Death and MI in DEFINE-FLAIR and iFR-SWEDEHEART Trials

Study Questions:

What are the pooled events for death and myocardial infarction (MI) in the DEFINE-FLAIR and iFR-SWEDEHEART trials?

Methods:

The investigators conducted a pooled analysis of death and MI in the DEFINE-FLAIR and iFR-SWEDEHEART clinical trials, which compared instantaneous wave-free ratio (iFR)-guided management versus fractional flow reserve (FFR)-guided management using binary cut-off values in both groups. The primary composite outcome of death, MI, and urgent revascularization at 12 months and the noninferiority designs were consistent across both 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.

Results:

In the DEFINE-FLAIR and iFR-SWEDEHEART trials, there was a numerical excess of death or MI events in the iFR compared with FFR groups. There is directional consistency for these spontaneous components of the primary outcome in both trials and also when considering death and MI as separate outcomes. Both trials have relevant design limitations. First, due to the concordance between iFR and FFR in 80% of patients, the randomized strategy could only influence outcome in 20% of trial participants, diluting the power of both studies to detect a clinically meaningful difference in outcomes. Second, in the context of other evidence, the discordance between iFR and FFR is greatest in stenoses of the left main and proximal coronary arteries, which is where revascularization may confer a survival advantage.

Conclusions:

The authors concluded that in a pooled meta-analysis of the DEFINE-FLAIR and iFR-SWEDEHEART trials, there is a numerical excess of death and MI events in the iFR group.

Perspective:

This pooled meta-analysis of the DEFINE-FLAIR and iFR-SWEDEHEART trials reports a numerical excess of death and MI events in the iFR group that is not statistically significant, and should be considered hypothesis generating. Considering death and MI, management guided by iFR may not be noninferior to management guided by FFR, and additional studies are indicated to understand this better. It should be noted that the populations studied in both trials were at relatively low cardiovascular risk, with incidence of death, MI, and repeat revascularization at 1 year approximately half of what was observed in the FAME trial, highlighting the limited power for detecting differences in outcomes between the two strategies in the current trials. This further underscores the need for additional comparative studies of iFR-guided management versus FFR-guided management.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Cardiac Surgery and SIHD, Interventions and ACS, Chronic Angina

Keywords: Acute Coronary Syndrome, Angina, Stable, Constriction, Pathologic, Coronary Stenosis, Fractional Flow Reserve, Myocardial, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Risk Factors, Treatment Outcome


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