Icosapent ethyl reduces MI events in statin-treated patients

In the REDUCE-IT STEMI trial, icosapent ethyl (IPE) reduced MI events overall and across an array of MI subtypes in statin-treated patients at increased cardiovascular (CV) risk.

 

“In the overall MI analyses (which includes fatal, nonfatal, STEMI, NSTEMI*), we saw a 31-percent relative risk reduction (RR) that is statistically significant,” said Professor Deepak Bhatt from Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, US, at ESC 2022.

 

The event rate in the IPE arm was 8.6 percent as opposed to 12.0 percent in the placebo arm (hazard ratio [HR], 0.69; p=0.000005). [ESC 2022, Late-Breaking Science Session]

 

The benefit was seen early and became significant at 26 months, Bhatt noted. “Therefore, by about 2 years, the reduction in MI became consistently statistically significant; so, it takes about that long for that endpoint to be influenced.”

 

When evaluated separately, both STEMI and NSTEMI events were lower with IPE vs placebo (2.7 percent vs 3.9 percent; HR, 0.60; p=0.0008 [STEMI] and 5.9 percent vs 7.8 percent; HR, 0.73; p=0.001 [NSTEMI]).

 

Results consistently favoured IPE over placebo when evaluating other MI subtypes, such as nonfatal (HR, 0.70) and spontaneous MI (HR, 0.67), MI defined by clinical presentation (HR, 0.66), biomarker elevations (HR, 0.67), and electrocardiographic changes (HR, 0.64), and type 1 MI, which comprised the bulk of MIs in this trial (HR, 0.67; p<0.0001 for all).

 

Other MI subtypes that were markedly reduced with IPE vs placebo were fatal (HR, 0.55; p=0.048), resuscitated (HR, 0.34; p=0.006), and PCI**-related MI (HR, 0.25; p=0.06), as well as MI leading to cardiac arrest (HR, 0.49; p=0.01).

 

Evaluation of MI by size showed a consistent, significant reduction – from the relatively smaller (≥1 x ULN***; HR, 0.67; p=0.0005) to the bigger MIs (≥100 x ULN; HR, 0.54; p=0.004). “[T]he bigger MIs [appear to have] a lower HR or a greater effect size with IPE vs placebo than the smaller MIs,” noted Bhatt. “[There was] indeed a statistically significant trend (p=0.000008), suggesting that there is, in fact, even greater benefit with IPE vs placebo on the big MIs.” Bhatt was quick to point out though that despite these results, it does not mean that “the smaller ones do not matter”.

 

EPA exposure response

In the placebo arm, there was no significant change in EPA^# level. When examining the association between higher EPA levels and lower MI rates, the relationship was significant but relatively muted (Cox-Stuart trend test p value for slope, 0.008). “[The] EPA levels are not being affected by the placebo but are rather determined by a person’s genetics, diet, and other factors that [we have yet to] understand,” noted Bhatt.

 

In the IPE arm, there was a 400-percent increase in EPA level. The relationship between higher levels of achieved on-treatment EPA and lower MI rates was more robust (Cox-Stuart trend test p value for slope, <0.001), as “the drug is raising EPA levels much more so than a person can just by virtue of diet and good genetics,” said Bhatt. “We believe the [large increase in EPA levels] is what’s driving the majority of benefit in the trial, not just for MI but for all endpoints.”

 

Safety outcomes

“Overall tolerability and adverse event patterns with IPE and placebo in patients who developed STEMI or NSTEMI were consistent with the full study,” said Bhatt.

 

Nonserious bleeding events, though numerically higher with IPE vs placebo, were not significantly different between arms (19 percent vs 14 percent; p=0.41 [STEMI] and 24 percent vs 18 percent; p=0.23 [NSTEMI]). These effects were seen regardless of background antithrombotic therapy.

 

In line with primary outcomes

In REDUCE-IT, all 8,179 participants had mildly elevated triglycerides (135–500 mg/dL), received dietary counselling, and had to be on a statin. They were randomized 1:1 to either IPE 2 g BID or placebo and were followed for up to 6.2 years.

 

The current outcomes reinforce the initial findings of significant reductions in the primary composite^## (HR, 0.75; p=0.00000001) and key secondary^### endpoints (HR, 0.74; p=0.0000006), and in first and subsequent events (RR, 0.69; p=0.0000000004), with IPE vs placebo. [N Engl J Med 2019;380:11-22; J Am Coll Cardiol 2019;73:2791-2802]

 

Taken together, the findings continue to underline the CV benefit of IPE in this patient setting.