Benefit of icosapent ethyl on coronary physiology assessed by computed tomography angiography fractional flow reserve: EVAPORATE-FFR(CT)

AIMS: Icosapent ethyl (IPE) significantly reduced ischaemic events in statin-treated patients with atherosclerosis or diabetes and elevated triglycerides in REDUCE-IT, including large reductions in myocardial infarction and elective, urgent, and emergent coronary revascularization. However, the mechanisms driving this clinical benefit are not fully known. The EVAPORATE trial demonstrated that IPE significantly reduced plaque burden. No study to date has assessed the impact of IPE on coronary physiology. Fractional flow reserve (FFR) derived from coronary computed tomography angiography (CTA) data sets (FFR(CT)) applies computational fluid dynamics to calculate FFR values in epicardial coronary arteries. Our objective was to assess the impact of IPE on coronary physiology assessed by FFR(CT) using imaging data from EVAPORATE. METHODS AND RESULTS: A total of 47 patients and of 507 coronary lesions at baseline, 9 months, and 18 months with coronary CTA and FFR(CT) were studied in a blinded core lab. The pre-specified primary endpoint was the FFR(CT) value in the distal coronary segment from baseline to follow-up in the most diseased vessel per patient using IPE compared with placebo. The pre-specified secondary endpoint was the change in translesional FFR(CT) (ΔFFR(CT)) across the most severe (minimum 30% diameter stenosis) coronary lesion per vessel. Baseline FFR(CT) was similar for IPE compared with placebo (0.83 ± 0.08 vs. 0.84 ± 0.08, P = 0.55). There was significant improvement in the primary endpoint, as IPE improved mean distal segment FFR(CT) at 9- and 18-month follow-up compared with placebo (0.01 ± 0.05 vs. −0.05 ± 0.09, P = 0.02, and −0.01 ± 0.09 vs. −0.09 ± 0.12, P = 0.03, respectively). ΔFFR(CT) in 140 coronary lesions was improved, although not statistically significant, with IPE compared with placebo (−0.06 ± 0.08 vs. −0.09 ± 0.1, P = 0.054). CONCLUSION: Icosapent ethyl demonstrated significant benefits in coronary physiology compared with placebo. This early and sustained improvement in FFR(CT) at 9- and 18-month follow-up provides mechanistic insight into the clinical benefit observed in the REDUCE-IT trial. Furthermore, this is the first assessment of FFR(CT) to determine drug effect.