Cardiac surprise, cholesterol drug Crestor

NEW ORLEANS -- AstraZeneca PLC's cholesterol drug Crestor sharply lowered risk of heart attacks among apparently healthy patients in a major study that challenges long-standing heart-disease prevention strategies and could substantially broaden the market for statins, the world's best-selling class of medicines.

Heart experts said the findings, presented Sunday at the annual scientific meeting of the American Heart Association, could reshape cholesterol-treatment guidelines used for more than a decade to fight cardiovascular disease, the world's leading killer. They could also help AstraZeneca boost its 9% share of the global cholesterol-drug market, which exceeds $15 billion and is now dominated by generic statins and by Pfizer Inc.'s Lipitor.

The study, called Jupiter, found that Crestor reduced the risk of heart-related death, heart attacks and other serious cardiac problems by 44% compared with those given placebos. The 17,802 participants were entering prime heart-attack ages--over 50 for men and over 60 years for women -- but none had evidence of serious heart disease or cholesterol levels high enough to call for treatment under current guidelines.

All participants did have elevated levels in their blood of C-reactive protein, or CRP, an inflammatory marker that in previous studies has been shown to identify patients at heart risk independent of their cholesterol levels. As a result, some experts say the study supports broad use of a high-sensitivity CRP test to find people who may be falsely assured by low cholesterol levels that they are protected from trouble and determine if they might be candidates for treatment.

"This takes prevention to a new level," said Douglas Weaver, head of cardiology at Henry Ford Hospital, Detroit, who wasn't involved with the Jupiter study. "It defines a new population" of patients at risk.

But others urged caution. "Before we expand treatment indications in any drastic way, we need to do due diligence," said Mark Hlatky, a cardiologist at Stanford University. "The idea that everybody should get CRP measured is premature and not backed up by good data." Little is known about the long-term effects of the aggressively low cholesterol levels achieved in the study, he added.

Moreover, despite large relative benefits, the actual number of patients helped was small: Just 393, or 2.2% of patients suffered a major cardiovascular event -- 142 on Crestor and 251 on placebo. Dr. Hltaky said that raises questions about the cost effectiveness of putting millions of low-risk patients on medication for the rest of their lives. Other critics said shortcomings in the study left them uncertain how CRP levels would be helpful beyond conventional risk factors in recommending patients for therapy.

Jupiter is the talk of the heart meeting here, which is expected to draw more than 25,000 cardiologists and other attendees involved in battling cardiovascular disease. Doctors and investors have been eagerly awaiting the results since last March, when the trial was halted after an interim check found overwhelming benefit for the drug. That was after patients had been followed for an average of just 1.9 years, two years earlier than planned.

The findings will stir new debate in a field already divided over the role of high-sensitivity CRP testing in clinical practice. They are certain to figure in deliberations of U.S. cholesterol experts who will take into account how many people should be treated with statins and how low cholesterol targets should be when they issue a major update of cholesterol guidelines next year. Jupiter researchers estimate some six million people in the U.S. meet the criteria of those participating in the study and thus might benefit from statin therapy; some analysts put the number above 10 million.

The study comes in the wake of the uproar early this year when the cholesterol drug Zetia failed to show a benefit in a controversial study. Though the Merck & Co. and Schering-Plough Corp. medicine isn't a statin, the episode prompted some to question the value of statin therapy. Researchers said the new data affirm the role of statins and should help ease lingering doubts about their value in heart disease prevention.

In the study, sponsored by AstraZeneca, levels of LDL or bad cholesterol among patients taking Crestor plunged 50% to an average of 55 from 108, the lowest ever achieved in a major statin study. CRP fell 37% and wasn't associated with how much LDL was reduced. Deaths from any cause were reduced by 20%, the first time that has been shown in people without diagnosed heart disease. Among women, the drug lowered risk of major events 46%, with a similar reduction for blacks and Hispanics. Risk of first heart attack, stroke and the need for procedures to clear or bypass clogged arteries declined at rates from 46% to 54%

"Those benefits are approximately twice as large as what doctors expect when you use statins in patients with [high cholesterol]," said Paul Ridker, a cardiologist at Harvard Medical School and Brigham and Women's Hospital who led the study. "And they didn't have [high cholesterol]. What they had was high CRP."

Dr. Ridker, who is a co-inventor on a CRP-related patent held by Brigham and who along with co-authors has received grant support and other fees from AstraZeneca, presented the data at the heart meeting. The study is being published online Sunday by the New England Journal of Medicine.

Dr. Ridker said an analysis by study statistician Robert Glynn of Brigham estimated that applying the Jupiter findings to medical practice for six million Americans for five years would prevent 250,000 heart attacks, strokes, artery-clearing procedures and heart-related deaths.

Reports of serious adverse events were evenly divided -- 1,352 on the drug and 1,377 on placebo -- as were reports of muscle weakness -- 1,421 on the drug and 1,375 on placebo. Muscle weakness is a side effect that causes some patients to go off statins. There were 270 cases of diabetes reported among Crestor patients, compared with 216 on placebo.

For London-based AstraZeneca, Jupiter fills a big void. Crestor, which had sales of $2.6 billion in the first nine months of this year, up 24% over 2007, is the most potent statin for reducing LDL cholesterol. Now the company finally has the kind of hard evidence its rivals have had that the drug prevents heart attacks and saves lives.

Still, the company faces challenges in quickly converting the Jupiter findings to higher sales. For one thing, it can't aggressively market the results until regulator approval a label change reflecting the data. That isn't likely until 2010, based on the company's plans to file an application with the Food and Drug Administration during next year's first half.

Analysts are split on the likely impact of the study. Morgan Stanley analysts said recently Jupiter should help Crestor "take significant market share from competitors," and also protect it somewhat from generics. The firm predicted Crestor revenues could grow to as much as $8 billion and 18% of the global statin market in 2014.

But Timothy Anderson of Sanford C. Bernstein said in a note to investors that physician adoption of the data could be slow, tempered by unanswered questions over the safety of aggressive long-term treatment of patients with normal cholesterol.