Patients at high risk for cardiovascular events who had the highest levels of eicosapentaenoic acid (EPA) in their blood one year after taking daily omega-3 carboxylic acid, a prescription-grade fish oil, had similar rates of major cardiovascular events as people taking a corn oil placebo, according to a secondary analysis of the STRENGTH trial presented May 16 during ACC.21 and simultaneously published in JAMA Cardiology. Researchers also found no increase in cardiovascular events among patients with the highest levels of docosahexaenoic acid (DHA) compared with placebo.

The double-blind, multicenter STRENGTH trial enrolled 13,078 people at high risk for major cardiovascular events from 675 sites in 22 countries between Oct. 30, 2014 and June 14, 2017. Patients were randomized to receive either 4 grams daily of omega-3 carboxylic acid (a combination of EPA and DHA) or corn oil as the placebo. Previously reported outcomes found no difference between the two groups in terms of the primary outcome – a composite of nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.

This remained true in the current secondary analysis, which examined a subset of 10,382 patients (5,175 receiving omega-3 carboxylic acid and 5,207 in the corn oil group) with available omega-3 fatty acid levels. Patients were grouped into tertiles based on achieved EPA and DHA plasma levels assessed at baseline and 12 months after randomization. The median plasma EPA level for patients taking fish oil was 89 (46-131) µg/mL and 91 (71-114) µg/mL for DHA, with the top tertile achieving levels of 151 (132-181) and 118 (102-143) µg/mL, respectively. The primary outcome occurred in 11.1% of patients treated with fish oil and 11% of patients in the placebo group. 

Researchers also found no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at one year compared with patients treated with corn oil; the event rate was 11.3% and 11%, respectively. For the top tertile of achieved DHA, the event rate was 11.4%. Researchers said they would have expected to see a difference in events among these patients if higher levels of EPA have a protective role. Further analyses examined changes in EPA or DHA over time and similarly showed neutral effects on cardiovascular outcomes.

The impetus for this post-hoc analysis was to further examine the strikingly divergent results between STRENGTH and REDUCE-IT, another large, randomized clinical trial that used a different omega-3 fatty acid formulation (icosapent ethyl, purified EPA only) and mineral oil as the placebo.

"This is an intensely controversial area. One fish oil trial after another has been neutral, but REDUCE-IT reported a striking 25% reduction in events compared with a placebo pill containing mineral oil. But in our analysis, among patients treated with fish oil we found no evidence that EPA is beneficial or that DHA is harmful," said Steven Nissen, MD, MACC, the study's lead author. "So, we have many patients taking fish oils but no evidence that they have favorable effects on the heart."

According to Nissen, the researchers "looked at the data multiple ways – absolute EPA and DHA levels, change in levels of these omega-3 fatty acids, red blood cell levels, and by primary and secondary prevention subgroups," and all of the analyses "showed no benefits or harms."

In a separate late-breaking clinical study also presented May 16 during ACC.21, researchers found that patients with severe hypertriglyceridemia and a specific genetic profile benefitted from taking evinacumab compared with placebo. 

The phase 2 trial enrolled 51 patients with hypertriglyceridemia at 17 sites in four countries in North America and Europe. The patients did not have familial hypercholesterolemia and had a history of triglyceride levels of 1,000 mg/dL and prior hospitalization for acute pancreatitis. At the time of screening, patients' triglyceride levels were ≥500 mg/dL despite maintaining a strict diet.

Two-thirds of the trial participants were randomly assigned to receive evinacumab via IV infusion at a dosage of 15 mg/kg every four weeks for a total of 24 weeks. One-third received a placebo for the first 12 weeks and then received evinacumab for the second 12 weeks. All participants underwent genetic testing to assess mutations in LPL pathway genes.

At the end of the 12-week placebo-controlled double-blind period, the median triglyceride level decreased by more than 800 mg/dL (57%) in patients taking evinacumab, compared with an overall increase of 50 mg/dL (1.8%) in participants taking a placebo.

Researchers noted the magnitude of triglyceride lowering with evinacumab was highly dependent on participants' genetic profile. Those with a double copy of certain mutations in LPL pathway genes had essentially no benefit from evinacumab, whereas patients with a single mutation or no mutations in LPL pathway genes saw triglyceride reductions of around 80%. Among patients with no identifiable LPL mutations, changes in the double-blind treatment and single-blind treatment (primary endpoint) showed a mean reduction in triglycerides of 27.1% and a median reduction of 68.8%.

Adverse events such as abdominal pain, acute pancreatitis and headache occurred in about 70% of patients in both groups, but there was no significant difference in the rate of adverse events between those taking evinacumab and those taking a placebo. While the trial was not designed to determine an effect on the occurrence of acute pancreatitis, the majority of acute pancreatitis events occurred either when patients were receiving placebo or more than four weeks after completing evinacumab treatment. A separate study is now underway to determine whether evinacumab reduces recurrent pancreatitis by lowering triglycerides.

"This trial has important clinical implications for this population with severe hypertriglyceridemia," said Robert S. Rosenson, MD, FACC, the study's lead author. "It also demonstrates the importance of genetic testing in people with severe hypertriglyceridemia because by performing genetic testing you are able to tell which individuals will respond to this therapy and which are unlikely to respond."

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Diet

Keywords: ACC Annual Scientific Session, ACC21, Dyslipidemias, Primary Prevention, Fatty Acids, Omega-3, Risk Factors, Dietary Supplements, Hypertriglyceridemia, Hyperlipidemias

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