ORLANDO -- It isn't often that a study involving a couple of hundred people shakes up medical science.
That's what happened Monday, when doctors formally reported that lowly niacin, a B vitamin, did a significantly better job of shrinking artery plaque than a billion-dollar blockbuster called ezetimibe, the active ingredient in the cholesterol drugs Zetia and Vytorin.
"The results are very clear," says lead investigator Allen Taylor of the Medstar Research Institute. "Niacin was superior."
The study involved just 208 people, but it was so carefully designed that even the expert called upon to critique the trial, John Kastelein of the University of Amsterdam, said "I fully support" the result.
Taylor and Kastelein presented their findings here Monday at a meeting of the American Heart Association. On Sunday evening, The New England Journal of Medicine published the results online.
If the study had occurred in a vacuum, it might have had less impact. But Taylor's study was the third in two years to challenge the effectiveness of one of the world's most popular heart drugs, with $21 billion in sales since it was introduced in 2003, Securities and Exchange Commission documents show.
Latest in string of studies
The drug's maker, Merck & Co., didn't wait for the bad news to break. In anticipation of the findings, executives including Peter Kim, president of Merck Research Laboratories, and Richard Pasternak, Merck's head of global scientific affairs, sought to discredit the study by calling it "flawed" and misleading in press interviews and through a letter sent to The New York Times.
No one challenges ezetimibe's power to lower LDL, or bad cholesterol, the basis on which the Food and Drug Administration granted approval. Studies with cholesterol-lowering statins demonstrate that driving down LDL levels can reduce heart risk by 25% to 40%. "Zetia and Vytorin offer physicians another tool they can use to get patients' cholesterol levels down," Kim says.
The big question is whether ezetimibe prevents heart disease and death. Because the FDA approved the drug based on its impact on cholesterol levels, Merck researchers have yet to provide an answer. The company's website says the drug's impact on heart disease and death "has yet to be determined."
Last year, a study called Enhance showed Vytorin, made of ezetimibe (Zetia) and simvastatin (a statin), did no better job of treating clogged arteries than simvastatin alone. A second study, called Seas, generated fresh controversy when researchers not only reported Vytorin's lackluster performance but vexing evidence that patients who took it appeared to die more often of cancer. An independent analysis challenged that by using data from other studies to assert there is no such risk.
The new study, called Arbiter 6-Halts, pitted ezetimibe against slow-release Niaspan, made by Abbott Laboratories. The study, sponsored by Abbott, involved 208 people with heart disease or serious heart risks. All had been taking statins and had low levels of bad cholesterol. Half of the patients were given Niaspan, and half were given Zetia.
Ultrasound images of neck arteries showed that Niaspan reduced artery plaque by 2%; Zetia did not. Two people in the Niaspan group had heart attacks or other major cardiac events, vs. nine in the Zetia group. One person in the Niaspan group and five people in the ezetimibe group died, Taylor says.
The result was so pronounced that the study was stopped in 14 months, after only 208 of 363 patients enrolled in the trial underwent ultrasound testing.
Kastelein, a heart specialist who has taken consulting fees from Merck, says the early stoppage didn't affect the results, though he would have preferred the study to continue. It offers "big, big support" for the use of niacin, he says.
A definitive answer coming?
But nothing in science is simple. Doctors, including Kastelein, have come to rely on ezetimibe because statin therapy doesn't always push LDL levels low enough to guard against heart attacks.
Ezetimibe offers a ready alternative, without the uncomfortable flushing and itching that trouble niacin users, especially at the 2-gram doses needed for cholesterol treatment. "In Europe, we hardly use it," Kastelein says. (Doctors discourage using over-the-counter niacin, because there's no evidence that it's safe or that it works.)
At the same time, Merck stands by its drug. Luciano Rossetti, Merck's head of global science strategy, says the company has enrolled nearly 15,000 of 18,000 patients for a trial designed to show, once and for all, whether ezetimibe works.
The trial will not end, Rossetti says, until more than 5,000 volunteers have heart attacks or major heart problems. So far, he says, doctors have logged about 2,300.
In an editorial in The New England Journal of Medicine, Kastelein says the total is so high, it is "uncertain whether the trial will ever reach completion."
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