The ground-breaking REDUCE-IT trial results showed that icosapent ethyl (Vascepa), an omega-3 acid, provided a 25% risk reduction in cardiovascular events in patients with well-managed LDL cholesterol who remain at high risk for cardiovascular events.
Results from the phase 3b REDUCE-IT trial were presented by Deepak L Bhatt, MD, MPH, Brigham and Women's Hospital, Boston, MA, in a late-breaking session at the American Heart Association’s Scientific Sessions 2018 in Chicago, IL.
Studies have shown that ezetimibe and PCSK9 inhibitors reduce future cardiovascular events, but do not reduce cardiovascular death, while the recent results indicate that icosapent ethyl significantly improves both, said Michael Miller, MD, a REDUCE-IT investigator and director of the Center for Preventive Cardiology, University of Maryland Medical Center, Baltimore, MD.
“REDUCE-IT now shows not only a 25% reduction in risk of future events, but also a 20% lowering of cardiovascular death,” Miller told MD Magazine®. “In this space—in the statin era—this is the first study to show a benefit on cardiovascular death on top of the 25% reduction in MACE events.”
[Full transcript below.]
The REDUCE-IT trial included 8179 patients (secondary prevention population 70.7%) who were followed for a median of 4.9 years. Participants were randomized to receive either 2 g of icosapent ethyl twice daily (n = 4089) or placebo (n = 4090).
The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. These events occurred in 17.2% of patients in the icosapent ethyl group compared with 22.0% of those in the placebo group (hazard ratio [HR], .75; 95% confidence interval [CI], .68-.83; P = .00000001).
The relative risk ratio for the primary endpoint was 24.8% while the absolute risk ratio was 4.8%, with a number needed to treat of 21 (95% CI, 15-33).
The key secondary endpoint, a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, was met, with these events occurring 16.2% of the icosapent ethyl group compared to 20.0% of the placebo group (HR, .74; 95% CI, .65-.83; P = .0000006). The relative risk ratio for the primary endpoint was 26.5% while the absolute risk ratio was 3.6%, with a number needed to treat of 28 (95% CI, 20-47).
The rate of cardiovascular death was significantly lower in the icosapent ethyl group versus the placebo group (4.3% vs. 5.2%; HR, .80; 95% CI, .66-.98; P = .03).
The overall rates of adverse events as well as rates of serious adverse events leading to trial discontinuation did not significantly differ between study arms. Pneumonia was the only serious adverse event that occurred in ≥2% of participants (2.6% in icosapent ethyl group; 2.9% in placebo group, P = .42).
Patients in the icosapent ethyl group were more likely than those in the placebo group to experience atrial fibrillation (5.3% vs. 3.9%; P = .003), peripheral edema (6.5% vs. 5.0%; P = .002), and constipation (5.4% vs. 3.6%; P <.001). However, the rates of anemia (4.7% vs 5.8%; P = .03) and diarrhea (9.0% vs 11.1%; P = .002) were lower in the icosapent ethyl group than in the placebo group.
An original article based on the REDUCE-IT trial, “Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia,” was published in the New England Journal of Medicine.
[Transcript has been edited for clarity.]
What were you investigating in the REDUCE-IT trial?
The REDUCE-IT trial was asking an important question and that question, until this study, was not determined. The question is: if you take a group of patients—these were patients that had high triglycerides and had either heart disease or had diabetes and other risk factors—can this concentrated, purified icosapent ethyl compound, also known as EPA, can that reduce the risk of cardiovascular events in people with either established disease or at high risk?
What was surprising about the REDUCE-IT results?
Well the results we think were quite surprising and prior studies in this space—the cholesterol-lowering space—have shown that it is very difficult to reduce risk of future events in people who already have established statin background. So, that's the first thing we've understood because there have been a number of trials that have had negative results.
So, you put somebody on medication such as niacin or a fibrate that has a nice effect on lowering triglycerides for example, but no benefit. The first study to show benefit was with a cholesterol-lowering medication known as ezetimibe, which showed about a 6% reduction on top of a statin. Then more recently the injectable PCSK9 inhibitors have shown about a 15% reduction in events. Now neither of those studies showed any benefit with respect to cardiovascular death reduction, so REDUCE-IT now shows not only a 25% reduction in risk of future events, but also a 20% lowering of cardiovascular death. So, in this space—in the statin era—this is the first study to show a benefit on cardiovascular death on top of the 25% reduction in MACE events.
What are the clinical implications of the REDUCE-IT results?
Yeah, I think this would have a pretty significant effect on the way we practice medicine. I like to kind of compare this to when the Flores trial—this is the first large clinical trial with statin therapy with simvastatin therapy—came out almost 25 years ago. And when that study came out, Michael Brown who won the Nobel Prize with [Joseph] Goldstein said this was like when Babe Ruth pointed to centerfield in Chicago against the Chicago Cubs. That showed this magical risk-reduction that was going to be a home run. In the same way, this study is a home run, because it shows for the first time that people with high risk—these are people with high triglycerides, diabetes, metabolic syndrome, and other risk factors—have a big-time event [reduction] on top of a statin and reducing risk [of cardiovascular death].