Research News

AE analysis raises safety questions about Crestor

Results still show statins are safe, says AHA

A review of adverse events reported to the FDA raises concern about the relative safety of rosuvastatin (Crestor) at its commonly used doses, researchers say. Some health professionals downplayed the study, however, saying the results still highlight the safety of statins for their indicated uses.

For their analysis, the researchers looked at adverse events associated with rosuvastatin that were reported to the FDA’s Adverse Event Reporting System (AERS) during the drug’s first year of marketing. The researchers, from Tufts University in Boston, compared the rates of rosuvastatin adverse effects with those seen with other statins — atorvastatin (Lipitor), simvastatin (Zocor), pravastatin (Pravachol) — during the same time frame and as well as during their respective first year of marketing. Rosuvastatin also was compared to cerivastatin (Baycol) during its first year of marketing. Cerivastatin is no longer on the market; it was withdrawn in 2001 after the FDA received numerous reports of severe myopathy, rhabdomyolysis, proteinuria, nephropathy, and kidney failure.

The primary analysis examined the composite endpoint of adverse event reports of rhabdomyolysis, proteinuria, nephropathy, or renal failure. The researchers found that compared to the statins still on the market, rosuvastatin was "severalfold" more likely to be associated with the composite endpoint. The rosuvastatin adverse events tended to happen within the first 12 weeks of therapy, and 62% of the adverse events occurred at doses of 10 mg/d or less. Rosuvastatin did have less than half the rate of side effects reported for cerivastatin during its first year. The death rates associated with rosuvastatin were also lower than with the other statins, and these deaths were not directly attributed to treatment with the drug.

The researchers said their approach took advantage of the "real-life" population exposure captured in the FDA AERS. Controlled premarketing trials may exclude patients predisposed to an adverse event, although the patients may receive the drug after marketing, they said. In addition, trials often are underpowered to detect relatively rare adverse events. "Postmarketing assessments such as the one presented here are helpful in attempts to identify safety concerns that can potentially be missed early on," the researchers stated.

Limitations of the study include the possible underreporting of actual adverse events and the voluntary nature of the reporting system. In addition, publicity about safety concerns associated with rosuvastatin may have contributed to the increase adverse event reporting for the drug.

In their conclusion, the authors advised a cautious approach. "It would seem prudent at the current time for health care providers to consider other statins as first-line therapy, to initiate therapy in appropriate patients at lower doses, to consider combination LDL-C–lowering therapy (e.g., statin combined with ezetimibe), and to vigilantly monitor for adverse events if rosuvastatin is used." Their results were published on the web site of Circulation, a publication of the American Heart Association, in late May.

In an editorial that accompanies the article, one physician said he is bothered by the use of a composite endpoint in which severe myopathy is combined with an apparently benign form of proteinuria. The pooling of different endpoints compounds the limitations of the AERS, said Scott M. Grundy, MD, PhD, director of The Center for Human Nutrition and departments of clinical nutrition and internal medicine at UT Southwestern Medical Center in Dallas.

Grundy also questioned the use of the FDA’s AERS as a tool for making clinical decisions when the FDA itself has published information about its limitations. In a response to a petition filed by the consumer group Public Citizen, which had requested rosuvastatin be removed from the market for safety reasons, the FDA talked about the system limitations, such as the unknown relationship between prescriptions and numbers of patients treated and duration of treatment. In its response, the FDA also detailed a comprehensive examination of the drug. The agency concluded that patients taking rosuvastatin do not have a greater risk of muscle toxicity than patients taking the other approved statins. The agency also found no convincing evidence that rosuvastatin poses a risk of serious renal injury.

Adverse event rate still low

Grundy also stressed that statins are generally safe and they substantially reduce risk for coronary disease in higher-risk patients. However, the drugs do have side effects and should be used according to current cholesterol-management guidelines, he says.

In press statements after the publication of the study, the researchers made a case that statins, as a class, are safe medications. "They have been widely used for almost 20 years and several studies clearly show that statins reduce heart disease, stroke, and total mortality," said senior author Richard H. Karas, MD, PhD, director of the Preventive Cardiology Center and the Women’s Heart Center at Tufts-New England Medical Center.

The analysis reported relative risks, not absolute risk, which indicates a person’s chance of actually having an adverse event. The absolute risk of adverse events with rosuvastatin appears low, with 145 muscle or kidney complications out of 5.2 million prescriptions during the drug’s first year, which is an absolute risk of 1 in 35,862, he added.

"The overwhelming majority of people who are taking it will have no problem at all," said Alice K. Jacobs, MD, president of the American Heart Association in Dallas. "This analysis shows that statins are safe, and that physicians should continue to offer their patients what is still one of the best tools we have for treating elevated cholesterol."