The Wall Street Journal-20080117-Cutting Through the Confusion Over Vytorin- Despite Negative Study- Doctors Say Drug Remains An Option to Fight Cholesterol
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Cutting Through the Confusion Over Vytorin; Despite Negative Study, Doctors Say Drug Remains An Option to Fight Cholesterol
Patients are swamping doctors' offices wondering if they should stop taking the anticholesterol drug Vytorin, in the wake of a report questioning its ability to slow the progression of heart disease.
The message from many heart experts: Don't panic.
Despite high-profile news coverage and the widely quoted views of a prominent cardiologist, the study's findings offer only limited new information to influence whether patients should take the drug. And the study, known as Enhance, offers no clear signals that patients should stop using Vytorin.
"Enhance is not an alarming study," says Richard Milani, head of preventive cardiology at the Ochsner Clinic, New Orleans. "There were no safety issues related to the trial that people were somehow being harmed on Zetia."
The main finding was that Vytorin, which is marketed by a joint venture of Merck & Co. and Schering-Plough Corp., failed to prove more effective than a cheaper generic drug in stanching the development of disease in blood vessels in the neck.
Vytorin and its sister drug, Zetia, are widely used to help patients lower LDL, or bad cholesterol, beyond levels achieved using popular cholesterol pills called statins. Vytorin is a combination of Zetia and a statin. The statin, Zocor, is now available as a generic pill called simvastatin.
The American College of Cardiology Tuesday issued an unusual statement cautioning doctors and patients against making decisions based on the Enhance findings. The statement said Vytorin and Zetia remain "reasonable" options in certain situations to help patients reach recommended cholesterol goals to reduce heart-attack risk. The college, the leading professional society for cardiologists, issued the statement after members reported they were getting calls from worried patients. One practice said it received 500 calls, said James Dove, president of the college.
The statement stood in contrast to the position of Steven E. Nissen, chairman of cardiovascular medicine at the Cleveland Clinic and past president of the college, who was widely quoted urging doctors to stop prescribing the drugs for patients except as "a last resort." Dr. Nissen said the lack of efficacy found in the study suggested that the drugs had no benefit.
Dr. Nissen said his views and the college's are consistent in advising use of the drugs only when doctors and patients have exhausted their options with statins. But, he said, "Here we are, six years after this drug was marketed and promoted with a massive marketing campaign and has become a $5 billion drug" without evidence that it works as well as a statin. Now, "the first trial we have, is reported much too late and doesn't show really any evidence of benefit."
Patients and many practicing physicians are caught in the controversy, uncertain what course to take. Following are some key issues raised by the Enhance study.
What did the study show?
The 720-patient study indicated that patients taking Vytorin reached LDL levels 17% lower than those taking Zocor alone but derived no benefit as measured by the buildup of disease-causing plaque in their carotid, or neck, arteries. That measure is a commonly used surrogate marker for risk of heart attacks and stroke. There was a very small increase in the thickness of the arteries among Vytorin patients.
The data were released by the drug companies in a news release, not in the more standard form of an abstract or peer-reviewed published article. As a result, details about the safety and effectiveness of the drug remain unclear.
"It's premature to use this study to change how an entire nation is prescribing medication," says Kevin Graham, president and head of preventive cardiology at Minneapolis Heart Institute in Minnesota.
If LDL was lower, why isn't there a benefit from Vytorin?
It isn't clear. Zetia reduces LDL cholesterol by blocking absorption in the gut, unlike statins, which inhibit its production in the liver. Dr. Nissen and other researchers believe this different mechanism may not have the same impact on the biology of the arteries or other factors that could prevent heart attacks. In any event, researchers agree that the findings don't undercut the prevailing view that lower is better when it comes to LDL.
If the drug doesn't prevent heart attacks, why is it on the market?
The drug was approved by the Food and Drug Administration based on its ability to lower LDL. As is typically the case with many drugs the agency didn't demand proof that using the drug actually reduced the risk of heart attacks or stroke.
The Enhance results are now part of a larger debate over what kind of evidence the FDA should require before approving a drug. Studies that answer questions about heart attacks, strokes and mortality take many years, thousands of patients, and would lead to prolonged delays getting a drug to market. Looking at a proxy, like LDL, allows a cheaper, faster -- albeit less definitive -- trial.
Who should take the drugs?
Many doctors say the findings don't change the dominant view that Zetia or Vytorin should be used only for patients who can't tolerate statins, or who don't get to aggressive goals on a high-dose statin alone. It shouldn't be used as first-line treatment. Dr. Nissen believes that with nearly one million prescriptions a week, the drugs are being inappropriately prescribed for many patients who haven't given statins a true test.
"Physicians should be using higher doses of statins long before they go to adding a drug where we don't have any evidence showing" it improves a patient's chances to avoid a heart attack or stroke, says Paul Ridker, preventive cardiologist at Brigham and Women's Hospital, in Boston.
But Neal Shadoff, a cardiologist at Presbyterian Heart Group, Albuquerque, N.M., says doubling the dose of a statin gives patients only an additional 6% reduction in LDL with the risk of increased side effects while Zetia offers a 15% to 20% drop and fewer side effects. While he primarily relies on statins and acknowledges that data on Zetia and Vytorin are far from complete, he believes the drugs are important tools in helping patients get to their goals.
Are better data on the way?
A study called Improve-It, being led by doctors at Harvard and Duke universities, is under way to see if Vytorin reduces heart attacks, strokes and death. Data aren't expected until 2011.
"This Enhance trial is just a reminder that you don't know until you've done the definitive trial," says Duke's Robert Califf.
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Anna Wilde Mathews contributed to this article.
