Fractional flow reserve-guided percutaneous coronary intervention vs. medical therapy for patients with stable coronary lesions: meta-analysis of individual patient data

Frederik M Zimmermann, Elmir Omerovic, Stephane Fournier, Henning Kelbæk, Nils P Johnson, Martina Rothenbühler, Panagiotis Xaplanteris, Mohamed Abdel-Wahab, Emanuele Barbato, Dan Eik Høfsten, Pim A L Tonino, Bianca M Boxma-de Klerk, William F Fearon, Lars Køber, Pieter C Smits, Bernard De Bruyne, Nico H J Pijls, Peter Jüni, Thomas Engstrøm, Frederik M Zimmermann, Elmir Omerovic, Stephane Fournier, Henning Kelbæk, Nils P Johnson, Martina Rothenbühler, Panagiotis Xaplanteris, Mohamed Abdel-Wahab, Emanuele Barbato, Dan Eik Høfsten, Pim A L Tonino, Bianca M Boxma-de Klerk, William F Fearon, Lars Køber, Pieter C Smits, Bernard De Bruyne, Nico H J Pijls, Peter Jüni, Thomas Engstrøm

Abstract

Aims: To assess the effect of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) with contemporary drug-eluting stents on the composite of cardiac death or myocardial infarction (MI) vs. medical therapy in patients with stable coronary lesions.

Methods and results: We performed a systematic review and meta-analysis of individual patient data (IPD) of the three available randomized trials of contemporary FFR-guided PCI vs. medical therapy for patients with stable coronary lesions: FAME 2 (NCT01132495), DANAMI-3-PRIMULTI (NCT01960933), and Compare-Acute (NCT01399736). FAME 2 enrolled patients with stable coronary artery disease (CAD), while the other two focused on non-culprit lesions in stabilized patients after acute coronary syndrome. A total of 2400 subjects were recruited from 54 sites world-wide with 1056 randomly assigned to FFR-guided PCI and 1344 to medical therapy. The pre-specified primary outcome was a composite of cardiac death or MI. We included data from extended follow-ups for FAME 2 (up to 5.5 years follow-up) and DANAMI-3-PRIMULTI (up to 4.7 years follow-up). After a median follow-up of 35 months (interquartile range 12-60 months), a reduction in the composite of cardiac death or MI was observed with FFR-guided PCI as compared with medical therapy (hazard ratio 0.72, 95% confidence interval 0.54-0.96; P = 0.02). The difference between groups was driven by MI.

Conclusion: In this IPD meta-analysis of the three available randomized controlled trials to date, FFR-guided PCI resulted in a reduction of the composite of cardiac death or MI compared with medical therapy, which was driven by a decreased risk of MI.

Figures

Figure 1
Figure 1
Design of trials included in individual patient data meta-analysis.
Figure 2
Figure 2
Primary composite endpoint of cardiac death or myocardial infarction. The cumulative incidence of the primary endpoint of cardiac death or myocardial infarction was significantly reduced in subjects randomized to fractional flow reserve-guided percutaneous coronary intervention compared with medical therapy alone. Dashed lines are crude time-to-event curves and solid lines are fitted cumulative incidence curves as predicted from a mixed effects flexible parametric model. Only the fitted curves should be used for inferences about the treatment effect.
Figure 3
Figure 3
Subgroup analyses of primary composite endpoint of cardiac death or myocardial infarction. Pre-specified subgroup analyses of the primary outcome are shown according to clinical presentation (stable coronary artery disease vs. acute coronary syndrome) and fractional flow reserve status (patients with at least one stable coronary lesion with a positive fractional flow reserve of ≤0.80 vs. patients with only lesions with a negative fractional flow reserve of >0.80). The Post hoc subgroup analyses of the primary endpoint specified are shown according to age (>60 years or ≤60 years), sex, diabetes status, previous myocardial infarction, and smoking. CAD, coronary artery disease; FFR, fractional flow reserve; HR, hazard ratio; MT, medical therapy; PCI, percutaneous coronary intervention. P-values for interaction are for within-trial interaction unless indicated otherwise. *P-value for interaction is for across-trial interaction.
Figure 4
Figure 4
Landmark analyses of primary composite endpoint and its components. The hazard ratios of the primary composite outcome of cardiac death or myocardial infarction and of components of the primary composite outcome shown according to the time from randomization (7 days or less vs. 8 days or more). The solid boxes represent hazard ratios for 7 days or less after randomization, the open boxes represent hazard ratios for 8 days or more from randomization. Arrows indicate that the ends of the confidence interval are either less than 0.4 or more than 5. FFR, fractional flow reserve; HR, hazard ratio; PCI, percutaneous coronary intervention.

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