Fractional flow reserve use in coronary artery revascularization: A systematic review and meta-analysis

Summary Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) is recommended in revascularization guidelines for intermediate lesions. However, recent studies comparing FFR-guided PCI with non-physiology-guided revascularization have reported conflicting results. PubMed and Embase were searched for studies comparing FFR-guided PCI with non-physiology-guided revascularization strategies (angiography-guided, intracoronary imaging-guided, coronary artery bypass grafting). Data were pooled by meta-analysis using random-effects model. 26 studies enrolling 78,897 patients were included. FFR-guided PCI as compared to non-physiology-guided coronary revascularization had lower risk of all-cause mortality (odds ratio [OR] 0.79 95% confidence interval [CI] 0.64–0.99, I2 = 53%) and myocardial infarction (MI) (OR 0.74 95% CI 0.59–0.93, I2 = 44.7%). However, no differences between groups were found in terms of major adverse cardiac events (MACEs) (OR 0.86 95% CI 0.72–1.03, I2 = 72.3%) and repeat revascularization (OR 1 95% CI 0.82–1.20, I2 = 43.2%). Among patients with coronary artery disease (CAD), FFR-guided PCI as compared to non-physiology-guided revascularization was associated with a lower risk of all-cause mortality and MI.


INTRODUCTION
Fractional flow reserve (FFR) was developed in the 1990s to determine the functional significance of angiographically apparent coronary artery stenosis using intracoronary pressure measurements. 1 Nowadays, FFR has become the standard to guide decisions on percutaneous coronary revascularization, achieving class 1A recommendation in both US 2 and European 3 guidelines. Alongside the growing evidence supporting FFR-guided revascularization strategies, 4-6 several other revascularization approaches, such as angiography, 7,8 intravascular ultrasound, 9,10 and optical coherence tomography-guided [11][12][13] revascularization, have been proposed to optimize revascularization strategies in terms of functional/imaging results, but also in terms of short-and long-term clinical outcomes. Even though these different strategies have been extensively investigated, comparative studies against the current clinical standard, FFR, are scarce. 14 This becomes of increasing importance in light of recent evidence-based practice trials using FFR-guided percutaneous coronary intervention (PCI) with new-generation drug-eluting stents, where no benefit of physiological guidance could be documented. 15,16 Overall, our knowledge on the impact of an FFR-guided PCI strategy on clinical outcomes compared to angiography or invasive imaging-guided revascularization strategies in contemporary practice has resulted in conflicting results. Hence, we conducted a systematic review and meta-analysis of randomized and observational trials from studies of FFR-guided PCI vs. other revascularization strategies (angiography-guided PCI, intracoronary imaging-guided PCI, coronary artery bypass grafting [CABG]), aimed at comparing FFR-guided PCI in terms of its benefits on clinical outcomes against different revascularization approaches. Figure 1 displays the PRISMA study search and selection process. A total of 26 studies, 12 RCTs and 14 observational, were identified and included in this study. The main features of included trials are presented in Table 1.

Clinical outcomes
Patients undergoing FFR-guided PCI as compared to those undergoing non-physiology-guided coronary revascularization had a lower risk of all-cause mortality (OR 0.79 95% CI 0.64-0.99, I 2 = 53%) and MI (OR 0.74 95% CI 0.59-0.93, I 2 = 44.7%). However, no differences between groups were found in terms of MACE (OR 0.86 95% CI 0.72-1.03, I 2 = 72.3%) and repeat revascularization (OR 1 95% CI 0.82-1.20, I 2 = 43.2%). (Figure 2). NNT to prevent one death was 100 patients, and NNT to prevent one MI was 500 patients (Graphical abstract). Nevertheless, high heterogeneity was found, resulting in prediction intervals that showed a possible null effect on the risk of all-cause mortality and MI ( Figure 2).

Risk of bias assessment
Tables S2 and S3 summarize the results of the risk of bias assessment. Among observational studies, 4 presented moderate overall risk of bias and 10 were considered at serious overall risk of bias. Among RCTs, 1 was considered at low overall risk of bias and 11 presented some concerns.   Figure S6). iScience Article

Sensitivity analyses
At leave-one-out sensitivity analysis, when removing any of the following studies FAMOUS-NSTEMI, 20 FLAVOR, 21 Frolich et al., 22 Hu et al., 23 Li et al., 24 Lunardi et al., 25 Parikh et al., 26 or Puymirat et al. 27 the risk of all-cause mortality was no longer significantly reduced in patients undergoing FFR-guided PCI. Also when removing the Di Giogia et al. 2020 28 or the FAME (fractional flow reserve versus angiography for guiding percutaneous coronary intervention) 3, 29 a lower risk of MACE emerged in patients undergoing FFR-guided PCI. Results were consistent with the primary analysis for the rest of outcomes by iteratively removing one study at a time (Tables S5-S8). Meta-regression showed impact of number of diseased vessels and follow-up duration on all-cause death and MI. No impact of percentage of population presenting with ACS, number of diseased vessels, time of follow-up, and treatment effect was shown for the remaining outcomes (Table S4). Publication bias was detected for all-cause mortality as shown by Harbord test (p = 0.005). Funnel-plot distributions and Harbord test of the remaining outcomes indicated absence of publication bias and small study effect ( Figures S1-S4).

DISCUSSION
In this study we evaluated FFR-guided PCI with non-physiology-guided revascularization strategies (angiography-guided PCI, intracoronary imaging-guided PCI, CABG) in patients with CAD. The main findings of this study can be summarized as follows.
(1) The risk of all-cause mortality and MI in patients undergoing FFR-guided PCI is lower as compared with those undergoing non-physiology-guided revascularization, with an NNT of 100 patients to prevent one death. However, high heterogeneity was found, resulting in prediction intervals that showed a possible null effect on the risk of death and MI. iScience Article (2) The risk of repeat revascularization and MACE does not differ between patients treated with FFRguided PCI and those treated with non-physiology-guided revascularization strategies.

FFR evidence leading to current guidelines recommendations
There is emerging evidence supporting the role of FFR to assess lesion significance and guide revascularization decisions. This is endorsed by the fact that the class of recommendation for FFR to assess intermediate (50%-70%) coronary artery stenosis and direct revascularization plan has been upgraded from a 2A recommendation 30 to a 1A recommendation in 2021 US guidelines 2 and 2018 European guidelines. 3 Several large-scale trials have established the efficacy and superiority of FFR-guided PCI as compared to angiography-guided PCI in terms of mortality, MI, or repeat revascularization. The DEFER (fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis) trial has shown that deferral of PCI of a functionally nonsignificant stenosis is not associated with increased risk of MACE at long-term follow-up. 4 The FAME 1 trial compared FFR with angiography to guide revascularization and found that FFR-guided PCI was associated with reduced adverse cardiac events at 1-year follow-up, 5 while at 5-year follow-up long-term outcomes of FFR-guided PCI led to equivalent results in terms of MACE compared with angiography-guided PCI, but with the use of fewer stents. 31 The FAME 2 trial determined that FFR-guided PCI plus medical therapy was associated with lower rates of death, MI, or urgent revascularization as compared to medical therapy alone for patients with functionally significant stenoses, 6 although still half of patients with abnormal FFR results did not experience adverse events or required revascularization during 5 years of follow-up. 32 Other trials have questioned the effectiveness of FFR-guided PCI in different clinical settings and found conflicting results. Many studies and meta-analyses have compared FFR-guided PCI with angiography-guided PCI; 33,34 however, in recent years an interest has emerged in comparing FFR-guided PCI with imaging-guided PCI and CABG and some important trials have been conducted. 21,29,35 Therefore, it is important to compare the role of FFR-guided PCI with all available evidence on different revascularization strategies to provide a comprehensive and quantitative assessment of evidence about the contemporary efficacy of FFR-guided PCI which we aimed to achieve with this meta-analysis.

Ongoing FFR controversy
The FAME 3 29 trial documented that FFR-guided PCI was associated with higher risk of MACE as compared to CABG in patient with multivessel CAD, hence establishing that FFR-guided PCI was not noninferior to CABG. 29 The FUTURE (FUnctional Testing Underlying coronary REvascularization) trial compared an FFRguided revascularization strategy to a traditional angiography-guided strategy without FFR in all-comer multivessel CAD patients. 16 The trial was prematurely stopped due to an observed significantly higher all-cause mortality in the FFR-guided group. However, this observation was not confirmed by the intention-to-treat analysis at 1-year follow-up. At 1-year follow-up, no significant difference between FFR-guided based strategy and angiographic-guided strategy was found in terms of MACE. 16 The FLOWER-MI (flow evaluation to guide revascularization in multivessel ST-elevation myo-cardial infarction) trial also deduced that in patients with ST-segment elevation MI undergoing complete revascularization, an FFR-guided strategy did not show any benefit over an angiography-guided strategy with respect to the risk of death, MI, or urgent revascularization at 1 year. 15 Furthermore, studies have suggested that FFR-guided PCI results in lower stroke events than non-physiology-guided PCI. 36 However, Gioia et al., 2020, only observed this decreased stroke risk at 1 year for FFR-guided PCI as compared to angiography-guided strategy, but no difference was seen at 5-year follow-up. 37 Hence, studies conducted so far have given mixed results with some of them establishing FFR as gold standard and others questioning its effectiveness and positive outcomes. Consequently, there is an urgent need to pool and analyze the results from these trials to institute the efficacy of FFR-guided PCI which we aimed to accomplish with this meta-analysis.

Comparison with current results
In the present investigation including 26 studies and 78,897 patients, patients undergoing FFR-guided PCI as compared to other revascularization strategies (angiography-guided PCI, intracoronary imaging-guided PCI, or CABG) were associated with a reduced risk of all-cause mortality, which is mechanistically explained by a significant reduction in the risk of MI. Like the FAME 1 trial 5 and unlike FUTURE 16  iScience Article Concordant with FAME 3 trial, 29 our subgroup analysis concluded that FFR is associated with higher risk of MACE and repeat revascularization as compared to CABG.
Despite our analysis proving superiority of FFR-guided PCI compared to non-physiology-guided revascularization strategies altogether in hard endpoints such as all-cause mortality and MI, some aspects are worth highlighting. The reduced risk of all-cause mortality was not consistent neither at leave-one-out sensitivity analysis nor at subgroup analysis. In addition, wide prediction intervals showed possible null effect on the risk of all-cause mortality. Similarly, important limitations were shown in the lower risk of MI in patients undergoing FFR-PCI such as wide prediction intervals, and subgroup analysis results were non-consistent with this risk reduction.  39 have recently conducted a meta-analysis and concluded that non-fatal MI did not meet the threshold to be designated as a surrogate measure for all-cause or cardiovascular mortality in primary, secondary, and mixed prevention and revascularization trials. 39,40 Despite the important limitations of the aforementioned study such as including trials that used time-to-event statistics for composite endpoints which considers only the first event, 41 the risk reduction in MI instituted by our study should be interpreted with caution due to the reasons discussed above.

FFR use in ACS
It should be highlighted that the class 1A recommendation for FFR to evaluate coronary artery stenosis and direct revascularization strategies applies to patients presenting with stable CAD. 2,3 In an acute setting, hemodynamics and FFR evaluation differs from that of patients with stable CAD. Despite some studies showing that the addition of FFR-guided revascularization of non-infarct-related arteries is associated with lower risk of all-cause mortality and MACE as compared to patients with ST-segment elevation MI who are only treated with PCI for the infarct-related artery, 42,43 other studies have questioned its usefulness in patients presenting with ACSs. 44,45 Different trials and meta-analyses have shown that deferral of revascularization based on non-ischemic FFR in patients presenting with ACSs is associated with higher risk of mortality and MACE as compared to stable CAD patients, which has been attributed to higher rates of unplanned revascularization. [44][45][46][47] A proposed mechanism is that in an acute setting, MI causes microvascular dysfunction not only limited to the myocardium supplied by the culprit artery, reducing the hyperemic response to a vasodilating agent like adenosine, and FFR, which is a hyperemic index, tends to underestimate the true severity of stenosis leading to false-negative FFR. 48 Hitherto, FFR threshold to define a significant stenosis in ACS patients' needs to be investigated and FFR values derived from stable CAD should be used with caution for decision making in ACS patients.

FFR versus intracoronary imaging for PCI guidance
Finally, intracoronary imaging with intravascular ultrasound or optical coherence tomography has the potential to identify vulnerable plaques at risk of future events and physiologically nonsignificant lesions requiring preventive treatment and even guide revascularization deferrals for patients with ACSs. 49 The FORZA (fractional flow reserve vs. optical coherence tomography to guide revas-cularization of intermediate coronary stenoses) trial randomized patients to undergo FFR-guided PCI or optical coherence tomography-guided PCI. 35 At 13-month follow-up optical coherence tomography-guided PCI was associated with lower risk of MACE and angina as compared to FFR-guided PCI. 35 COMBINE OCT-FFR (combined optical coherence tomography morphologic and fractional flow reserve hemodynamic assessment of non-culprit lesions to better predict adverse event outcomes in diabetes mellitus patients) trial divided the diabetic patients with FFR-negative lesions into two groups based on the presence or absence of R1 thin-cap fibroatheroma lesion assessed by optical coherence tomography. 50 This study deduced that presence of thin-cap fibroatheroma was associated with five times higher risk of MACE as compared to its absence despite the lack of ischemia, 50 thus, establishing the significance of studying the anatomical plaque characteristics. These findings highlight the increased frequency of vulnerable plaques in patients with multivessel disease and hint at the future need to use intracoronary imaging to guide the revascularization of non-culprit lesions in ACS patients with multivessel disease.

Limitations
The results of our investigation should be interpreted in light of some limitations. First, this is a study-level meta-analysis providing average treatment effects; the lack of patient-level data from the included studies prevents us from assessing the impact of baseline clinical and procedural characteristics on treatment effects. Second, minor differences in definition were present for some endpoints, limiting the reliability of effect estimates. Finally, the limited number of studies in some subgroups (i.e., those undergoing intracoronary imaging-guided PCI) may reduce the power for detecting significant differences between groups.

Evidence before this study
Recently published studies comparing FFR-guided PCI with non-physiology-guided revascularization strategies (angiography-guided, intracoronary imaging-guided, CABG) have reported conflicting result. Some trials have established FFR as gold standard for coronary revascularization (FAME, FAME 2) while others have questioned its effectiveness and positive outcomes (FAME 3, FUTURE, FLOWER MI). Consequently, there is an urgent need to pool and analyze the results from published evidence to institute the efficacy of FFR-guided PCI. Therefore, we performed a systematic review and meta-analysis of studies comparing FFR-guided PCI with non-physiology-guided revascularization strategies.

Added value of this study
This is the most comprehensive systematic review and meta-analysis of evidence evaluating FFR-guided PCI versus non-physiology-guided revascularization strategies (angiography-guided, intracoronary imaging-guided, CABG). We included findings of 78,897 patients from 26 studies. Patients undergoing FFR-PCI as compared to those undergoing non-physiology-guided revascularization strategies were associated with a lower risk of all-cause mortality and MI, while no differences between groups were found in terms of MACE and repeat revascularization. The NNT to prevent one death was 100 patients.

Implications of all the available evidence
In patients with CAD undergoing coronary revascularization, FFR-guided PCI was associated with a lower risk of all-cause mortality, which is mechanistically explained by a reduced risk of MI. Notwithstanding, the results should be interpreted with caution. The one-size-fits-all approach should not be applied when evaluating the role of FFR to guide revascularization as patients with multivessel disease and those presenting with ACS represent different clinical scenarios where the impact of FFR-guided PCI is yet under debate.

Conclusions
Among patients with CAD, FFR-guided PCI as compared to non-physiology-guided revascularization strategies was associated with a lower risk of all-cause mortality and MI. No differences between groups were shown in the risk of MACE and repeat revascularization. However, these findings should be interpreted with caution given high heterogeneity leading to prediction intervals that show a possible null effect on the risk of all-cause death and MI.

STAR+METHODS
Detailed methods are provided in the online version of this paper and include the following:  This study is a meta-analysis and did not use or generate any reagents.

Data and code availability
This meta-analysis used data from published studies which are referenced in the manuscript. The methods used for meta-analysis are referenced are explained in the 'methods' section.

EXPERIMENTAL MODEL AND STUDY PARTICIPANT DETAILS
Our study does not use experimental models typical in the life sciences.

METHODS DETAILS
We performed a meta-analysis which included randomized clinical trials (RCTs) and observational studies. Inclusion criteria was the studies comparing FFR-guided PCI with non-physiology-guided revascularization strategies and availability of clinical outcome data (Data S1). We also excluded the studies comparing FFRguided PCI with optimal medical therapy and studies using physiology assessment different from FFR. The risk of bias assessment is outlined it Tables S2 and S3. The search strategy, selection, and data extraction were performed in accordance with The Cochrane Collaboration and PRISMA guidelines. The primary outcome was all-cause mortality. Secondary outcomes were myocardial infarction (MI), repeat revascularization and major adverse cardiac events (MACE).

Search strategy and selection criteria
Randomized clinical trials (RCTs) and observational studies including patients with coronary artery disease (CAD) undergoing coronary revascularization were evaluated for inclusion in this meta-analysis. Eligible studies had to satisfy the following pre-specified inclusion criteria: 1) studies comparing FFR-guided PCI with non-physiology-guided revascularization strategies (angiography-or intracoronary imaging-guided PCI or CABG) and 2) availability of clinical outcome data. Exclusion criteria were: 1) studies comparing FFR-guided PCI with optimal medical therapy and 2) studies using physiology assessment different from FFR.

Data extraction
Three investigators (JSS, JF, and JMS) independently assessed studies for possible inclusion, with the senior investigator (HGG) resolving discrepancies. Non-relevant articles were excluded based on title and abstract. The same investigators independently extracted data on study design, measurements, patient characteristics, and outcomes, using a standardized data-extraction form. Data extraction conflicts were discussed and resolved with the senior investigator (HGG).
Data about authors, year of publication, inclusion and exclusion criteria, sample size, baseline patients' features, endpoint definitions, effect estimates, and follow-up time were collected.

Outcomes of interest
The pre-specified primary endpoint was all-cause death. Secondary clinical endpoints were myocardial infarction (MI), repeat revascularization, and major adverse cardiac events (MACEs). For clinical studies not reporting MACE, data on major adverse cardiac and cerebrovascular events were used. Each endpoint was assessed according to the definitions reported in the original study protocols, as summarized in Table S1.

Risk of bias
The risk of bias in each study has been assessed using the revised Cochrane risk of bias tool (RoB 2.0) 18 for RCTs and the Risk of Bias in Non-randomized Studies of Interventions assessment tool from Cochrane handbook (ROBINS-I) 19 for observational studies. Three investigators (JSS, JF, and JMS) independently assessed five domains of bias in RCTs: (1) randomization process, (2) deviations from intended interventions,  (Tables S2 and S3).

Statistical analysis
Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the DerSimonian and Laird random-effects model, with the estimate of heterogeneity being taken from the Mantel-Haenszel method. The number of patients needed to treat (NNT) to prevent one event was calculated from weighted estimates of pooled ORs from the random-effects meta-analytic model. The presence of heterogeneity among studies was evaluated with the Cochran Q chi-squared test, with p % 0.10 considered of statistical significance, and using the I 2 test to evaluate inconsistency. A value of 0% indicates no observed heterogeneity, and larger values indicate increasing heterogeneity. I 2 values of %25%, %50%, and >50% indicated low, moderate, and high heterogeneity, respectively. Publication bias and small study effect were assessed using funnel plots. The presence of publication bias was investigated with Harbord and Egger tests, and by visual estimation with funnel plots. Two separate pre-specified subgroup analyses according to: 1) the control revascularization strategy (i.e., angiography-guided, intracoronary imaging-guided, CABG) and 2) study design (i.e., RCT vs. observational studies) were performed. OR with 95% CI was reported in each subgroup. To assess the interaction between these potential effect modifiers and treatment, a random-effects meta-regression analysis with the ''empirical Bayes'' (Paule-Mandel) method to estimate the between-study variance Tau 2 and the Hartung-Knapp-Sidik-Jonkman adjustment was performed. The meta-regression coefficient and its corresponding p value were reported (the statistical level of significance was two-tailed p < 0.1). Furthermore, we assessed the presence of interaction between number of diseased vessels, follow-up duration, and percentage of population presenting with acute coronary syndrome (ACS) and treatment for all endpoints by performing meta-regression analyses with the same method as earlier.
Pre-specified sensitivity analyses were performed by iteratively removing one study at a time to confirm that our findings were not driven by any single study. We calculated 95% prediction intervals for the effect estimates of each outcome to present the expected range of true effects in a future trial, based on the extent of heterogeneity. Analyses were performed according to the intention-to-treat principle.

QUANTIFICATION AND STATISTICAL ANALYSIS
DerSimonian and Laird random-effects model was used to calculate odds ratios (OR) and 95% confidence intervals (CI) and estimate of heterogeneity was taken from the Mantel-Haenszel method. The presence of heterogeneity among studies was evaluated with the Cochran Q chi-square test, and using the I 2 test to evaluate inconsistency. We used Harbord and Egger tests to identify the presence of publication bias in addition to visual estimation with funnel plots (Figures S1-S4). A random-effects meta-regression analysis (Table S4) with the ''empirical Bayes'' (Paule-Mandel) method was employed to estimate the between study variance Tau 2 and the Hartung-Knapp-Sidik-Jonkman adjustment was performed to study the interaction between potential effect modifiers and treatment. A leave-one-out sensitivity analysis was performed for the outcomes by removing one study at a time to confirm that our findings were not driven by any single study (Tables S5-S8). Stratified analyses according to the revascularization strategy and study design was also performed ( Figures S5-S6). The statistical level of significance was two-tailed p < 0.05. Publication bias was detected for all-cause mortality as shown by Harbord test (p = 0.005). Stata software version 13.1 was used for statistical analyses.

ADDITIONAL RESOURCES
Our study has not generated or contributed to a new website and it is not part of a clinical trial.

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