The Reduction of Cardiovascular Events with Icosapent Ethyl‚ÄìIntervention Trial (REDUCE-IT) REVASC

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Macrovascular Residual Risk Studies

16 February 2021

The latest data from REDUCE-IT show that treatment with high-dose icosapent ethyl reduces coronary revascularizations in statin-treated patients with elevated triglyceride (TG) levels.

Peterson BE, Bhatt DL, Steg Ph.G, et al. Reduction in revascularization with icosapent ethyl: insights from REDUCE-IT REVASC. Circulation 2020; doi 10.1161/CIRCULATIONAHA.120.050276.

STUDY SUMMARY

Objective:

To investigate the effects of icosapent ethyl, a highly purified ethyl-ester form of eicosapentaenoic acid, versus placebo (mineral oil) on first and total (first plus subsequent) coronary revascularization events

Study design:

REDUCE-IT (1) was a phase 3b, double-blind, randomized, placebo-controlled trial in which high-risk patients with elevated TG despite statin therapy were randomly allocated (1:1) to treatment with icosapent ethyl 4 g daily (2 g twice daily) or matching placebo.

Study population:

The REDUCE-IT population comprised 8,179 patients with elevated TG (135-499 mg/dL), controlled low-density lipoprotein cholesterol (LDL-C, 41-100 mg/dL) and either established cardiovascular disease or primary prevention patients with diabetes plus other risk factors.

Study outcome:

· The primary composite endpoint of the REDUCE-IT trial was major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.

· For REDUCE-IT REVASC the key endpoint was coronary revascularization. This was categorized as first or subsequent coronary revascularization events, by subtype (elective, urgent, emergent, or salvage revascularization procedures), as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). Each subtype of revascularization, as well as elective coronary revascularization after 30 days, were prespecified to be analyzed as individual endpoints.

Methods:

The analysis of revascularization events was prespecified. As for the main REDUCE-IT study, Hazard ratios and 95% confidence intervals were generated using a Cox proportional-hazards model using treatment group as the covariate, and stratified by geographic region, cardiovascular risk category, and use of ezetimibe. Log rank test statistics and p-values were generated from Kaplan-Meier analyses of the individual endpoints, also stratified by geographic region, cardiovascular risk category, and use of ezetimibe. Various statistical modelling approaches were used to compare recurrent revascularization rates for the two treatment groups.

Main results:

Over the 4.9-year median follow-up period, there were 376 (9.2%) first coronary revascularizations in the icosapent ethyl group versus 544 (13.3%) in the placebo group, resulting in a 34% relative risk reduction (p<0.0001) and 4.1% absolute risk reduction in events (number needed to treat [NNT] of 24) (Table 1). The benefit was observed early, with a statistically significant difference between the treatment arms from 11 months of treatment.

There were even larger relative risk reductions with icosapent ethyl versus placebo for second revascularization events (by 51%, p<0.0001) and third or subsequent events (by 50%, p=0.04). Overall, total (first and subsequent) revascularizations were reduced by 36% with icosapent ethyl versus placebo (negative binomial rate ratio 0.64; 95% confidence interval [CI], 0.56-0.74; p<0.0001).

There were similar differences for icosapent ethyl versus placebo for relative risk reductions in other subtypes of first revascularization, ranging from 38% for emergent to 32% for elective revascularization (Table 1). There were insufficient events for analysis of the effects of treatment on salvage revascularization (only 2 patients in the placebo group).

Table 1. Analysis of first coronary revascularization endpoints

Endpoint	Icosapent ethyl N=4089	Placebo N=4090	Hazard ratio (95% CI)	p-value	Absolute RR (%)
	n (%)
All revascularizations	376 (9.2)	544 (13.3)	0.66 (0.58–0.76)	<0.0001	4.1
Emergent or urgent revascularization	216 (5.3)	321 (7.8)	0.65 (0.55–0.78)	<0.0001	2.6
Emergent revascularization	41 (1.0)	65 (1.6)	0.62 (0.42–0.92)	0.016	0.6
Urgent revascularization	181 (4.4)	268 (6.6)	0.66 (0.54–0.79)	<0.0001	2.1
Elective revascularization	194 (4.7)	278 (6.8)	0.68 (0.57–0.82)	<0.0001	2.1

RR = risk reduction

Treatment with icosapent ethyl also led to significant relative risk reductions in:

PCI by 32% (7.7% vs. 10.9%; Hazard ratio 0.68; 95% CI 0.59-0.79; p<0.0001), with an absolute risk reduction of 3.2% and a NNT of 31, and
CABG by 39% (1.9% vs. 3.0%; Hazard ratio 0.61; 95% CI, 0.45-0.81; p=0.0005), with an absolute risk reduction of 1.1% and a NNT of 91.

Conclusion:

Icosapent ethyl reduced the need for first and subsequent coronary revascularizations in statin-treated patients with elevated triglycerides and increased cardiovascular risk. To our knowledge, icosapent ethyl is the first non-LDL-lowering treatment that has been shown to reduce CABG in a blinded, randomized trial.

COMMENT

This analysis of the REDUCE-IT REVASC study showed that treatment with high-dose icospaent ethyl led to significant reduction in first (by 34%) and total (by 36%) coronary revascularization events compared with placebo among high-risk patients with elevated triglycerides despite well controlled LDL-C levels with statin treatment. The magnitude of benefit for coronary revascularization compares with a 37% risk reduction observed with simvastatin versus placebo in the Scandinavian Simvastatin Survival Study (4S) (2). Importantly, significantly fewer patients allocated to treatment with icosapent ethyl underwent CABG, a finding that the authors report as novel for a non-LDL-C lowering intervention.

These findings lend some support to the contention that elevated TG levels may be a contributor to the residual risk that persists among high-risk patients despite well-controlled LDL-C levels with a statin. It is, however, important to note that the magnitude of benefit of icosapent ethyl in reducing cardiovascular events, and in this analysis, coronary revascularization, exceeds the modest TG-lowering effect of this treatment (1), suggesting additional mechanisms beyond lipid lowering contribute to this effect (3-5).

References

1. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.

2. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the

Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-9.

3. Bhatt DL, Steg PG, Miller M, Juliano RA, Ballantyne CM. Reply: Ischemic event reduction and triglycerides. J Am Coll Cardiol 2019;74:1849-50.

4. Mason RP, Libby P, Bhatt DL. Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid. Arterioscler Thromb Vasc Biol. 2020; epub ahead of print. ATVBAHA119313286. doi:10.1161/ATVBAHA.119.313286

5. Mason RP. New insights into mechanisms of action for omega-3 fatty acids in atherothrombotic cardiovascular disease. Curr Atheroscler Rep 2019;21,2.

Key words

REDUCE-IT; icosapent ethyl; eicosapentaenoic acid; revascularization; prevention