Placebo effects?
Concerns about the mineral oil placebo cast doubt on that benefit. Table 4 of the supplement accompanying REDUCE-IT’s publication in the New England Journal of Medicine shows significant increases of non–HDL cholesterol, LDL cholesterol, apolipoprotein B, and hsCRP in the control group.
Jane Armitage, MBBS, a professor of clinical trials and epidemiology, clinical trial service unit at Oxford University (England), said in an interview: “I was surprised by the backlash and at the time felt that it was unlikely that the mineral oil was the problem. But the size of benefit was still out of kilter.”
“Two further pieces of evidence have influenced my thoughts since then,” she said. One is the lack of effect of high doses of fish oils in the STRENGTH trial. STRENGTH tested 4 g of omega-3 oil containing a mixture of EPA and DHA and found no benefit in statin-treated, high-risk patients.
“The amount of EPA [was] substantially less than given in REDUCE-IT,” Armitage said, “but it seems to me that in a similar hypertriglyceridemic population, if the effect were due to the EPA, you would have seen some impact in STRENGTH – and none was seen.”
“The other piece of evidence is in a paper by Paul Ridker, MD, et al. on the changes in biomarkers during REDUCE-IT,” she said. “Several inflammatory biomarkers associated with atherosclerosis rose during the study among those allocated mineral oil, but remained largely unchanged in the EPA group. This is in contrast to what is seen with these biomarkers in other large trials, where no changes were seen in the placebo groups, and once again raises the possibility that the apparent benefits of EPA may be related to hazard from the mineral oil.”
Still room for benefit?
Based largely on the results of REDUCE-IT, Vascepa is currently approved by the Food and Drug Administration as an adjunctive therapy to lower the risk for CV events among adults with elevated triglyceride levels (≥ 150 mg/dL). Patients must also have either established CVD or diabetes and two or more additional CV risk factors and are advised to continue physical activity and maintain a healthy diet.
Dr. Nissen, the principal author of the STRENGTH trial, said in an interview, “REDUCE-IT is an outlier. Other trials of omega-3 fatty acids, some of them very large, showed no benefits, and a meta-analysis of nearly 78,000 patients showed no beneficial effects. In this context,” he said, “the large ‘benefit’ observed in REDUCE-IT doesn’t make any sense.”
Dr. Nissen noted that a secondary analysis of STRENGTH further showed that higher plasma EPA levels did not reduce CV outcomes. He also highlighted the elevated risk of atrial fibrillation with EPA. “We need to see another study comparing EPA to a neutral comparator such as corn oil, which had no significant effect on lipid or inflammatory biomarkers in STRENGTH,” he said. “Without such a trial, the results of REDUCE-IT cannot be accepted as definitive.”
Dr. Ridker, the lead author of the REDUCE-IT substudy that found biomarker changes with the mineral oil placebo, said in an interview: “Is it possible that EPA is an outstanding drug? Absolutely, and I continue to think it useful for our very high-risk, secondary-prevention patients when we are running out of options.”
“But,” said Dr. Ridker, who is a professor at Harvard Medical School, Boston, and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s, “the reality ... is that ongoing uncertainties need resolution.” Like Dr. Nissen, he thinks the best way to resolve these uncertainties is through a second trial using a fully neutral comparator. “I am hopeful that the U.S. National Institutes of Health will see fit to undertake such an endeavor, perhaps with support from industry partners.”
Although Dr. Armitage is no longer in clinical practice, when asked how she might use EPA, she said it might be reasonable for patients who meet the prescribing criteria and remain high risk after all other risk factors have been addressed. She added that, although EPA is approved in the United Kingdom, she doesn’t think it is being widely prescribed.
Salim S. Virani, MD, PhD, a professor in the Sections of Cardiology and Cardiovascular Research at Baylor College of Medicine who has published articles about REDUCE-IT and on the eligibility and cost of EPA in the Veterans Affairs system, said in an interview: “In my personal opinion, clinicians [should] first optimize diet and lifestyle and work on secondary causes, as they play a very big role in hypertriglyceridemia.” He also recommended optimizing LDL-C levels because of “consistent data showing that LDL [cholesterol] control leads to significant reduction in atherosclerotic CVD events.”
“Once these two steps are taken and triglycerides still remain elevated,” he said, “then adding EPA in patients with established atherosclerotic CVD or those with diabetes plus other CV risk factors may be a reasonable option to further lower residual atherosclerotic CVD risk.”