Rosuvastatin Linked to Excess Adverse Events

Mitchel L. Zoler

Adverse event reports filed during the first year that rosuvastatin was on the U.S. market showed that its use was linked with significantly more adverse events than other statins.

From October 2003 to September 2004, more than 5 million prescriptions for rosuvastatin (Crestor) were filled in the United States. Rosuvastatin use was associated with about 28 adverse events reports of rhabdomyolysis, proteinuria, nephropathy, or renal failure for every 1 million prescriptions filled, a rate two to eight times higher than that for atorvastatin (Lipitor), pravastatin (Pravachol), or simvastatin (Zocor) according to the report (Circulation 2005;111:3051-7). But experts differed on the clinical message of these findings.

"This additional safety information is important for both patients and physicians to consider," said Richard H. Karas, M.D., director of the Preventive Cardiology Center and the Women's Heart Center at Tufts-New England Medical Center in Boston, and senior author of the report. He and his associates concluded that "it would seem prudent at the current time for health care providers to consider other statins as first-line therapy."

A more skeptical view was given by Scott M. Grundy, M.D., who wrote an editorial that accompanied the report (Circulation 2005;111:3016-9).

"I don't see any clear-cut evidence to choose one statin over another," he said during a press briefing. "On the basis of this study, I don't know that rosuvastatin is more dangerous" than other statins, said Dr. Grundy, director of the Center for Human Nutrition at the University of Texas Southwestern Medical Center in Dallas. He cited the limitations of adverse event reports as a way to gauge the safety of a drug and to compare safety among drugs and noted that in March 2005, the Food and Drug Administration denied a request to remove rosuvastatin from the U.S. market.

"The FDA had the same database [that Dr. Karas used] and they did not determine that rosuvastatin was more dangerous [than other statins]," said Dr. Grundy at the press briefing. "The disagreement is whether the evidence is strong enough evidence to say that there is a difference [among statins]."

The Circulation study analyzed reports for a variety of individual adverse events, such as myopathy and liver effects, as well as for several combinations of events including the primary analysis, which totaled the reports of rhabdomyolysis, proteinuria, nephropathy, or renal failure. The analysis looked at reports for all statins during the first 12 months when rosuvastatin was available in the United States, as well as reports made during the year when each statin was first available

The consistent pattern in virtually all of these comparisons was that the number of adverse event reports for rosuvastatin was significantly higher than for atorvastatin, pravastatin, or simvastatin.

Despite significantly higher relative risk linked to rosuvastatin use, Dr. Karas and the other speakers at the press briefing stressed that the absolute incidence of adverse events was low with rosuvastatin and with all other approved statins.

"This paper heightens our sensitivity to the possibility of a signal of increased adverse events with rosuvastatin, but it has limitations," commented Elliott Antman, M.D., director of the coronary care unit at Brigham and Women's Hospital in Boston and senior associate editor of Circulation. "The overarching issue is to get patients [who need treatment] on statins to help achieve their lipid goals. If rosuvastatin is the statin that is most available to a patient based on insurance reimbursement, then that's perfectly acceptable," Dr. Antman said.

When asked to comment on this story for this newspaper, Ali AbuRahma, M. D., chief of vascular surgery, Robert C. Byrd Health Sciences Center, Charleston, W.Va., stated that when consumer advocate reports were published in major U.S. newspapers several months ago, the call for a ban on rosuvastatin was renewed and the medication was placed under the microscope. At the time, FDA records showed 11 cases of rhabdomyolysis reported to the agency since late February, in addition to 14 previously known cases. Seven of the most recent patients were taking a dose of 10 mg.

After an initial investigation, the FDA declared rosuvastatin was an important option for some patients because it appeared slightly more potent than other statins. The FDA suggested that the dose be lowered to 5 mg to 10 mg, and also warned never to exceed 40 mg daily, according to Dr. AbuRahma. Further studies and monitoring of this medication may be warranted, he concluded.