However, Vascepa was haunted by questions that the landmark study called REDUCE-IT used a placebo made from mineral oil, which may have affected statin absorption and skewed results.
These questions reappeared during the American Heart Association meeting last fall when investigators from Cleveland Clinic presented results from STRENGTH. This study looked at omega-3 carboxylic acid, a drug that contains both EPA and docosahexaenoic acid (DHA). The second omega-3 is good for the brain and eyesight, but can increase low-density lipoprotein (LDL) cholesterol. AstraZeneca discontinued STRENGTH more than a year ago 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 today when Dr. Steven Nissen, chairman of the Cleveland Clinic for Cardiovascular Medicine, presented additional results from STRENGTH in a late session that cast doubt on the results of REDUCE-IT and resulted in a call for head-to-head studies to resolve the matter. Bhatt, surprised by the November newspaper, served as a panelist for today’s findings, which were published in a new paper in JAMA Cardiology.
“Additional research is needed with attempts to compare corn oil to mineral oil and compare purified EPA to other formulations of omega-3 fatty acids,” said Nissen.
In the post-hoc analysis, the STRENGTH researchers examined a subset of 10,382 patients, of whom 5175 received the omega-3 carboxylic acid and 5207 the corn oil placebo. As with the original findings, there was no real difference in events: 11.1% in those treated with the fish oil capsule and 11% in those treated with placebo. The researchers divided the group into tertiles based on the levels of EPA and DHA in the blood. They found:
- The mean plasma EPA levels for 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 the event rates in patients with high EPA levels would be different compared to those taking corn oil after a 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 – according to the overall results.
Similarly, the event rate for patients with the highest tertile DHA levels was 11.4%. When the researchers examined the relationship between changes in 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 an increase of 69%.
In his remarks after Nissen’s presentation, Bhatt said that the lack of a relationship in a negative study “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 amounts of high-intensity statin use.
“If you measure enough traits, you will see some traits that are slightly different,” replied Nissen. “I don’t think that’s enough of a difference in high-intensity statin use to explain the results we saw.”
Speaking at a press conference after the meeting, Nissen said the uncertainty needed more research to clear up the matter. “We have all of these neutral studies and a single unreplicated study that shows an advantage,” he said.
Given how long Vascepa has been in the market, could damage studies provide some guidance? The answer, Nissen said in an email to the American Journal of Managed Care®, was “no”.
“I don’t think observational data can answer these tough questions,” he said. “We’ll need more [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. “
Nits was dull. “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. Association between ω-3 fatty acid levels achieved and serious adverse cardiovascular outcomes in patients at high cardiovascular risk – a secondary analysis of the STRENGTH study. JAMA Cardiol. Published online May 16, 2021. doi: 10.1001 / jamacardio.2021.1157