Management of Hypercholesterolemia - Episode 1

The REDUCE-IT Trial and CV Outcomes

August 15, 2019

Deepak L. Bhatt, MD, MPH: The REDUCE-IT trial randomized over 8000 patients with hypertriglyceridemia to either icosapent ethyl, 4 grams a day, or placebo. Patients had to have triglycerides greater than or equal to 135 [mg/dL] and less than 500 [mg/dL] while on statin therapy with well-controlled LDL [low-density lipoprotein] cholesterol. Patients additionally had to have cardiovascular risk, meaning either secondary prevention-type patients—those with stable coronary artery disease, cerebrovascular disease, or peripheral artery disease—or primary prevention patients, specifically those with diabetes and at least 1 additional cardiovascular risk factor. So these patients were randomized to 1 of these 2 arms and followed for an average of about 5 years.

The primary endpoint of the REDUCE-IT trial was 5-point MACE [major adverse cardiovascular events], meaning cardiovascular death, myocardial infarctions, stroke, hospitalization for unstable angina, or revascularization. This was significantly reduced in the overall trial—about a 25% relative risk reduction that was highly statistically significant. The key secondary endpoint of cardiovascular death, MI [myocardial infarction], stroke, and so-called hard MACE was also significantly reduced about by about 26%. We’ve done additional analyses of the data looking not just at the time to first event, which is the conventional way of doing such analyses, but instead also looking at total events—the sum of initial events and recurrent events. And [we] have found that 30% reduction in total events. From a patient’s perspective, of course, that’s how they look at things. Patients care about having second events. They’d rather not have a stroke after an MI or cardiovascular death after an episode of unstable angina.

From a patient-centric perspective, perhaps the total events are really the more appropriate way of looking at data, though the conventional and historic way is time to the first event. But really, anyway you slice the data, significant reductions, both in relative and absolute terms, in important ischemic events.

We’ve also examined a number of different subgroups. Most recently, patients were examined by their baseline tertile of triglyceride levels. The trial was not designed or powered for subgroup analyses. Such trials never are. But we did find significant reductions in ischemic events in all 3 tertiles, including the lowest tertile of baseline triglycerides, and that included patients with triglycerides as low as 100 [mg/dL], even though the inclusion criteria, as stated, were that it was really 150 [mg/dL]. However, we allowed variation in triglycerides, and indeed, there was even greater variation when we looked at an average of a couple of measurements, as is known to be the case with triglycerides. The bottom line is that we got patients with triglycerides as low as 100 [mg/dL]. Even though it was in that range of 100 to 150 [mg/dL] or so, it seemed to derive substantial benefit from icosapent ethyl versus placebo—arguing, at least indirectly, that some of the benefit might be beyond just triglyceride reduction.

Transcript edited for clarity.