“What I would like to see is a trial in future with a clearly neutral comparator. It’s hard to recommend taking your patients off Vascepa now, but I have a high threshold at this point to start patients on it because of these concerns,” he added.
A “manufactured controversy”
The lead investigator of the REDUCE-IT trial, Deepak L. Bhatt, MD, professor of medicine, Harvard Medical School, Boston, described Dr. Lincoff’s comments as “absurd.”
Dr. Deepak Bhatt
In an interview, he said the Japanese JELIS trial , while having some limitations, also showed a benefit of icosapent ethyl, which “in the context of this manufactured controversy about the mineral oil placebo in REDUCE-IT, completely rebuts concerns about the placebo in REDUCE-IT being toxic.”
Dr. Bhatt also suggested that DHA may counter some of the benefits of EPA. “It appears that the STRENGTH trial leadership is trying to stir up controversy, rather than just reporting objectively that they have a negative trial,” he added.
Dr. Lincoff outlined other possible explanations for the difference between the two trials.
He noted that icosapent ethyl increased levels of EPA by 45% in REDUCE-IT more than did the combined product used in STRENGTH. “But this moderate difference seems insufficient to account for the markedly different results of the two trials,” Dr. Lincoff added, “and both trials showed a 19% reduction in triglycerides, suggesting they have similar biochemical effects.”
There is also the possibility of an adverse effect of DHA, he noted, “but this has never been seen in previous studies.”
Another explanation could be differences in trial populations, with REDUCE-IT including more patients with established cardiovascular disease. “But the results were no different in this group compared to the patients without established cardiovascular disease, so this explanation is unlikely,” Dr. Lincoff suggested.
STRENGTH trial
The STRENGTH trial included 13,078 statin-treated participants with high cardiovascular risk , hypertriglyceridemia, and low levels of HDL cholesterol from 22 countries.
They were randomly assigned to a 4 g per day of carboxylic acid formulation of EPA and DHA or to corn oil as an inert comparator.
The trial was halted when 1,384 patients had experienced a primary endpoint event (of a planned 1,600 events), based on an interim analysis that indicated a low probability of clinical benefit of the active treatment.
At this point, the primary efficacy endpoint – a composite of cardiovascular death, nonfatal myocardial infarction , nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization – occurred in 12.0% of patients treated with the omega-3 product vs. 12.2% of those who received corn oil (hazard ratio [HR], 0.99; P = .84).
A greater rate of gastrointestinal adverse events was observed in the omega-3 group (24.7%) than in corn oil–treated patients (14.7%). An increased rate of new-onset atrial fibrillation was also observed in the omega-3 group (2.2% vs 1.3%; HR, 1.69).
Uncertainty prevails
The moderator of an AHA press conference at which the STRENGTH trial was discussed, Amit Khera, MD, professor of medicine and director of preventive cardiology at UT Southwestern Medical Center, Dallas, said in an interview that questions about how Vascepa brought about the benefits shown in REDUCE-IT have been ongoing since that trial was published.