Cardiologists are still grappling with clinical trial results released last week that showed that Vascepa, a fish-oil-derived drug, reduced heart attacks, strokes, and deaths from cardiovascular disease by 25% in patients who had elevated triglycerides, or particles of fat in the blood. Views range from “healthy skepticism” to a hope that the study could rank among the most important ever in cardiology.
The apparently astounding benefit was paired with a number of caveats that some doctors worry could have inflated Vascepa’s apparent benefit, including a mystery as to exactly how the medicine works, a placebo that could have hurt patients, and previous studies of lower doses of similar fish oil drugs that were resoundingly negative. (Vascepa is a purified form of eicosapentaenoic acid, or EPA, a component of fish oil.) Some top researchers have visibly struggled with the results. The drama has been accentuated because Amarin Pharmaceuticals, Vascepa’s maker, is a small company with a devoted following of vocal individual investors.
How much can a doctor’s opinion shift on these data? When the headline results were released by press release in September, Sekar Kathiresan, director of the Cardiovascular Disease Initiative at the Broad Institute, at first reacted to the news by saying “Wow!” When he saw the results as published in the New England Journal of Medicine, he worried about exactly how the drug was working, and said he was “probably a little too enthusiastic with my initial comment.” But he now thinks his initial reaction was probably right, and that the Vascepa results constitute a major advance.
James Stein, Robert Turell Professor of Cardiovascular Research at the University of Wisconsin, is a skeptic, believing that the placebo group in the study probably raised cardiovascular risk, making Vascepa look better than it was. But he’s still planning to try Vascepa in some patients. “I don’t know how much to discount it’s effectiveness,” Stein says. Even if he assumes that half of the effect was from the placebo, the benefit is still better than moving from a low dose of atorvastatin, the popular cholesterol drug, to a higher one. He doesn’t plan to prescribe the drug (or other fish oils) to people on anti-clotting drugs like Plavix, though, because it may increase the risk of bleeding. “That’s where I am today,” he says.
In an editorial that accompanies the study’s publication in the print edition of the New England Journal of Medicine, John J.P. Kastelein and Erik S.G. Stroes of the Academic Medical Center, University of Amsterdam, Amsterdam write: “We welcome these results with surprise, speculation, and hope.” They express concern that the data aren’t explained by Vascepa’s expected mechanism of lowering triglycerides, that the result conflicts with previous trials of fish oils, and that the placebo group may have had an effect. Kastelein is among the researchers conducting a 13,000 patient study of Epanova, another fish-oil-derived drug manufactured by AstraZeneca,
Should doctors use Vascepa? “They should use it,” Kastelein wrote via email. “The only thing we are waiting for is to learn whether Vascepa is unique or other fish-oil preparations or other doses of EPA have less, similar or better efficacy.”
Not everyone is so sure. “I have what I would say is some healthy skepticism about the results,” says Eric Topol, the Gary & Mary West Endowed Chair of Innovative Medicine, Scripps Research. The main reason, he says, is that the study doesn’t fit with the many other studies of lower doses of fish oil preparations that have shown no benefit. Another worry, he says, is that triglyceride-lowering does not seem to explain the cardiovascular benefit that was seen. “That is distressing,” he says, “because we have no idea what the mechanism is. The assertion that it’s just because of high EPA dose or pure EPA, that’s all speculation.”
Topol also has concerns that the placebo may have raised cholesterol and c-reactive protein. “They happened to have a placebo that’s not inert,” he says. That won’t explain the results he says, but it’s also not helping to sort things out. He says he’s not comforted by an analysis showing that the results hold up when researchers analyzed them with just the patients in the placebo group whose low-density lipoprotein (LDL, the “bad cholesterol”) went up, or just those in whom LDL stayed flat. “That’s just one way of looking at it,” he says. “It probably should be looked at in multiple ways.” Still, he says: “At the end of the day, I don’t think that the main explanation is that the placebo is the problem. I doubt it was the singular problem. It was contributing.”
“There’s too many warts here to make [it seem] that this is pure triumph,” Topol says. “There’s some things that just don’t compute.”
Other top cardiology researchers had far more positive views. Jane Armitage, an epidemiologist at the Nuffield Department of Population Health at Oxford University, writes via email that it is “very unlikely that the small dose of the placebo oil is likely to have caused any problem, although it is slightly odd that they chose a mineral oil rather than a vegetable oil.” She argues the results are “believable in light of the prior evidence.”
Unlike other experts, who largely believe that Vascepa’s effects must go beyond lowering triglycerides to preventing cardiovascular disease in other ways, perhaps by reducing the risk of sudden cardiac death or clots, Armitage believes that the 44 milligram per deciliter drop in triglycerides seen in the study could explain the benefit. She points to a 2011 analysis of multiple studies of fibrates, a different type of triglyceride-lowering drug, which showed a similar benefit in patients with high triglycerides. Other fish oil trials probably failed because they used much lower doses. “It seems that high doses of fish oils are needed to gain benefit at least in this high triglyceride population,” Armitage writes.
Even most proponents of the argument that the placebo in the study was harmful doubt that it increased the rate of events more than 5%; it’s the lack of a clear understanding of how the drug is working that bothers them most. But Rory Collins, the head of the Nuffield department at Oxford , argued in an email that other factors could explain the increase in cholesterol seen in the placebo group. One factor is that low cholesterol was required for patients entering the study. That could have meant that researchers were picking people at what was a low cholesterol level for them, and the levels simply returned to normal. (This is called regression to the mean.) It also could be the result, he says, of statistical quirks because the tests weren’t collected in random order — and effect that researchers could test for by going back to banked blood samples.
“An effect of the mineral oil remains a possibility, but my guess would be that it is largely if not wholly an effect of the high-dose EPA through mechanisms beyond merely lowering [triglycerides],” Collins writes. He poses a provocative question: what if the Vascepa study, called REDUCE-IT, is to EPA what a 1995 study called 4S was to cholesterol-lowering drugs called statins?The 4S study, also known as the Scandinavian Simvastatin Survival Study, was funded by Merck and released in 1994. It was the first study to show that a cholesterol-lowering statin drug prevented heart attacks and, indeed, saved lives in patients who already had heart disease. It started years of debate, and the drug used in the study, Zocor, was surpassed by rival medicines made by other companies. But the statins become one of the most popular classes of drugs the world has ever seen, generating hundreds of billions of dollars in sales and saving countless lives.
It’s a question, not an answer. In recent years, new cardiovascular drugs have been commercial flops even when they seemed like scientific successes. But it is a tantalizing possibility.