REDUCE-IT: Icosapent ethyl reduces ischemic events in high-risk patients
CHICAGO — In patients with elevated triglycerides at high CV risk despite statin therapy, icosapent ethyl was superior to placebo for reducing risk for ischemic events, according to results of the anticipated REDUCE-IT trial.
The trial of icosapent ethyl (Vascepa, Amarin Pharmaceuticals), a pharmaceutical-grade omega-3 fatty acid, enrolled 8,179 patients (median age, 64 years; 71% men) who had fasting triglycerides 135 mg/dL to 499 mg/dL despite taking statins and who had established CVD (70.7%) or diabetes plus other risk factors (29.3%). Patients were assigned icosapent ethyl 2 g twice daily or placebo and followed for a median of 4.9 years. All had LDL levels ranging from 41 mg/dL to 100 mg/dL.
Reduction in CV events
The primary endpoint of CV death, nonfatal MI, nonfatal stroke, coronary revascularization or unstable angina occurred less often in the icosapent ethyl group compared with the placebo group (17.2% vs. 22%; HR = 0.75; 95% CI, 0.68-0.83; P = .00000001; absolute difference, 4.8%; 95% CI, 3.1-6.5; number needed to treat to prevent one primary endpoint event = 21; 95% CI, 15-33), Cardiology Today’s Intervention Chief Medical Editor Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, reported at the American Heart Association Scientific Sessions.
“Treatment with icosapent ethyl significantly reduced cardiovascular events, including a 20% reduction in cardiovascular death, a 31% reduction in heart attack, a 28% reduction in stroke and a low rate of adverse events,” Bhatt said during a presentation. “There was a consistent benefit across all subgroups, including in the primary and secondary prevention cohorts.”
The key secondary endpoint, defined as CV death, nonfatal MI or nonfatal stroke, was also lower in the icosapent ethyl group (11.2% vs. 14.8%; HR = 0.74; 95% CI, 0.65-0.83; P = .0000006; absolute difference, 3.6%; 95% CI, 2.1-5; number needed to treat to prevent one key secondary endpoint event = 28; 95% CI, 20-47).
The researchers also performed hierarchical testing of additional ischemic endpoints. In this analysis, the rates of the additional ischemic endpoints, including death from CV causes, were also lower in the icosapent ethyl group (4.3% vs. 5.2%; HR = 0.8; 95% CI, 0.66-0.98).
“The highly significant reductions in the primary and secondary cardiovascular endpoints in the presence of relatively modest effects of blood lipids and lipoproteins suggest the possibility that other properties of this drug such as the antithrombotic or anti-inflammatory effects” could have prompted the results, Carl E. Orringer, MD, FACC, FNLA, associate professor of medicine at University of Miami Miller School of Medicine, said during a discussant presentation at the press conference.
Hospitalization for atrial fibrillation or flutter occurred more often in the icosapent ethyl group (3.1% vs. 2.1%; P = .004) and there was a trend toward more serious bleeding events in the icosapent ethyl group (2.7% vs. 2.1%; P = .06), Bhatt and colleagues found.
All-cause death did not significantly differ between the groups (icosapent ethyl group, 6.7%; placebo group, 7.6%; HR = 0.87; 95% CI, 0.74-1.02; P = .09).
Median change in triglyceride levels between baseline and 1 year was –18.3% (–39 mg/dL) in the icosapent ethyl group and 2.2% (4.5 mg/dL) in the placebo group (difference, 19.7% or 44.5 mg/dL; P < .001).
During the study, LDL rose a median of 3.1% (2 mg/dL) in the icosapent ethyl group and 10.2% (7 mg/dL; difference, 6.6% or 5 mg/dL; P < .001) in the placebo group.
The treatment effect of icosapent ethyl on the primary endpoint was greater in patients who had baseline triglycerides of at least 200 mg/dL and baseline HDL of 35 mg/dL or less (P for interaction = .04), according to the accompanying manuscript simultaneously published in The New England Journal of Medicine.
Overall adverse events and adverse events leading to study drug discontinuation did not significantly differ between the groups.
Growing therapeutic armamentarium
Commenting on the findings, as the study population was 90% white, the agent should be studied more thoroughly in other races and ethnicities, Orringer said.
“Unlike other drugs shown to be effective as add-ons to statins, this one appears to work via a mechanism that is unrelated to LDL receptor expression,” Orringer said during the press conference. “We now have three therapies [icosapent ethyl, ezetimibe and PCSK9 inhibitors] proven in randomized controlled trials that show a favorable risk-benefit ratio for cardiovascular disease in combination with statin treatment. As this is the first study that showed this in hypertriglyceremic patients, we have a very important addition to our therapeutic armamentarium for these patients.” – by Erik Swain
Bhatt DL, et al. LBS.01 – Late Breaking Clinical Trials: Answers to Critical Questions in Cardiovascular Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.
Disclosures: The study was funded by Amarin Pharmaceuticals. Bhatt reports he has financial ties with numerous drug and device companies, including receiving research funding from Amarin.