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BOSTON, May 23-A new analysis of post-marketing safety reports suggests that patients using Crestor (rosuvastatin), a super-potent statin, are more likely to develop serious side effects than patients taking Lipitor (atorvastatin), Zocor (simvastatin), or Pravachol (pravastatin).

Patients taking Crestor are eight times more likely to develop rhabdomyolysis, nephropathy, renal failure or proteinuria than patients taking Pravachol, and 6.5 times more likely to develop those complications than patients taking Lipitor, said a study, published today in Circulation, Journal of the American Heart Association. The adverse event risk was 2.2 fold higher for Crestor versus Zocor.

AstraZeneca, the maker of Crestor, said in a statement: "We strongly disagree with the conclusions of this study."

Richard H. Karas, M.D., Ph.D., director of preventive cardiology and the Woman's Heart Center at Tuft-New England Medical Center, noted that the absolute risk remains low: 28 events per million prescriptions for Crestor, versus 13 per million for Zocor, 3.5 per million for Pravachol, and 4.3 per million for Lipitor.

Yet, Dr. Karas and colleagues did not recommend that Crestor be withdrawn from the market. Instead, they suggested "that vigilant surveillance for adverse effects during initiation of therapy may help ameliorate the risk of toxicity when rosuvastatin is used."

That said, they concluded that it "would seem prudent at the current time for doctors to consider other statins as first-line therapy, to initiate therapy in appropriate patients at lower doses, to consider combination LDL-cholesterol-lowering therapy (e.g. statin combined with ezetimide), and to vigilantly monitor for adverse events if rosuvastatin is used."

Dr. Karas compared the adverse event reporting rates for Pravachol, Zocor, Lipitor, and Crestor using a composite endpoint of rhabdomyolysis, proteinuria, nephropathy or renal failure.

During an AHA press briefing he repeatedly hammered home the message that the absolute risk of an adverse event with Crestor was low -- just 145 cases of rhabdomyolosis or renal complications reported for 5.2 million Crestor prescriptions during its first year on the market, which is an absolute risk of 1 in 35,862.

"This is not the type of risk that will impact the clinical care of a single patient," Dr. Karas said. "It is the impact on populations that is of concern."

Nonetheless, he pointed out the increased risk appears early in Crestor treatment and at low doses -- 10 mg.

And the AHA signaled its concern about the new study by arranging a telephone press conference to review the study and an accompanying editorial by renowned cholesterol authority Scott Grundy, M.D., Ph.D., director of the Center for Human Nutrition and Departments of Clinical Nutrition and Internal Medicine at the University of Texas Southwestern Medical Center, Dallas.

Elliott Antman, M.D., of Harvard Medical School, director of the coronary care unit at Brigham and Woman's Hospital in Boston and a Circulation senior associate editor, set the tone by cautioning the press against sensational reporting of the new data. But he also noted that the paper had been fast-tracked to publication in just five weeks since "we appreciated that there is significant interest in this topic."

In his editorial Dr. Grundy was critical of Dr. Karas's paper and noted that the FDA conducted a "careful and through analysis of the same data" and came up with a different conclusion. The FDA report, which was issued in March 2005, came in response to a request from Sidney M. Wolfe, M.D., director of the Health Research Group of Public Citizen asking the FDA to remove Crestor from the market.

Moreover, during the press briefing Dr. Grundy flatly stated that even with the report from Dr. Karas and colleagues he had "no evidence that one statin is safer than another."

He added that even when muscle or kidney problems are reported those "events seem dose related and will reverse when the drug is stopped or the dose lowered." Dr. Grundy said, too, that most adverse events occur in patients who "don't meet AHA/ACC criteria for statin therapy."

The statin guidelines list as high risk individuals: frail elderly (over age 80) who have small body frames, patients with multisystem disease, patients following surgery, patients taking multiple drugs, patients consuming more than a quart of grapefruit juice daily, and patients who abuse alcohol.

Dr. Grundy was also critical of the study design with combined a relatively minor endpoint -- proteinuria -- with severe endpoints such as renal failure.

In 2001 the statin called Baycol (cerivastatin) was withdrawn from the market after reports of a significant increase in risk of rhabdomyolysis. Dr. Karas included Baycol in a comparison of adverse events reported during the first year of marketing of statins.

In that first year of marketing analysis (compares adverse events of each drug during its first year on the market), Crestor had fewer serious adverse events reported than Baycol (P <0.001) or Zocor (P-value not significant) but reported more serious adverse events in its first year of sales than Lipitor or Pravachol (P <0.001 versus both). In the concurrent time period analysis (first year of Crestor versus other drugs taken in the same year), each of the adverse end points was more likely to occur with Crestor compared to Zocor, Pravachol, or Lipitor (P-values range from <0.01 to <0.001).

There were fewer deaths related to the composite endpoint among patients taking Crestor or Zocor -- but there were more deaths from all causes among people taking Crestor, although the numbers were low -- six deaths among Crestor-treated patients, three for Zocor, one for Pravachol and two among patients taking Lipitor.

Alice K. Jacobs, M.D., president of the AHA, urged physicians to use the data included in the Karas study to help "inform decisions about statin therapy," but she said that the choice of treatment should be based on "treatment to cholesterol goals."

As a class, the statins are very safe, said Dr. Jacobs, who cautioned that risk associated with stopping statin therapy outweigh the risks associated with taking the drugs -- even the potential for increased risk with Crestor.

In an interview Dr. Karas said he will continue to prescribe Crestor, but only in selected cases and not as first line therapy. "I typically assess the degree of LDL lowering required and balance that against the risk for side effects from statins. I would start with Lipitor or Zocor and if the patient is unable to get to goal, I would consider switching to Crestor."

He added that he would only consider using Crestor in patients who needed "to lower LDL by 35% to 40%" and noted that there is only a modest incremental benefit in LDL lowering for Crestor versus matched doses of Lipitor or Zocor. "If you get a 55% reduction with Lipitor or Zocor, you will get 60% with Crestor."

Asked to define "vigilant surveillance for adverse effects", Dr. Karas said "check liver function every six to eight weeks, talk to patients, find out if they are having muscle pain. If they are having muscle pain, check kidney function." He noted that these are the standard follow-up recommendations for all statins but said "we've gotten pretty complacent with the other statins. If we are going to use this statin, we can't be complacent."

Related articles:

• FDA Orders New Warning Label for Crestor

• Death of Crestor (rosuvastatin) Patient Not Caused by Drug, Company Says