Prescription EPA benefits statin-treated patients with history of PCI

A daily, 4-gram dose of icosapent ethyl (IPE) led to a significant reduction in ischaemic events in a subgroup of patients from the REDUCE-IT* cohort who had prior PCI**, according to the prespecified analysis of the REDUCE-IT PCI trial presented at TCT 2020.

“Compared with placebo, IPE 4 g daily significantly reduced first and total events in patients with prior PCI,” said Dr Benjamin Peterson from the Brigham and Women’s Hospital, Boston, Massachusetts, US. The hazard ratio [HR] for first events was 0.66 (p<0.0000001), while the rate ratio [RR] for total events was 0.61 (p=0.000000003). [TCT 2020, Best of Abstracts]

Over a median of 4.9 years, there was a marked reduction in the rates of the primary composite*** (25.6 percent vs 37.6 percent; HR, 0.66; p=0.0000000003) and key secondary^# endpoints (15.4 percent vs 23.5 percent; HR, 0.66; p=0.000006) with IPE vs placebo.

The benefit was consistent across the other^## prespecified hierarchy of endpoints, with HRs ranging from 0.59 to 0.72.

Except for a slightly increased rate of atrial fibrillation/flutter with IPE vs placebo (3.4 percent vs 2.2 percent; p=0.04), IPE was generally well-tolerated. There were similar bleeding (12.7 percent vs 12.1 percent; p=0.60) and serious bleeding rates (3.2 percent vs 2.8 percent; p=0.42) between the IPE and the placebo arms.

“[Taken together,] these data reflect the substantial impact of IPE on the at-risk REDUCE-IT population, including patients with prior PCI,” said Peterson.

REDUCE-IT PCI saw 41.7 percent of the 8,179 REDUCE-IT participants who had undergone prior PCI (n=3,408; median age 63 years, 79 percent male). Patients were randomized to receive IPE 2 g BID or placebo. For this subgroup, participants were randomized at a median of 2.9 years after PCI.

Consistent findings from the get-go

The benefits of IPE vs placebo were already seen from the outset, with the primary REDUCE-IT results reflecting significantly reduced risks of the primary composite (HR, 0.75; p=0.00000001) and key secondary endpoints (HR, 0.74; p=0.0000006), as well as total events (RR, 0.69; p=0.0000000004). [NEJM 2019;380:11-22; JACC 2019;73:2791-2802]

In REDUCE-IT REVASC^###, the 34-percent reduction (HR, 0.66; p=0.0000000008) in revascularization events with IPE vs placebo was, as per Peterson, “the largest reduction in coronary revascularization reported since early statin trials.” Revascularization subtypes consistently and significantly dropped as well, be it elective (HR, 0.68; p=0.00003), urgent (HR, 0.66; p=0.00001), or emergent revascularization (HR, 0.62; p=0.02).

“The effectiveness of IPE was demonstrated strongly early, with statistical significance consistently reached by 11 months. [However,] this effect is likely underestimated because patients with planned coronary revascularization procedures were excluded from the trial,” he added.

Nothing short of extraordinary

Discussant Professor Anthony Gershlick from the University of Leicester, England, lauded the findings. “[Given] the p values, [this is the] most extraordinary thing I’ve seen in a long while. [It is] almost unbelievable, because if it wasn’t for the hard endpoints, you’d have to say that maybe the patients were unblinded or the trial finished at the point at which they presented for their revascularization.”

Gershlick asked whether there was any correlation with triglyceride reduction, given “such an extraordinary effect from a drug that is added to statins”, and also considering that atheroma regression takes a long time.

Peterson said that there were indeed modest triglyceride reductions in the main trial and the subanalysis. “[However,] that is not the only mechanism at play here. [T]his trial had a comparable reduction in the inflammatory markers seen in the CANTOS^Ŧ trial. [While] the mechanism behind that is not totally understood, there [could be] a strong anti-inflammatory component.” [N Engl J Med 2017;377:1119-1131]

Moreover, in the EVAPORATE^ŦŦ study, which used high-resolution CT images to evaluate plaques, [Eur Heart J 2020;doi:10.1093/eurheartj/ehaa652] there was a rapid plaque reduction (within 9 months) or slowing of the progression of the fibrofatty plaques, added Peterson. “We wish there was a core lab … that could help us sort that out. [Nonetheless,] EVAPORATE may indeed help us look at that.”

Regarding drug uptake, Peterson said, “We hope to see more use of it … We hope this can work its way into the guidelines. [A] majority of these patients may well benefit from IPE, and this has also been confirmed in European, Canadian, and US registry data where there is quite a large subgroup of patients that will benefit from this.”