: direct referral to the intervention center versus interhospital transport. EP - 711 SN - 1936-8798 IS - iss. 7 SP - 705 JF - Jacc. Cardiovascular Interventions VL - vol. 3 N1 - 1 juli 2010 DO - http://dx.doi.org/10.1016/j.jcin.2010.04.010 ER - TY - JOUR AU - Verheugt, F.W.A. AU - Khan, M. AU - Ruiter, G.S. De AU - Riezebos, R.K. PY - 2010 UR - https://hdl.handle.net/2066/89926 TI - Oral anticoagulants before and after ablation for atrial fibrillation. EP - 914 SN - 1099-5129 IS - iss. 7 SP - 913 JF - Europace VL - vol. 12 N1 - 1 juli 2010 DO - https://doi.org/10.1093/europace/euq159 ER - TY - JOUR AU - Daly, C.A. AU - Clemens, F. AU - Sendon, J.L. AU - Tavazzi, L. AU - Boersma, E. AU - Danchin, N. AU - Delahaye, F. AU - Gitt, A. AU - Julian, D. AU - Mulcahy, D. AU - Ruzyllo, W. AU - Thygesen, K. AU - Verheugt, F.W.A. AU - Fox, K.M. PY - 2010 UR - https://hdl.handle.net/2066/88085 AB - AIMS: To examine resting heart rate (HR) in a population presenting with stable angina in relation to prior and subsequent pharmacological treatment, comorbid conditions and clinical outcome. METHODS AND RESULTS: The European Heart Survey was a prospective, observational, cohort study of 3779 patients with stable angina newly presenting to cardiology services. Mean baseline resting HR was 73 beats/min (bpm) and 52.3% of patients had a baseline HR > 70 bpm. Over half of patients were on no chronotropic medication at baseline. Patients with chronic respiratory disease or diabetes had higher resting HRs (75-76 bpm), and were more likely to have been receiving calcium channel blockers at baseline assessment. Overall, beta-blockers were the most common treatment administered following cardiologist assessment, but were used less frequently in patients with chronic respiratory disease and diabetes, and the dosages used were less than that found to be effective in clinical trials. Mean daily doses of metoprolol, bisoprolol, carvedilol, and atenolol were 75 mg, 6 mg, 19 mg and 55 mg, respectively. Higher HR at baseline was associated with higher rates of cardiovascular mortality and hospitalisation for heart failure. CONCLUSION: Control of ischaemic symptoms through heart rate modification in patients with angina is currently inadequate, both by primary referring physicians and cardiologists. Given the adverse outcome associated with higher resting heart rates in this as in other studies, and the availability of specific HR reducing strategies, attention should be given to achieving optimal HR control. TI - Inadequate control of heart rate in patients with stable angina: results from the European heart survey. EP - 217 SN - 0032-5473 IS - iss. 1014 SP - 212 JF - Postgraduate Medical Journal VL - vol. 86 N1 - 1 april 2010 DO - https://doi.org/10.1136/pgmj.2009.084384 ER - TY - JOUR AU - Scirica, B.M. AU - Braunwald, E. AU - Belardinelli, L. AU - Hedgepeth, C.M. AU - Spinar, J. AU - Wang, W. AU - Qin, J. AU - Karwatowska-Prokopczuk, E. AU - Verheugt, F.W.A. AU - Morrow, D.A. PY - 2010 UR - https://hdl.handle.net/2066/89426 AB - BACKGROUND: Most studies examining the relationship between ventricular tachycardia (VT) after acute coronary syndrome and sudden cardiac death (SCD) were performed before widespread use of reperfusion, revascularization, or contemporary medical therapy and were limited to ST-elevation myocardial infarction. The incidence and prognostic implications of VT in patients with non-ST-elevation acute coronary syndrome receiving contemporary care have not been examined. METHODS AND RESULTS: The Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non-ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG recording was performed for the first 7 days after randomization and evaluated in a blinded core laboratory. SCD (n=121) was assessed over a median follow-up of 1 year. A total of 6345 patients (97%) had continuous ECG recordings evaluable for analysis. Compared with patients with no VT (n=2764), there was no increased risk of SCD in patients with only ventricular triplets (n=1978, 31.2%) (1.4% versus 1.2%); however, the risk of SCD was significantly greater in patients with VT lasting 4 to 7 beats (n=1172, 18.5%) (SCD, 2.9%; adjusted hazard ratio, 2.3; P<0.001) and in patients with VT lasting at least 8 beats (n=431, 6.8%) (SCD, 4.3%; adjusted hazard ratio, 2.8; P=0.001). This effect was independent of baseline characteristics and ejection fraction. VT occurring within the first 48 hours after admission was not associated with SCD. CONCLUSIONS: Nonsustained VT is common after admission for non-ST-elevation acute coronary syndrome, and even short episodes of VT lasting 4 to 7 beats are independently associated with the risk of SCD over the subsequent year. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00099788. TI - Relationship between nonsustained ventricular tachycardia after non-ST-elevation acute coronary syndrome and sudden cardiac death: observations from the metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndrome-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial. EP - 462 SN - 0009-7322 IS - iss. 5 SP - 455 JF - Circulation VL - vol. 122 DO - https://doi.org/10.1161/CIRCULATIONAHA.110.937136 ER - TY - JOUR AU - Lopes, R.D. AU - Alexander, J.H. AU - Al-Khatib, S.M. AU - Ansell, J. AU - Diaz, R. AU - Easton, J.D. AU - Gersh, B.J. AU - Granger, C.B. AU - Hanna, M. AU - Horowitz, J. AU - Hylek, E.M. AU - McMurray, J.J. AU - Verheugt, F.W.A. AU - Wallentin, L. PY - 2010 UR - https://hdl.handle.net/2066/88254 AB - Atrial fibrillation (AF) is associated with increased risk of stroke that can be attenuated with vitamin K antagonists (VKAs). Vitamin K antagonist use is limited, in part, by the high incidence of complications when patients' international normalized ratios (INRs) deviate from the target range. The primary objective of ARISTOTLE is to determine if the factor Xa inhibitor, apixaban, is noninferior to warfarin at reducing the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism in patients with AF and at least 1 additional risk factor for stroke. We have randomized 18,206 patients from over 1,000 centers in 40 countries. Patients were randomly assigned in a 1:1 ratio to receive apixaban or warfarin using a double-blind, double-dummy design. International normalized ratios are monitored and warfarin (or placebo) is adjusted aiming for a target INR range of 2 to 3 using a blinded, encrypted point-of-care device. Minimum treatment is 12 months, and maximum expected exposure is 4 years. Time to accrual of at least 448 primary efficacy events will determine treatment duration. The key secondary objectives are to determine if apixaban is superior to warfarin for the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism, and for all-cause death. These will be tested after the primary objective using a closed test procedure. The noninferiority boundary is 1.38; apixaban will be declared noninferior if the 95% CI excludes the possibility that the primary outcome rate with apixaban is >1.38 times higher than with warfarin. ARISTOTLE will determine whether apixaban is noninferior or superior to warfarin in preventing stroke and systemic embolism; whether apixaban has particular benefits in the warfarin-naive population; whether it reduces the combined rate of stroke, systemic embolism, and death; and whether it impacts bleeding. TI - Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. EP - 339 SN - 0002-8703 IS - iss. 3 SP - 331 JF - American Heart Journal VL - vol. 159 N1 - 1 maart 2010 DO - https://doi.org/10.1016/j.ahj.2009.07.035 ER - TY - JOUR AU - Dewilde, W. AU - Verheugt, F.W.A. AU - Breet, N. AU - Koolen, J.J. AU - Berg, J.M. ten PY - 2010 UR - https://hdl.handle.net/2066/89856 AB - Chronic oral anticoagulant treatment is obligatory in patients (class I) with mechanical heart valves and in patients with atrial fibrillation with CHADS2 score >1. When these patients undergo percutaneous coronary intervention with placement of a stent, there is also an indication for treatment with aspirin and clopidogrel. Unfortunately, triple therapy is known to increase the bleeding risk. For this group of patients, the bottom line is to find the ideal therapy in patients with indications for both chronic anticoagulation therapy and percutaneous intervention to prevent thromboembolic complications such as stent thrombosis without increasing the risk of bleeding. (Neth Heart J 2010;18:444-50.). TI - 'Ins' and 'outs' of triple therapy: Optimal antiplatelet therapy in patients on chronic oral anticoagulation who need coronary stenting. EP - 450 SN - 1568-5888 IS - iss. 9 SP - 444 JF - Netherlands Heart Journal VL - vol. 18 N1 - 1 september 2010 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2010 UR - https://hdl.handle.net/2066/87725 TI - The role of percutaneous coronary intervention of acute coronary syndrome. EP - 28 SN - 1734-1922 IS - iss. 1a SP - s25 JF - Archives of Medical Science VL - vol. 6 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/87725/87725.pdf?sequence=1 ER - TY - JOUR AU - Verheugt, F.W.A. PY - 2010 UR - https://hdl.handle.net/2066/87207 AB - Warfarin reduces the risk of stroke in atrial fibrillation by around 60%, while antiplatelet therapy is much less effective. Bleeding is, however, a notable adverse effect with warfarin. Another major drawback of warfarin is the need for frequent clotting assessment. Oral agents have been developed that directly inhibit the activity of thrombin (factor IIa), as well as drugs that directly block activated factor X (factor Xa), which is the first enzyme in the final common pathway to the activation of thrombin. These drugs have fast onset and offset of action and anticoagulation does not seem to need monitoring. These new agents for stroke prevention in atrial fibrillation are being investigated in ongoing phase III trials. In one of these trials an oral thrombin blocker has so far shown superiority to warfarin in efficacy and safety. In this Review, I address the potential of modern oral anticoagulants to improve stroke prevention in atrial fibrillation. TI - Novel oral anticoagulants to prevent stroke in atrial fibrillation. EP - 154 SN - 1759-5002 IS - iss. 3 SP - 149 JF - Nature Reviews. Cardiology VL - vol. 7 N1 - 1 maart 2010 DO - http://dx.doi.org/10.1038/nrcardio.2009.235 ER - TY - JOUR AU - Gomes, M.E.R. AU - Aengevaeren, W.R.M. AU - Lenders, J.W.M. AU - Verheugt, F.W.A. AU - Smits, P. AU - Tack, C.J.J. PY - 2010 UR - https://hdl.handle.net/2066/88116 AB - BACKGROUND: By stimulating sympathetic afferents, repetitive myocardial ischemia induces a state of increased sympathetic tone. HYPOTHESIS: Removing the ischemic trigger by revascularization using percutaneous coronary intervention (PCI) might thus reduce central sympathetic activity in symptomatically stable angina patients. METHODS: A total of 20 patients with stable angina > or = New York Heart Association (NYHA) class II with persistent symptoms despite maximal pharmacological therapy and a clinical indication for PCI, were included in our study. Sympathetic nervous system activity was measured before and 1 month after PCI by a combination of techniques: direct muscle sympathetic nerve activity (MSNA), neurochemical (plasma catecholamine levels), and heart rate variability (HRV). RESULTS: All patients completed the study. After PCI there was a significant reduction in MSNA (pre-PCI 72 +/- 4 to post-PCI 53 +/- 4 burst/100 beats, P < .05) and low frequency/high frequency (LF/HF) ratio (3.7 +/- 0.6 vs 2.4 +/- 0.4, P < .05) consistent with a decline in sympathetic activity. Plasma norepinephrine levels were reduced after PCI, but this difference did not reach statistical significance (1.84 +/- 0.17 vs 1.73 +/- 0.13 nmol/L, P = not significant). CONCLUSION: Coronary revascularization by PCI reduces sympathetic activity in patients with established myocardial ischemia. TI - Improving myocardial perfusion by percutaneous coronary intervention reduces central sympathetic activity in stable angina. EP - 21 SN - 0160-9289 IS - iss. 6 SP - E16 JF - Clinical Cardiology VL - vol. 33 N1 - 1 juni 2010 ER - TY - JOUR AU - Gomes, M.E.R. AU - Smits, P. AU - Verheugt, F.W.A. AU - Tack, C.J.J. PY - 2010 UR - https://hdl.handle.net/2066/88788 AB - AIMS: Percutaneous coronary interventions (PCI) evoke an inflammatory response and have been reported to decrease adiponectin levels. If persistent over time, the inflammatory response and low adiponectin levels would induce insulin resistance, rendering PCI potentially hazardous for glucose metabolism. We investigated whether PCI decreased insulin sensitivity after one month and if so, whether this was related to a lasting elevation of inflammatory markers and decrease in adiponectin levels. METHODS AND RESULTS: Insulin sensitivity (euglycemic hyperinsulinaemic clamp) was measured in 19 patients with stable coronary artery disease before and one month after PCI. Also, levels of inflammatory mediators and adiponectin were assessed. Insulin sensitivity was not affected by the PCI procedure. There were no persistent increases in IL-6, hs-CRP and adiponectin levels after PCI. CONCLUSIONS: The inflammatory response seen immediately after PCI does not translate to a medium-term negative effect on insulin action. TI - Effect of PCI on inflammatory markers, adiponectin and insulin resistance. EP - 840 SN - 1774-024X IS - iss. 7 SP - 838 JF - Eurointervention VL - vol. 5 N1 - 1 februari 2010 DO - https://doi.org/10.4244/EIJV5I7A140 ER - TY - JOUR AU - Gomes, M.E.R. AU - Mulder, A. AU - Bellersen, L. AU - Verheugt, F.W.A. AU - Smits, P. AU - Tack, C.J.J. PY - 2010 UR - https://hdl.handle.net/2066/88047 AB - AIMS: Alpha-adrenergic receptor-mediated vasoconstriction might underlie the insulin resistance seen in conditions associated with increased sympathetic tone, like chronic heart failure (CHF). Alpha-adrenergic receptor blockade by phentolamine could improve forearm blood flow (FBF) and forearm glucose uptake (FGU) in CHF patients. METHODS AND RESULTS: In 8 CHF patients and in 12 healthy volunteers, FBF (plethysmography) and FGU were measured in both forearms during a 150 min hyperinsulinaemic euglycaemic clamp procedure. During the final 30 min of the clamp, phentolamine was infused into one arm (experimental arm) at a dose of 5.0 mug; min(-1) dL(-1) of forearm volume. Insulin infusion (t = 0-120 min) increased FGU in the two groups, without affecting FBF. In the CHF group, alpha-adrenergic receptor blockade by phentolamine (t = 120-150 min) further increased FGU in the experimental arm from 3.0 +/- 0.7 to 5.0 +/- 0.9 mumol min(-1) dL(-1) (P = 0.03). Forearm glucose uptake in the contralateral forearm remained unchanged. In the control group, phentolamine infusion did not increase FGU in the experimental forearm. The increase in blood flow in response to phentolamine was similar in both groups (CHF: 2.1 +/- 0.3-7.5 +/- 1.7 mL min(-1) dL(-1), P < 0.001; controls 1.5 +/- 0.2-5.5 +/- 0.8 mL min(-1) dL(-1), P < 0.001 for both, CHF vs. control, P = 0.2). Phentolamine did not affect FBF in the control arm in either group. CONCLUSION: Alpha-adrenergic receptor blockade improves FGU in CHF patients. As the increase in FBF is similar in controls and CHF patients, this might be explained by an improved glucose-extraction capacity in CHF patients. TI - Alpha-receptor blockade improves muscle perfusion and glucose uptake in heart failure. EP - 1066 SN - 1388-9842 IS - iss. 10 SP - 1061 JF - European Journal of Heart Failure VL - vol. 12 N1 - 1 oktober 2010 DO - https://doi.org/10.1093/eurjhf/hfq135 ER - TY - JOUR AU - Gomes, M.E.R. AU - Lenders, J.W.M. AU - Bellersen, L. AU - Verheugt, F.W.A. AU - Smits, P. AU - Tack, C.J.J. PY - 2010 UR - https://hdl.handle.net/2066/89087 AB - OBJECTIVES: Increased (central) sympathetic activity is a key feature of heart failure and associated with worse prognosis. Animal studies suggest that statin therapy can reduce central sympathetic outflow. This study assessed statin effects on (central) sympathetic activity in human chronic heart failure (CHF) patients. METHODS: Sympathetic activity was measured in eight patients with CHF patients during 8 weeks after discontinuation and 4 weeks after restart of statin therapy by microneurography for direct muscle sympathetic nerve recording (MSNA) and measurement of arterial plasma norepinephrine concentrations. RESULTS: During discontinuation of statin therapy, MSNA was significantly increased (73 +/- 4 vs. 56 +/- 5 and 52 +/- 6 bursts/100 beats, p = 0.01). Burst frequency was significantly higher after statin discontinuation (42 +/- 3 burst/min without statin vs. 32 +/- 3 and 28 +/- 3 burst/min during statin therapy, p = 0.004). Mean normalized burst amplitude and total normalized MSNA were significantly higher after statin discontinuation (mean normalized burst amplitude 0.36 +/- 0.04 without statin vs. 0.29 +/- 0.04 and 0.22 +/- 0.04 during statin, p < 0.05; total normalized MSNA 15.70 +/- 2.78 without statin, vs. 9.28 +/- 1.41 and 6.56 +/- 1.83 during statin, p = 0.009). Arterial plasma norepinephrine levels and blood pressure were unaffected. INTERPRETATION: Statin therapy inhibits central sympathetic outflow in CHF patients, as measured by MSNA. TI - Sympathoinhibitory effect of statins in chronic heart failure. EP - 78 SN - 0959-9851 IS - iss. 2 SP - 73 JF - Clinical Autonomic Research VL - vol. 20 N1 - 1 april 2010 DO - https://doi.org/10.1007/s10286-009-0041-2 ER - TY - JOUR AU - Gomes, M.E.R. AU - Tack, C.J.J. AU - Verheugt, F.W.A. AU - Smits, P. AU - Lenders, J.W.M. PY - 2010 UR - https://hdl.handle.net/2066/89086 AB - BACKGROUND: Experimental animal data suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) might reduce enhanced sympathetic activity, a hallmark of hypertensive patients. This hypothesis was tested for the first time in patients with primary hypertension. METHODS AND RESULTS: Using a prospective, randomized, placebo-controlled, double-blind, cross-over design, a proof-of-principle trial was performed in 13 patients with mild to moderate primary hypertension, who were randomly assigned to a regimen of atorvastatin (80mg/day) for 3 weeks, followed by placebo for 3 weeks or to a regimen of placebo for 3 weeks, followed by atorvastatin (80mg/day) for 3 weeks. Microneurography was used at the end of each treatment period to measure sympathetic nervous system activity (muscle sympathetic nerve activity: MSNA). Heart rate variability (HRV) and plasma norepinephrine concentrations were also measured. Additionally, effects on blood pressure (BP) and heart rate (HR) were assessed by 24-h ambulatory BP measurement. Atorvastatin reduced postganglionic MSNA (atorvastatin 35.0+/-2.0 vs placebo: 39.2+/-1.5 bursts/min, P=0.008) and heart frequency corrected MSNA (atorvastatin: 58.5+/-2.0 vs placebo: 64.7+/-3.0 bursts/100 beats, P=0.02). Atorvastatin had no significant effect on plasma norepinephrine levels, HRV, BP or HR. CONCLUSIONS: In patients with mild to moderate hypertension, atorvastatin reduces postganglionic MSNA, which supports the hypothesis that HMG-CoA reductase plays a role in sympathetic nervous system activity. TI - Sympathoinhibition by atorvastatin in hypertensive patients. EP - 2626 SN - 1346-9843 IS - iss. 12 SP - 2622 JF - Circulation Journal VL - vol. 74 DO - https://doi.org/10.1253/circj.CJ-10-0427 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/89086/89086.pdf?sequence=1 ER -