A widely prescribed and expensive cholesterol drug is not as effective as niacin, a cheap vitamin, in helping to unclog coronary arteries in people already taking statins, the standard medicines used to lower cholesterol, according to a new study.

The research, which appears Monday in the New England Journal of Medicine, is sending rumbles through the medical community because it is the third recent study to raise questions about the effectiveness of Zetia and its sister drug, Vytorin, highly profitable pharmaceuticals made by Merck & Co.

"This is the third strike," said Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. "The studies are telling us that it doesn't appear to produce benefits. This is a drug used by millions of Americans, a very big seller, in a health-care system where costs are a major issue. And the question has to be, is this the right approach?"

Vytorin and Zetia are among the most popular prescription drugs. Last year, physicians in the United States wrote a total of more than 29 million prescriptions for them, and worldwide sales totaled $4.56 billion, according to Merck.

Although the drugs have been shown to reduce cholesterol, there is no evidence that they prevent heart attacks, strokes and other cardiovascular problems.

Top Merck executives are vigorously defending their drugs and have dismissed the new research as limited.

"I don't think a clinician or a doctor or a patient should use this as the basis for any decision-making whatsoever," said Richard Pasternak, vice president of Merck research laboratories. "I worry that people might unnecessarily come off a drug that is approved and accepted."

He and other critics said the study appearing Monday involved just 200 patients, was ended early, and examined what is known as a surrogate marker -- the amount of plaque on artery walls -- rather than evaluating the rate of heart attacks and stroke.

Because plaque can clog arteries and restrict blood flow to the heart and brain, cardiologists view plaque as a good indication for the risk of heart attack and stroke.

The study has been highly anticipated by the medical community and financial analysts, and is the buzz at the annual meeting of the American Heart Association, which began Sunday in Orlando.

Introduced in 2002 and 2004 amid heavy direct-to-consumer marketing, Zetia and Vytorin became blockbusters for Merck and Schering-Plough, which had collaborated on their development. The companies recently merged.

But new research has placed the drugs under greater scrutiny and the number of written prescriptions has been slipping, although together they still represent big business for Merck.

Last year, a study released by Merck showed that Zetia did not reduce plaque in arteries compared with patients taking only statins, which are much less expensive and available in generic form. Although released in January, the study had been completed in 2006, prompting a class-action lawsuit alleging that Merck intentionally withheld unfavorable results of a clinical trial. The company paid $41.5 million in August to settle the claims.

Another study published last year showed a potential increase in cancer among patients taking Zetia and Vytorin, compared with those taking only statins.

Taken as a whole, the new research is unnerving, said Harlan Krumholz, a Yale University cardiologist. "The accumulating evidence isn't giving you any confidence," he said. "This is a very expensive drug being used without any strong evidence that it's benefiting patients." Zetia and Vytorin should be "drugs of last resort, if used at all," Krumholz said. "And anyone who uses it should make sure patients are informed that they're taking a gamble."

Statins, such as Lipitor, have long been used to lower cholesterol and reduce cardiovascular disease. They inhibit the production of LDL, or low-density lipoprotein, often called "bad" cholesterol, which can lead to plaque buildup in arteries.

Zetia, the brand name for ezetimibe, uses a different mechanism. It blocks the absorption of cholesterol from food in the intestines. It has been shown by Merck to lower LDL by 18 percent on average. It is designed for patients who cannot tolerate statins, or for whom high-dose statins are not working.

Vytorin is Zetia combined with a statin, simvastatin, in one pill.

The study released Monday followed about 200 patients who were already taking statins. Some were also given Niaspan, a modified form of Vitamin B, or niacin. The rest took Zetia. Researchers took images of the artery leading to the brain to measure the thickness of the artery walls over 14 months.

The patients who took Niaspan had less plaque in their arteries and also had higher levels of high-density lipoprotein or HDL. Known as "good" cholesterol, HDL is believed to remove cholesterol from the arteries and carry it back to the liver, where it is passes from the body.

The patients who took Zetia had more plaque in their arteries but lower levels of LDL. They also had more heart attacks, strokes and other cardiovascular problems than the patients taking niacin. Merck President Peter Kim said the fact that Zetia lowers LDL cholesterol makes it valuable. "It's very well established that lowering LDL saves lives," he said.

Roger S. Blumenthal, a cardiologist at Johns Hopkins, criticized the new study in an editorial also published Monday in the New England Journal of Medicine. Blumenthal, who has been a paid speaker for Merck, noted that the new study was halted early, which meant results from 40 percent of the participants were not included in the final analysis.

The study's author, Allen J. Taylor of Walter Reed Army Medical Center and Washington Hospital Center, said the trial ended early because the results were quickly apparent. "It couldn't be more clear," Taylor said. "It would have been unreasonable to continue the experiment because the trial had met its objective -- niacin is superior to ezetimibe."

Kim said any conclusions about Zetia and Vytorin should wait until Merck completes a large-scale clinical trial. It involves 15,000 patients and is not expected to yield results until at least 2012.

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