However, Vascepa was followed by questions that the groundbreaking REDUCE-IT study used a placebo made from mineral oil, which interfered with statin absorption and may have skewed results.
These questions re-emerged during the American Heart Association meeting last fall when investigators from the Cleveland Clinic presented the results of STRENGTH. This study looked at omega-3 carboxylic acid, a drug that contains both EPA and docosahexaenoic acid (DHA); the second omega-3 is beneficial for the brain and eyesight, but can increase 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 was not all. STRENGTH used a corn oil placebo, which the researchers called a “neutral comparator,” and the paper in JAMA presenting the results openly questioned the REDUCE-IT results.
The debate continued at ACC on Sunday as Steven Nissen, MD, chairman of the Cleveland Clinic for Cardiovascular Medicine, presented additional results from STRENGTH during a recent session that cast doubts on REDUCE-IT’s results and with a call for direct comparison ended studies to clarify the matter. Bhatt, surprised by the November paper, served as a panelist for today’s findings, which have appeared in a new article in JAMA Cardiology.
“Additional research is needed, with studies comparing corn oil to mineral oil and comparing purified EPA with other formulations of omega-3 fatty acids,” said Nissen.
In the post-hoc analysis, STRENGTH researchers examined a subset of 10,382 patients enrolled in the study, of whom 5175 received omega-3 carboxylic acid and 5207 the corn oil placebo. As with the original results, there was no real difference in events: 11.1% in those given the fish oil capsule and 11% in those given placebo. The researchers divided the group into tertiles based on EPA and DHA levels in the blood. They found:
- The median plasma EPA levels in patients taking fish oil were 89 (46-131) µg / ml and 91 (71-114) µg / ml for DHA.
- The upper tertile values 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 effect, the researchers would have expected that in patients with high EPA levels compared to those who took corn oil, a difference in event rates would be found after one year as the EPA levels of the Patients increased.
But they didn’t find that. Instead, after one 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 results.
Similarly, the event rate for patients with the top tertile DHA levels was 11.4%. When the researchers examined the association between changing EPA or DHA levels over time, they found no effect on cardiovascular outcomes.
They found that there was an effect on atrial fibrillation over time – small in absolute terms, but up by 69%.
In his remarks after Nissen’s presentation, Bhatt said that the lack of a relationship in a negative study “doesn’t tell us so much as that those specific drugs that were studied didn’t work”.
He asked Nissen about the fact that the patients in the different tertiles consumed different amounts of high-intensity statins.
“If you measure enough features, you will see some features that are a little different,” replied Nissen. “I don’t think that’s any difference in using high-intensity statins to explain the results we’ve seen.”
During a press conference following the meeting, Nissen said the uncertainty requires more research to clear the matter. “We have all of these studies that are neutral and one study that has not been replicated and shows any benefit,” he said.
Given how long Vascepa has been in the market, could claims studies provide some guidance? The answer, Nissen said in an email to the American Journal of Managed Care®, was a resounding “no”.
“I don’t think observational data can answer these difficult questions,” he said. “We need additional” [randomized controlled trials] to see if this drug is effective in reducing cardiovascular events. A neutral comparator such as corn oil must be used for such experiments. “
Nissen was blunt. “Fish oils significantly increase the risk of atrial fibrillation, and there is no solid evidence that they help the heart anyway,” Nissen said in a statement. “It’s a sad story for cardiology.”
Nissen SE, Lincoff AM, Wolski K, et al. Relationship between ω-3 fatty acids achieved and serious cardiovascular side effects in patients with high cardiovascular risk – a secondary analysis of the STRENGTH study. JAMA Cardiol. Published online May 16, 2021. doi: 10.1001 / jamacardio.2021.1157