Meta-Analysis of Death and Myocardial Infarction in the DEFINE-FLAIR and iFR-SWEDEHEART Trials

In patients with coronary heart disease, revascularization can improve symptoms and, in certain high-risk subgroups, may improve prognosis. Coronary angiography provides anatomic information, and the physiological significance of a stenosis can be determined using fractional flow reserve (FFR). Decisions on the need for and mode of revascularization can be optimized using FFR. However, this process involves administering adenosine to induce hyperemia. Generally, this is well tolerated, but in some healthcare systems, adenosine is either not licensed, unavailable, or expensive, limiting the use of FFR-guided management. Recently, alternative approaches to FFR have emerged, including resting indices such as Pd/Pa and instantaneous wave free ratio (iFR).1,2 Hybrid algorithms incorporating a resting index reduce the need for adenosine by ≈50% or a hybrid algorithm utilizing contrast FFR reduces adenosine use even further (~65%).3 These diagnostic approaches represent clinically useful advances provided health outcomes are not compromised. The DEFINE-FLAIR trial (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation)1 and the iFR-SWEDE-HEART trial (Instantaneous Wavefree Ratio versus Fractional Flow Reserve in Patients with Stable Angina Pectoris or Acute Coronary Syndrome)2 compared iFRversus FFR-guided management using binary cutoff values in both groups. The primary composite outcome of death, myocardial infarction (MI), and urgent revascularization at 12 months and the noninferiority designs were consistent across both trials. Overall, an iFR-guided strategy was associated with a lower use of revascularization, and the primary end point results of both trials met the prespecified noninferiority criteria. The numerically dominant component of the primary outcome was unplanned revascularization. The rationale of our study was to assess the risk of death and MI between the iFRand FFR-guided groups in a pooled analysis of these trials. Our objective was to undertake a meta-analysis of the pooled events for death and MI in the DEFINE-FLAIR and iFR-SWEDE-HEART trials. The principal summary measure was the risk ratio (95% confidence interval [CI] and P value) calculated for each study. Meta-analysis estimates were calculated from a random effects model using the REML method. Fixed effects analyses using the Cochrane-Mantel-Haenzel method produced near identical results (not shown). I2 was used to measure the consistency of the meta-analysis. The analysis was conducted with R (version 3.10) using the metaphor (https://CRAN.R-project.org/package=metafor) and rmeta (https://CRAN.R-project.org/package=rmeta) packages. The study characteristics and results are summarized in the Table. In total, 160 deaths or MI events occurred in 4345 participants during the 12 months after randomization. Of these events, 90 occurred in the iFR group (n=2159), and 70 events occurred in the FFR group (n=2186) (hazard ratio, 1.30; 95% CI, 0.96‒1.77; P=0.09). Considering the hazard ratio for death or MI, the lower CI limit crosses unity. The upper CI limit indicates that the risk of this adverse outColin Berry, MBChB, PhD* John D. McClure, PhD* Keith G. Oldroyd, MD(Hons)