Hit piece - in case anyone wants to read...
A new analysis of Vascepa, a medicine derived from fish oil and used to prevent heart attacks in a select group of patients, raises big questions about the evidence that the medicine is effective. Several experts say the questions require a new clinical trial to be conducted, and some even say the Food and Drug Administration should reconsider the product’s approval.
In a twist, the new data come from an analysis funded by Amarin itself.
The results “raise the concern that the apparent lowering of cardiovascular risk observed with icosapent ethyl may —in fact — have been an increase in cardiovascular risk with the comparator, mineral oil,” said Gregory Curfman, deputy editor at the Journal of the American Medical Association, using the generic name for Vascepa.
Here is what happened. In 2018, researchers working with Amarin presented results from a five-year, 8,179-patient study, REDUCE-IT, that showed giving Vascepa to heart patients with elevated triglycerides reduced the rate at which a combination of cardiovascular problems – heart attack, stroke, procedures to unblock arteries, and chest pain – occurred from 22 per 100 patients to 17 per 100 patients. That’s a 25% reduction.
That study led the FDA to approve Vascepa, which was previously used only to lower extremely high triglyceride levels, in a much broader population to treat heart disease. But critics always had a concern.
As a placebo, Amarin had chosen to use mineral oil because it closely resembles Vascepa in appearance. But there were concerns, because in the mineral oil group, levels of two proteins in the blood that raise the risk of heart attacks and strokes went up. They were low-density lipoprotein, or LDL, the so-called bad cholesterol, and C-reactive protein, or hsCRP, a measure of inflammation in the body.
That raised the concern that the study wasn’t showing that Vascepa prevented heart attacks, but that mineral oil caused them — or at least that the drug’s impressive benefit might be blunted by harm caused by the placebo. The FDA considered this possibility, but decided that the effects of mineral oil were unlikely to account for the positive result.
In the new study, Amarin funded Paul Ridker at Brigham & Women’s Hospital, a well-known scientist who pioneered the use of hsCRP as a blood test to measure cardiovascular risk, to re-analyze blood samples taken from patients in the REDUCE-IT trial to see how levels of other chemicals that have been connected to increases in cardiovascular risk changed.
Those are the new results, published in Circulation, a medical journal. They show that for every one of seven different measures — including two other measures of inflammation and several different ways of measuring harmful cholesterol levels — blood levels worsened in the mineral oil group over a period of more than two years. But levels in the group that received Vascepa did not budge.
The paper says that these kinds of changes were not seen in the control arms of other trials Ridker’s laboratory had analyzed, including a pivotal study of the cholesterol drug Crestor, a study testing the rheumatoid arthritis drug methotrexate for its heart benefit, and a trial of a different fish-oil-derived medicine that used corn oil, not mineral oil, as a placebo.
The paper concludes ‘the effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain.”
Ridker declined to comment on the paper, directing all questions on the article to Deepak Bhatt, also a cardiologist at the Brigham, who was a lead investigator of the REDUCE-IT trial and is listed as senior author on the new publication.
Bhatt wrote in an email that the new biomarker data are “highly correlated” with the already known changes to LDL and CRP. He said that these biomarker changes “don’t really provide any additional mechanistic insights into the clinical benefits seen in the trial,” which he says were driven by a 400% increase in levels of eicosapentaenoic acid, an ingredient in fish oil.
When asked why this conclusion differed so much from the published paper, Bhatt replied, “Such are the vagaries of peer review.”
He said the authors submitted “several external analyses” that were not retained by journal editors and outside reviewers in the final version of the paper. “The full set of analyses provide a more balanced perspective, but I suppose we will now have to publish those elsewhere and later.”
Ridker’s silence and Bhatt’s comments give the impression that the editing of the paper may have been contentious.
Amarin said in a statement that analyses like this are meant to explore new hypotheses, and expressed its confidence in the original result.
But Sanjay Kaul, a frequent FDA adviser and researcher at Cedars-Sinai Medical Center in Los Angeles, basically agreed with this analysis, saying “any such impact is unlikely to materially dilute the overall robust evidence of benefit in REDUCE-IT.”
Other cardiologists were more concerned by the new data. Curfman noted that the study did not measure potentially beneficial markers, and that inflammatory chemicals in the blood are what are known as surrogates, which are seen as less trustworthy than hard outcomes like heart attack. Still, he said, the only way to know if Vascepta is reducing cardiovascular risk is to run another study.
“If Amarin intends to stand behind icosapent ethyl as a beneficial clinical product, it should sponsor such a trial,” he said.
Other experts were even more concerned.
Steven Nissen, a cardiologist at the Cleveland Clinic, ran a study of a rival fish-oil-derived product from AstraZeneca — the study that used corn oil as a placebo. In that study, there was no benefit. He has previously raised concerns that mineral oil may not have been a good choice as a placebo, and he said the new data raise further concerns.
“These findings are the closest thing I’ve seen in a long time to a smoking gun,” Nissen said. A broad range of inflammatory and lipid markers associated with atherosclerosis changed for the mineral oil group, but not the Vascepa group. When the FDA reviewed the study, the agency just had data on hsCRP and LDL. For other so-called biomarkers, such as Lp-PLA2, a cholesterol-related protein some companies are targeting with drugs, to go up as well raises more concerns.
“I think if you read this in totality it leaves open a major question whether REDUCE-IT is a false positive or not and I believe FDA should re-review the label to see if it is appropriate,” Nissen said. “I do not believe physicians should use icosapent ethyl without a study using a neutral comparator such as corn oil.”
“I think this is all the more important because it’s being written by the people who did the trial and what they said, in their words, is that this throws into doubt the results of the original study,” said Harlan Krumholz, a professor of cardiology at Yale University. “This is important news that has to get to patients and doctors.”
Krumholz, who is Ridker’s brother-in-law but was not involved in the trial, said that the result “is sufficiently important that the FDA should re-review its initial decision and the guideline recommendations should be re-visited.”
Despite pleas from experts that Amarin run another large and expensive trial, that is now unlikely. The company is currently facing generic competition for Vascepa in the U.S., and its first quarter revenue fell 34% to $94 million in the first quarter of 2022. Given that cardiovascular outcome studies can cost hundreds of millions of dollars, the company is unlikely to fund one. A trial would likely have to be funded by the National Institutes of Health or some other public source.
Such a study could help solve a giant medical mystery — whether fish oil drugs can help prevent heart disease. Researchers have been fascinated by the potential of the compound, and the omega-3 fatty acids like the EPA in Vascepa, since the 1970s when researchers postulated that they might explain low rates of heart disease among the Inuit. Just about every piece of research since, including that original paper, has been contested. Large clinical trials have mostly not shown a benefit to fish oil pills. One exception, though, was for a product similar to Vascepa that showed a benefit in a Japanese trial.
It had originally appeared that the Vascepa study had at last provided a positive answer, that a type of fish-oil-derived medicine could prevent heart attacks at a high dose. Instead, it has only deepened the existing mystery.
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