Another Blow For Schering And Merck

On Sunday, executives at Merck and Schering-Plough were visibly shocked when an expert panel here at the American College of Cardiology meeting told thousands of doctors not to use their top-selling drugs, Zetia and Vytorin. That night, at a press conference, they strongly contested arguments that they had not proved the drugs were safe.

On Monday morning, things got worse. Rival AstraZeneca said it had stopped its 15,000-patient clinical trial of its Crestor because an independent safety committee said there was proof the drug prevents heart attacks, strokes and deaths. The result came six months ahead of schedule.

For the medical community, the Crestor news is a big deal for two reasons. First, it provides definitive proof Crestor has lifesaving benefits like other statin drugs, such as Lipitor, Zocor and Pravachol. Second, it provides key evidence that these medicines can prevent heart attacks even in patients who have normal cholesterol but have other risk factors for heart disease.

In particular, the patients in the Crestor trial had high levels of C-reactive protein (CRP) in the blood. The protein is thought to be a measure of inflammation in the arteries, and inflamed arteries are more likely to develop the clots that cause heart attacks and strokes. The experiment was designed to test whether people who had normal levels of bad cholesterol but high CRP could be helped by statin therapy. Up until now, evidence for statins has been mainly in people with high "bad" cholesterol, properly known as low-density lipoprotein (LDL).

"It's splendid news, and that's sort of what they were waiting for to decide where CRP fit," says Roger Blumenthal, who directs preventative cardiology at Johns Hopkins University. "This is a boon to AstraZeneca and the field."

Weighing the proof that high CRP is a risk factor for heart disease that should be treated will have to wait until the study's results are analyzed and presented. But the study could also be a big victory for Paul Ridker, the Brigham and Women's Hospital cardiologist who headed up this trial and has spent a lot of his career doing pioneering work on CRP.

The study is more bad news for Merck and Schering-Plough , though. The American College of Cardiology panel and two editorials in The New England Journal of Medicine recommended sidelining use of Zetia, a kind of cholesterol drug that works differently from statins, and Vytorin, a combo pill of Zetia and the statin Zocor. Instead, they said, push the doses of statins where there is proven evidence.

"We now have data for every statin marketed that shows a reduction in morbidity and mortality," says Steven Nissen of the Cleveland Clinic, who had recommended Zetia be treated as a "last resort" months ago. "This really does emphasize what the panel said yesterday. Whatever statins do, and however they do it, it really works across the entire class. It really is a tremendous emphasis that statins are the first choice and why they are the first choice."

Nissen has a somewhat tangled history with Merck and Schering-Plough. He raised concerns about Merck's Vioxx in 2001, before the drug was yanked from the market. And Merck and Schering-Plough scrapped plans to do a Vytorin imaging trial with him.

But the emerging consensus about Zetia has been striking: The majority of cardiologists interviewed at the American College of Cardiology meeting foresee a pullback in use of the drug until there is more science about how exactly it works. Merck and Schering-Plough have one trial testing whether Zetia prevents heart attack and stroke, and the study is not expected to end until 2012. The Zetia trial started exactly three years after the Crestor trial that was just halted, according to ClinicalTrials.gov.