REDUCE-IT USA: Results From the 3146 Patients Randomized in the United States

Deepak L Bhatt, Michael Miller, Eliot A Brinton, Terry A Jacobson, Ph Gabriel Steg, Steven B Ketchum, Ralph T Doyle Jr, Rebecca A Juliano, Lixia Jiao, Craig Granowitz, Jean-Claude Tardif, Brian Olshansky, Mina K Chung, C Michael Gibson, Robert P Giugliano, Matthew J Budoff, Christie M Ballantyne, REDUCE-IT Investigators, Deepak L Bhatt, Michael Miller, Eliot A Brinton, Terry A Jacobson, Ph Gabriel Steg, Steven B Ketchum, Ralph T Doyle Jr, Rebecca A Juliano, Lixia Jiao, Craig Granowitz, Jean-Claude Tardif, Brian Olshansky, Mina K Chung, C Michael Gibson, Robert P Giugliano, Matthew J Budoff, Christie M Ballantyne, REDUCE-IT Investigators

Abstract

Background: Some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. This prespecified REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial) subgroup analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States.

Methods: REDUCE-IT randomized 8179 statin-treated patients with qualifying triglycerides ≥135 and <500 mg/dL and low-density lipoprotein cholesterol >40 and ≤100 mg/dL and a history of atherosclerosis or diabetes mellitus to icosapent ethyl 4 g/d or placebo. The primary composite end point was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary composite end point was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. A hierarchy was prespecified for examination of individual and composite end points.

Results: A total of 3146 US patients (38.5% of the trial) were randomized and followed for a median of 4.9 years; 32.3% were women and 9.7% were Hispanic. The primary composite end point occurred in 24.7% of placebo-treated patients versus 18.2% of icosapent ethyl-treated patients (hazard ratio [HR], 0.69 [95% CI, 0.59-0.80]; P=0.000001); the key secondary composite end point occurred in 16.6% versus 12.1% (HR, 0.69 [95% CI, 0.57-0.83]; P=0.00008). All prespecified hierarchical end points were meaningfully and significantly reduced, including cardiovascular death (6.7% to 4.7%; HR, 0.66 [95% CI, 0.49-0.90]; P=0.007), myocardial infarction (8.8% to 6.7%; HR, 0.72 [95% CI, 0.56-0.93]; P=0.01), stroke (4.1% to 2.6%; HR, 0.63 [95% CI, 0.43-0.93]; P=0.02), and all-cause mortality (9.8% to 7.2%; HR, 0.70 [95% CI, 0.55-0.90]; P=0.004); for all-cause mortality in the US versus non-US patients, Pinteraction=0.02. Safety and tolerability findings were consistent with the full study cohort.

Conclusions: Whereas the non-US subgroup showed significant reductions in the primary and key secondary end points, the US subgroup demonstrated particularly robust risk reductions across a variety of individual and composite end points, including all-cause mortality.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01492361.

Keywords: United States; eicosapentaenoic acid ethyl ester; fatty acids, omega-3; lipids; prevention and control; triglycerides.

Figures

Figure 1.
Figure 1.
Kaplan-Meier curves for the primary composite end point in the US subgroup. The y axis represents the cumulative incidence rate. Primary composite end point events were cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. The curves were visually truncated at 5.7 years because a limited number of events occurred beyond that time point; all patient data were included in the analyses. *Estimated Kaplan-Meier event rate at ≈5.7 years. HR indicates hazard ratio; and no. at risk, number of patients at risk for an event.
Figure 2.
Figure 2.
Kaplan-Meier curves for the key secondary composite end point in the US subgroup. The y axis represents the cumulative incidence rate. Key secondary composite end point events were cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The curves were visually truncated at 5.7 years because a limited number of events occurred beyond that time point; all patient data were included in the analyses. *Estimated Kaplan-Meier event rate at ≈5.7 years. HR indicates hazard ratio; and no. at risk, number of patients at risk for an event.
Figure 3.
Figure 3.
Hierarchical testing of end points in the US subgroup. The prespecified plan for hierarchical testing of end points for the US subgroup. The rates of all end points including total mortality were significantly lower in the icosapent ethyl group than in the placebo group. HR indicates hazard ratio; and ITT, intention to treat.
Figure 4.
Figure 4.
Total mortality in the US subgroup. Kaplan-Meier event curves for the end point of all-cause mortality in the US subgroup. The y axis represents the cumulative incidence rate. The curves were visually truncated at 5.7 years because a limited number of events occurred beyond that time point; all patient data were included in the analyses. *Estimated Kaplan-Meier event rate at ≈5.7 years. HR indicates hazard ratio; and no. at risk, number of patients at risk for an event.

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