Clinical Relevance of Impaired Physiological Assessment After Percutaneous Coronary Intervention: A Meta-analysis

Background Despite the optimal angiographic result of percutaneous coronary intervention (PCI), residual disease at the site of the culprit lesion can lead to major adverse cardiac events. Post-PCI physiological assessment can identify residual stenosis. This meta-analysis aims to investigate data of studies examining post-PCI physiological assessment in relation to long-term outcomes. Methods Studies were included in the meta-analysis after performing a systematic literature search on July 1, 2022. The primary end point was the incidence of major adverse cardiac events, vessel-orientated cardiac events, or target vessel failure. Results Low post-PCI fractional flow reserve, reported in 7 studies with fractional flow reserve cutoff values between 0.84 and 0.90, including 4017 patients, was associated with an increased rate of the primary end point (hazard ratio [HR], 2.06; 95% CI, 1.37-3.08). One study reported about impaired post-PCI instantaneous wave-free ratio with instantaneous wave-free ratio cutoff value of 0.95 in relation to major adverse cardiac events, showing a significant association (HR, 3.38; 95% CI, 0.99-11.6; P = .04). Low post-PCI quantitative flow ratio, reported in 3 studies with quantitative flow ratio cutoff value between 0.89 and 0.91, including 1181 patients, was associated with an increased rate of vessel-orientated cardiac events (HR, 3.01; 95% CI, 2.10-4.32). Combining data of all modalities, impaired physiological assessment showed an increased rate of the primary end point (HR, 2.32; 95% CI, 1.71-3.16) and secondary end points, including death (HR, 1.41; 95% CI, 1.04-1.89), myocardial infarction (HR, 2.70; 95% CI, 1.34-5.42) and target vessel revascularization (HR, 2.88; 95% CI, 1.91-4.35). Conclusions Impaired post-PCI physiological assessment is associated with increased adverse cardiac events and individual end points, including death, myocardial infarction, and target vessel revascularization. Therefore, prospective studies are awaited on whether physiology-based optimization of PCI results in better clinical outcomes.


Introduction
Physiology-guided percutaneous coronary intervention (PCI) is important to guide clinicians in the decision-making for coronary revascularization.Nonhyperemic pressure ratios, including resting full-cycle ratio and instantaneous wave-free ratio (iFR), and hyperemic pressure ratios, including fractional flow reserve (FFR), are used for physiological assessment.Lesions with resting full-cycle ratio value <0.89, iFR value <0.89, or FFR value <0.80 can cause myocardial ischemia. 1,2Using this FFR cutoff value for PCI compared with angiography-guided PCI results in a reduced rate of major adverse cardiovascular events (MACE). 3Unfortunately, despite the optimal angiographic result of PCI, the incidence of MACE after PCI remains high.In an all-comers follow-up study after PCI, MACE was reported in 19% to 32% of the patients at 2 years of follow-up, depending on the used stent type during PCI. 4 In addition, Stone et al 5 demonstrated that in up to 13% of all patients, major cardiovascular events after PCI are caused by residual or recurrent disease at the site of the culprit lesion.
Physiological assessment of lesions with the angiographically optimal result can be used to identify residual stenosis.Pijls et al 6 already demonstrated 2 decades ago that higher FFR values after PCI are associated with decreased rates of MACE.In the following decades, several studies reported on the association between FFR after PCI and adverse Abbreviations: FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; MACE, major adverse cardiac events; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; QFR, quantitative flow ratio; TVF, target vessel failure; TVR, target vessel revascularization; VOCE, vessel-orientated cardiac events.Keywords: fractional flow reserve; instantaneous wave-free ratio; percutaneous coronary intervention; physiological assessment; quantitative flow ratio; major adverse cardiac events.cardiac events.More recently, alternative modalities such as iFR and QFR have been studied in relation to adverse cardiac events, providing additional data.The studies, however, are diverse, performed with different technologies and providing outcomes with varying significance.Additionally, as a result of the small sample size, the power of several studies is low.
The goal of this systematic review and meta-analysis is to provide an overview of data with a minimum follow-up of 6 months on post-PCI physiological assessment and long-term outcomes in patients with acute coronary syndromes and chronic coronary syndrome and to provide a pooled analysis of post-PCI FFR, iFR and QFR data in relation with long-term outcomes.

Search strategy
This study was performed using the Meta-analysis of Observational Studies in Epidemiology guidelines. 7Systematic search of the literature was performed in PubMed, Embase, and Web of Science on July 1, 2022.
A combination of the following keywords for FFR was used: "Fractional Flow Reserve, myocardial," "FFR," "Coronary Circulation," "Treatment Outcome," "Percutaneous Coronary Intervention."A literature search on iFR and QFR was performed using the following keywords: "Post PCI iFR," "instantaneous wave-free ratio," "Post PCI QFR," and "Quantitative Flow Ratio."A literature search was preferably performed using Medical Subject Headings terms.Duplicates, animal studies, non-English language articles, systematic reviews, and meta-analyses were erased.In addition, abstracts only and unpublished studies were not included.Two independent reviewers (A.M.G and S.C.H.vdO) screened and identified all appropriate titles and abstracts.A review of the reference lists of these studies was performed to find additional relevant studies.After a full-text review, studies that reported data on the measurement of post-PCI FFR, iFR, and QFR and long-term outcomes in patients with acute coronary syndrome and chronic coronary syndrome were selected for inclusion in this systematic review and meta-analysis.If multiple studies from the same cohort were identified, selection was made based on the sufficiency of the data.The Newcastle-Ottawa Scale was used to assess the quality of the selected nonrandomized studies.

Data collection
Data of interest from the included studies were extracted by 2 independent reviewers (A.M.G. and S.C.H.vdO).General data included information on study design, in-and exclusion criteria, sample size, and demographic characteristics.Data on the procedural characteristics included information on angiographic data and pre-and post-PCI FFR, iFR, and QFR data.Follow-up data included information on the follow-up duration, indicated to be for at least 6 months, and data on the used end points, defined as MACE (defined as a composite of cardiac death, myocardial infarction [MI], and any revascularization), vessel-orientated cardiac events (VOCE) (defined as cardiovascular death, vessel-related [spontaneous] MI and [ischemia-driven] target vessel revascularization [TVR]) and target vessel failure (TVF) (defined as a composite of cardiac death, target vessel MI, and clinically-driven TVR), according to the individual study.

Statistical analysis
Statistical analysis was performed using Microsoft Excel 2016 (Microsoft Corporation) and MetaXL version 5.3 (EpiGear, www.ep igear.com).The primary end point of this study was the incidence of MACE, defined according to the individual study.If MACE was not reported, comparable definitions, including VOCE and TVF, were used as the primary end point.Secondary end points included the incidence of death, MI, and TVR.Meta-analysis was performed on a combination of the hazard ratios (HRs) for MACE, VOCE, or TVF in relation to post-PCI FFR, iFR, or QFR, depending on which end point was reported by the included studies.To avoid any influence of confounding factors, HRs derived from the multivariate analysis were used to calculate an overall HR.If HRs derived from the multivariate analysis were not available, HRs derived from univariate analysis were used.If only survival curves with P values were present, HRs were reconstructed using WebPlotDigitizer version 4.5 (https://automeris.io/WebPlotDigitizer)and the method from Parmar et al 8 If 2 or more studies provided sufficient data, an overall

Post-PCI FFR
A total of 32 articles were identified reporting data on post-PCI FFR and long-term outcomes (Supplemental Table S1).A total of 18 articles were excluded because no sufficient data were reported or data was overlapping.Data in 9 articles were incomplete.The corresponding authors of these articles were contacted and requested to supply additional data.Additional data was provided for 2 articles.Eventually, data in 7 articles 6,9-14 were sufficient to be included in the meta-analysis (Figure 1).Study quality assessment demonstrated good quality for 6 studies (Supplemental Table S2).All 7 studies reported data on MACE, VOCE, or TVF.An overview of the study characteristics is provided in Table 1, including the ratio between acute and chronic coronary syndromes and the cutoff value for impaired post-PCI physiological assessment.The studies included 65 to 959 patients (4017 patients in total).The median follow-up time was 23 months (6-31 months).Patient and procedural characteristics are summarized in Table 2 and Table 3. MACE was defined and reported by 5 studies (Table 1), with a total of 2543 patients.The prevalence of MACE over the 5 studies varied from 10.2% to 23.3%.VOCE was described in 1 study (n ¼ 639). 14TVF was described in 1 study (n ¼ 835) as well. 12The ratio between absolute numbers of adverse cardiac events and impaired post-PCI FFR is depicted in Figure 2. The meta-analysis showed a significant association between a low post-PCI FFR and the primary end point (HR, 2.06; 95% CI, 1.37-3.08)(Figure 3).The heterogeneity of the studies was 76%, suggesting that substantial between-study heterogeneity may be present in the studies, according to the Cochrane guideline. 15ensitivity analysis demonstrated that heterogeneity was predominantly present in the study of Pijls et al, 6 which had a relatively short follow-up time of 6 months.After excluding the study from Pijls et al 6 heterogeneity was reduced without significantly influencing the results (HR, 1.77; 95% CI, 1.23-2.53).Although a limited amount of studies is included, visual inspection of the funnel plot might suggest publication bias (Supplemental Figure S1).

Post-PCI iFR
Data on post-PCI iFR and the long-term outcome was only reported in 1 study (Figure 1). 16The DEFINE PCI Trial reported data on MACE.A summary of the study characteristics is provided in Table 1, including the ratio between acute and chronic coronary syndromes and the cutoff value for impaired post-PCI physiological assessment.The study included 467 patients.The follow-up period was 1 year.Patient characteristics are summarized in Table 2. MACE was reported in 19 (4.2%) patients.The ratio between absolute numbers of adverse cardiac events and impaired post-PCI iFR is depicted in Figure 2. The analysis of the data showed a significant association between the MACE rate over the 1-year follow-up and post-PCI iFR with a cutoff value of 0.95 (HR, 3.38; 95% CI, 0.99-11.6;P ¼ .04).

Post-PCI QFR
A total of 5 articles were identified reporting data on post-PCI QFR and long-term outcomes (Supplemental Table S3).excluded because no sufficient data was provided or the data was incomplete.Three studies [17][18][19] were sufficient to be included in the meta-analysis (Figure 1).Study quality assessment demonstrated good quality for all studies (Supplemental Table S2).All 3 studies reported on VOCE.An overview of the studies is provided in Table 1, including the ratio between acute and chronic coronary syndromes and the cutoff value for impaired post-PCI physiological assessment.The studies included 186 to 602 patients (1181 patients in total).The median follow-up period was 24 months (21-24 months).Patient and procedural characteristics were reported in Table 2 and Table 3.The prevalence of VOCE over the 3 studies varied from 6.7% to 9.4%.The ratio between absolute numbers of adverse cardiac events and impaired post-PCI QFR is depicted in Figure 2. The meta-analysis showed a significant association between an impaired post-PCI QFR and the incidence of VOCE (HR, 3.01; 95% CI, 2.10-4.32)(Figure 4).The heterogeneity of the studies was 0%.This suggests that there is  no between-study heterogeneity of importance. 15Funnel plot did not suggest publication bias, although the amount of studies included is limited (Supplemental Figure S2).

Discussion
The current meta-analysis studied the relation of post-PCI physiological assessment with adverse outcomes.Results demonstrate that patients with impaired post-PCI physiological assessment combining all modalities have significantly more adverse cardiovascular events with a median follow-up of 2 years.Moreover, impaired post-PCI physiological assessment results in an increased incidence of death, MI, and TVR.However, results are not influenced by the modality applied for physiological assessment.

Post-PCI physiology
Two prior meta-analyses have been performed, including several studies about post-PCI FFR and long-term outcomes, supporting the ideal FFR cutoff value defined as 0.90. 20,21Unfortunately, these meta-analyses included mainly retrospective studies.Recently, Diletti et al 9 performed a prospective study to confirm the relationship between the FFR cutoff value and MACE, showing no significant association.[19]22,23 The current meta-analysis pooled the data of the currently available studies on the value of post-PCI physiological assessment using FFR, iFR, and QFR.This is the first meta-analysis providing data about several physiological assessment modalities, including iFR and QFR.Besides the metaanalysis performed by Wolfrum et al, 21 this meta-analysis is the only study calculating the value of physiological assessment on individual end points, including death, MI, and TVR.However, more patients are included in this study, providing data and conclusions with a higher level of significance.Moreover, unlike prior meta-analyses, calculations represent a risk incidence over the entire follow-up time because the current meta-analysis is performed on HRs.HRs are preferable to odds ratios (ORs) because of the ability to represent the risk incidence over the follow-up period of the entire study instead of a single landmark in time.HRs are not calculated on cumulative data at a defined end point.HRs allow combining studies with different (median) follow-ups, while combining ORs at 1 year with ORs at 2 years may not be obvious.Moreover, an OR can only be calculated at the minimal follow-up of all patients in the study, while an HR can be calculated using all the follow-ups of all patients.The analysis in this study revealed an association between impaired post-PCI physiological assessment with the Central Illustration.Post-PCI physiological assessment and adverse cardiac events.Forest plots of hazard ratios (HR) of post-PCI physiological assessment and adverse cardiac events, including MACE, VOCE, and TVF, defined according to the included studies.Markers represent point estimates of HRs.Marker size represents study weight.Horizontal bars indicate 95% CIs.FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; MACE, major adverse cardiovascular events; PCI, percutaneous coronary intervention; QFR, quantitative flow ratio; TVF, target vessel failure; VOCE, vessel-orientated cardiac events.incidence of adverse cardiovascular events within 2 years.Moreover, impaired post-PCI physiological assessment is not only associated with an increased incidence of TVR but also with MI and death.Further analysis of the individual end point death should be performed by assessing specific patient characteristics, including the extent and complexity of the coronary artery disease, to enhance the clinical relevance of these findings.Nevertheless, it is unclear if optimizing the PCI result improves patient outcomes.

Causes of suboptimal physiology
Numerous vessel-related causes can result in an impaired post-PCI physiological assessment.The residual post-PCI pressure gradient is mainly caused by the presence of residual stenosis, which also includes diffuse coronary artery disease proximal and distal of the stent.In addition, a residual focal pressure gradient can be present within the stent. 24Biscaglia et al 18 investigated the location of residual stenosis post-PCI.Significant residual stenosis was present in 16% of the investigated vessels.In 87% of these vessels, the residual significant stenosis was either proximal or distal of the stent.In 13% of the vessels, there was significant residual stenosis at the location of the stent.Whereas focal residual stenosis proximal or distal of the stent often requires additional PCI, optimization of residual stenosis at the location of the stent or due to diffuse coronary artery disease proximal and distal of the stent is more difficult and may require further assessment using intracoronary imaging or pressure wire pullback curves.

Intracoronary imaging and physiology
Intravascular coronary imaging, such as optical coherence tomography (OCT), is an important tool for decision-making prior to PCI and post-PCI. 25Post-PCI OCT may help to detect incomplete lesion coverage, stent malapposition, stent underexpansion, intrastent plaque protrusion, and edge dissection. 26,27In patients with impaired post-PCI FFR OCT was feasible for detecting suboptimal stent deployment. 26,28Moreover, OCT-guided optimization using postdilation resulted in higher post-PCI FFR values when compared to angiography-guided optimization of the stent result. 28However, it is unclear whether OCT-guided optimization of PCI leads to lower adverse cardiac events in patients with impaired post-PCI FFR.Studies are currently ongoing to assess the additional value of other intracoronary imaging-guided optimization of the PCI results in patients with post-PCI FFR <0.90. 29essure wire pullback Pressure wire pullbacks can be used to distinguish residual focal and diffuse coronary artery disease as well as significant residual in-stent stenosis.30 In addition, the Pullback Pressure Gradient Global Registry (NCT04789317) is currently ongoing to determine the impact of the Pullback Pressure Gradient Index on clinical decision-making and the impact on clinical outcomes.In residual stenosis due to diffuse coronary artery disease, the pressure wire pullback shows a gradual pressure drop over the length of the entire vessel without any visible focal stenosis on angiography.31 To quantify the extent of diffuse coronary artery disease, Hoshino et al 10 recently presented a novel index, the D-index, calculated as the delta of the FFR value divided by the absolute distance between the 2 points where FFR was assessed.A higher D-index was significantly associated with MACE and VOCE.

Limitations
This meta-analysis has a few limitations.First, publication bias could result in the overestimation of the association between impaired physiological assessment and adverse cardiac events.Non-English language studies were excluded in this meta-analysis based on practical considerations.Although study quality is assessed using the Newcastle-Ottawa Scale, the assessment of studies could be different between individual reviewers due to the design of the assessment tool.Additionally, all the studies do not have the same level of evidence (ie, studies based on retrospective data compared with prospective observational studies).Second, this is a study-level data analysis.Characteristics were unavailable at the individual patient level and could not be corrected at the individual level.Regarding study-level characteristics, variation in cutoff values for post-PCI physiological assessment is present across studies, which may explain some variation in the outcome.However, given the similarity in cut-offs, any influence on the conclusion that impaired physiological assessment post-PCI is associated with the long-term outcome is not to be expected.While the variation is not considered so large as to change the conclusion, we cannot investigate associations between a specific cutoff point for the incidence of MACE, VOCE or TVF.Third, variation in outcome definition (MACE, VOCE, or TVF) across studies is present; however, because of the overlap of components, we neither expect this to swift the conclusion of our meta-analysis.Last, analyses performed may represent moderate to substantial betweenstudy heterogeneity.Although the measured effect of the included studies is different, they all point in the same direction.

Conclusions
The result of this meta-analysis shows that impaired post-PCI physiological assessment is associated with increased adverse cardiac events within 2 years.Moreover, impaired post-PCI physiological assessment is not only associated with an increased incidence of TVR but also with MI and death.Therefore, prospective studies are awaited on whether physiology-based optimization of PCI results in better clinical outcomes.

Declaration of competing interest
Dr Damman reported grants, speaker, and consultancy fees from Philips, grants and speaker fees from Abbot, and grants from AstraZeneca.Dr van Royen reported grants and speaker fees from Abbott and grants from Medtronic, Biotronik, and Philips.Dr van Geuns reported grants and personal fees from Boston Scientific, Abbott Vascular, Astra-Zeneca, and Amgen and grants from InfraRedx.Drs Griffioen, van den Oord, and author Teerenstra reported no conflicts of interest to declare.

Figure 5 .
Figure 5. Post-PCI physiological assessment and secondary end points.Forest plots of hazard ratios (HRs) of post-PCI physiological assessment and (A) death, (B) myocardial infarction, and (C) target vessel revascularization.Markers represent point estimates of HRs.Marker size represents study weight.Horizontal bars indicate 95% CIs.PCI, percutaneous coronary intervention.

Figure 4 .
Figure 4. Post-PCI QFR and adverse cardiac events.Forest plots of hazard ratios (HRs) of post-PCI QFR and adverse cardiac events, including VOCE, defined according to the included studies.Markers represent point estimates of HRs.Marker size represents study weight.Horizontal bars indicate 95% CIs.PCI, percutaneous coronary intervention; QFR: quantitative flow ratio; VOCE, vessel-orientated cardiac events.

Table 1 .
Characteristics of the included studies.

Table 2 .
Patient characteristics of the included studies.

Table 3 .
Procedural characteristics of the included studies.LAD, left anterior descending; LM, left main; NA, not available; PCI, percutaneous coronary intervention; QFR, quantitative flow ratio; RCA, right coronary artery; RCx, right circumflex.HR was calculated.P < .05 was considered statistically significant.HRs were plotted in a forest plot.Random effect models were used to calculate summary estimates and to construct forest plots.To assess the heterogeneity among the studies, the Q test and I 2 index were used.Publication bias was assessed by funnel plot.
Figure 2. Ratio between adverse cardiac events and impaired physiological assessment.The plot of absolute numbers of adverse cardiac events related to the number of impaired physiological assessments categorized for each study.FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; MACE, major adverse cardiovascular events; QFR, quantitative flow ratio.
represent point estimates of HRs.Marker size represents study weight.Horizontal bars indicate 95% CIs.FFR, fractional flow reserve; MACE, major adverse cardiovascular events; PCI, percutaneous coronary intervention; TVF, target vessel failure; VOCE, vessel-orientated cardiac events.