With No End in Sight on Omega-3 Debate, Nissen Calls for More Trials

Two leading cardiologists were divided Sunday during the 70th American College of Cardiology (ACC) Scientific Session on how to explain conflicting—and controversial—results from trials involving different formulations of omega-3 fatty acids.

In November 2018, Harvard’s Deepak L. Bhatt, MD, MPH, stunned the cardiology community with results that showed a purified form of icosapent ethyl (EPA) had reduced cardiac events or death by 25%. The fish oil capsules, which had been sold for several years as Vascepa to treat high triglycerides, later received an FDA indication as an add-on to statins to prevent cardiovascular events. (First quarter revenues for 2021 for Amarin, based on Vascepa sales, were $141.4 million.)

But Vascepa has been dogged by questions that the landmark trial, called REDUCE-IT, used a placebo of mineral oil that might have interfered with statin absorption and skewed results.

Those questions flared anew last fall during the American Heart Association meeting, when Cleveland Clinic investigators presented findings from STRENGTH. That trial studied omega-3 carboxylic acid, a drug that contains both EPA and docosahexaenoic acid (DHA); the second omega-3 benefits the brain and eyesight but can elevate low-density lipoprotein (LDL) cholesterol. More than a year ago, AstraZeneca pulled the plug on STRENGTH, after the Cleveland Clinic team found the drug had no effect on cardiovascular outcomes.

But that wasn’t all. STRENGTH used a corn oil placebo, which investigators called a “neutral comparator,” and the paper in JAMA presenting the results openly challenged the REDUCE-IT findings.

The debate continued Sunday at ACC, when Steven Nissen, MD, Cleveland Clinic’s chair of Cardiovascular Medicine, outlined more results from STRENGTH during a late-breaking session that cast doubt on REDUCE-IT’s findings and ended with a call for head-to-head studies to settle the matter. Bhatt, who was taken by surprise with the November paper, served as a discussant for today’s results, which appeared in a new paper in JAMA Cardiology.

“Additional research is needed, with trials designed to compare corn oil with mineral oil, and to compare purified EPA with other formulations of omega-3 fatty acids,” Nissen said.

In the post-hoc analysis, the STRENGTH researchers examined a subset of 10,382 patients enrolled in the study, of whom 5175 received omega-3 carboxylic acid and 5207 received the corn oil placebo. As with the original findings, there was no real difference in events: 11.1% among those treated with the fish oil capsule and 11% among patients on placebo. Researchers divided the group into tertiles based on EPA and DHA levels in the blood. They found:

• The median plasma EPA level for patients taking fish oil was 89 (46-131) μg/mL, and 91 (71-114) μg/mL for DHA.
• The top tertile levels were 151 (132-181) for EPA and 118 (102-143) for DHA (in μg/mL).

If EPA had a protective effect, and DHA a harmful one, researchers said they would have expected to see a difference in the event rates for patients with high EPA levels compared with those taking corn oil after a year, as patients’ EPA levels increased.

But this is not what they found. Instead, after a year, the event rates for those with the highest EPA levels were comparable to those taking corn oil: 11.3% for EPA and 11% for corn oil—in line with the overall findings.

Similarly, the event rate for patients with the top tertile of DHA levels, the event rate was 11.4%. When the investigators looked at relationship between changing EPA or DHA levels over time, they found no effect on cardiovascular outcomes.

They did find that over time, there was an effect on atrial fibrillation—small in absolute numbers, but a 69% increase.

In his remarks after the Nissen’s presentation, Bhatt said that the absence of relationship in a negative trial “doesn’t tell us that much other than these specific drugs studied didn’t work.”

He asked Nissen about the fact that the patients in the different tertiles had different levels of high-intensity statin use.

“If you measure enough characteristics, you’re going to see some characteristics that are a little bit different,” Nissen replied. “I don’t think that’s enough of a difference in high intensity statin use to explain the results that we saw.”

During a press conference after the session, Nissen said the uncertainty demands more research to settle the matter. “We’ve got all these trials that are neutral, and a single trial, not replicated, that shows a benefit,” he said.

Given how long Vascepa has been on the market, could claims studies offer any guidance? The answer, Nissen said in an email to The American Journal of Managed Care®, was resounding “no.”

“I don’t think observational data can answer these difficult questions,” he said. “We will need additional [randomized controlled trials] to determine whether this drug is effective at reducing cardiovascular events. Such trials must use a neutral comparator such as corn oil.”

Nissen was blunt. “Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in anyway,” Nissen said in a statement. “It’s a sad story for cardiology.”

Reference

Nissen SE, Lincoff AM, Wolski K, et al. Association between achieved ω-3 fatty acid levels and major adverse cardiovascular outcomes in patients with high cardiovascular risk a secondary analysis of the STRENGTH trial. JAMA Cardiol. Published online May 16, 2021. doi:10.1001/jamacardio.2021.1157