Fish Oil Use in Hypertriglyceridemia Reduces Risk of Ischemic Events, Over-The-Counter Fish Oil Supplements Still ‘Fishy’ Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia

 A study by Bhatt et al. published online in the New England Journal of Medicine, accompanied by a detailed supplement, was presented at AHA 2018 in Chicago, Illinois. The study demonstrated that among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly reduced among those who received 2 g of icosapent ethyl twice daily as compared with patients who received placebo.

It is a known fact that patients with elevated triglyceride levels are at increased risk for ischemic events. Although Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, was known to lower triglyceride levels, data was still required to determine its effects on ischemic events. In the light of this, the investigators performed a multicenter, randomized, double-blind, placebo-controlled trial involving 8179 patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter). The subjects were followed for a median duration of 4.9 years. The patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

In the study, the investigators found that the primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001). The rates of additional ischemic endpoints, as assessed according to a prespecified hierarchical schema, were significantly lower in the icosapent ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03). A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004). Moreover, serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06). The overall rates of adverse events were similar in the trial groups. Serious adverse events related to bleeding occurred in more patients in the icosapent ethyl group than in the placebo group, although the overall rates were low; there were no fatal bleeding events in either group, and the rates of adjudicated hemorrhagic stroke, serious central nervous system bleeding, and serious gastrointestinal bleeding were not significantly higher in the icosapent ethyl group than in the placebo group. The rate of hospitalization for atrial fibrillation or flutter was significantly higher in the icosapent ethyl group than in the placebo group, although the rates were low. The rates of adverse events and serious adverse events leading to discontinuation of trial drug were similar in the two groups.

Bhatt and his colleagues drew the conclusion that in REDUCE-IT, the risk of the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina, assessed in a time-to-event analysis, was significantly lower, by 25%, among the patients who received 2 g of icosapent ethyl twice daily than among those who received placebo, corresponding to an absolute between-group difference of 4.8 percentage points in the rate of the endpoint and a number needed to treat of 21. Furthermore, the risk of the key secondary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in a time-to-event analysis was also significantly lower, by 26%, in the icosapent ethyl group than in the placebo group, corresponding to an absolute between-group difference of 3.6 percentage points in the rate of the endpoint and a number needed to treat of 28. Lastly, prespecified hierarchical testing of other secondary endpoints revealed that the risks of a variety of fatal and nonfatal ischemic events were lower in the icosapent ethyl group than in the placebo group, including a 20% lower risk of cardiovascular death. The benefits were observed against a background of appropriate statin use among patients who had a median LDL cholesterol level of 75.0 mg per deciliter at baseline.

Speaking of the importance of the study, the investigators wrote, “The results of REDUCE-IT stand apart from the negative findings of several contemporary trials of other agents that also lower triglyceride levels, including other n−3 fatty acids, extended-release niacin, fenofibrate, and cholesteryl ester transfer protein inhibitors. It is not known whether the lack of benefit from n−3 fatty acids in previous trials may be attributable to the low dose or to the low ratio of EPA to docosahexaenoic acid (DHA). Both the formulation (a highly purified and stable EPA ethyl ester) and dose (total daily dose of 4 g) used in REDUCE-IT were different from those in previous outcome trials of n−3 fatty acids.” However, they warned that “The results of the current trial should not be generalized to other n−3 fatty acid preparations — in particular, dietary-supplement preparations of n−3 fatty acid mixtures, which are variable and unregulated and which have not been shown to have clinical benefit.”

Addressing possible mechanisms of action, the investigators professed that the reasons for the benefit of icosapent ethyl observed in REDUCE-IT were currently not known. The timing of the divergence of the Kaplan–Meier event curves suggested a delayed onset of benefit, which could reflect the time needed for a benefit from a reduction in triglyceride levels to be realized or could indicate that other mechanisms are involved. The modestly higher rate of bleeding events with icosapent ethyl suggested that there could be an antithrombotic mechanism of action. However, it was unlikely that an antithrombotic effect would reduce the rate of elective revascularization. Also, if the full explanation involved an antiplatelet or anticoagulant effect, one could expect a large increase in the rate of major bleeding events, which was not observed. It was possible that membrane-stabilizing effects could explain part of the benefit. According to them, stabilization or regression of coronary plaque (or both) could also play a part. Results of ongoing trials of moderate-to-high doses of pure EPA ethyl ester were awaited in order to provide further information on the effects of these agents.