Most serious side effects in statins may be higher in one of the newest drugs, rosuvastatin (Crestor)

May 26 2005

A post-market analysis of cholesterol-lowering drugs called statins indicates that some of the most serious side effects may be higher in one of the newest drugs, rosuvastatin (Crestor). The drug is the strongest statin available because it has the greatest effect per milligram on low-density lipoprotein ("bad" cholesterol).

However, researchers emphasize that the risk involved in taking this drug is low, and that statins are still the best drugs for treating elevated cholesterol and reducing a person's risk for developing heart disease and stroke. If a patient has side effects, they generally go away when the patient stops taking the drug.

As reported in Circulation: Journal of the American Heart Association, the researchers analyzed adverse events reports (AERS) sent to the U.S. Food and Drug Administration for rosuvastatin and compared them to AERS rates during the same concurrent time period for three other statins: atorvastatin (Lipitor), simvastatin (Zocor) and pravastatin (Pravachol).

The researchers also compared AERS rates during the first year of marketing of each of the statins, which allowed a comparison of rosuvastatin to the three statins as well as to cerivastatin (Baycol). Cerivastatin, the most potent statin per milligram ever to receive FDA approval, was withdrawn from the market in 2001 after the FDA received numerous reports of severe myopathy (muscle weakness), rhabdomyolysis (muscle deterioration resulting in toxins released in the blood that can lead to renal failure), proteinuria (protein in the urine), nephropathy (a reduced ability of the kidneys to filter toxins from the blood) and kidney failure.

Researchers found that rosuvastatin was associated with a higher rate of muscle and kidney complications than the older statins, but at less than half the rate of the side effects reported for cerivastatin during its first year.

"As a class, statins are very 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, M.D., Ph.D., director of the Preventive Cardiology Center and the Women's Heart Center at Tufts-New England Medical Center in Boston.

"The absolute risk with this statin is low. The overwhelming majority of people who are taking it will have no problem at all," said Alice K. Jacobs, M.D., president of the American Heart Association. "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."

In the primary analysis, researchers looked for side effects that included four muscle or kidney complications: rhabdomyolysis (muscle deterioration resulting in toxins released in the blood that can lead to renal failure), proteinuria (protein in the urine), nephropathy (a reduced ability of the kidneys to filter toxins from the blood) and kidney failure. When the AERS was compared to the four drugs over the same concurrent time period, the rate of rosuvastatin AERS was significantly higher than the other statins. The same findings were true when the four statins were compared at the one-year marketing time period, with the exception that both rosuvastatin and simvastatin had higher AERS than pravastatin or atorvastatin.

Researchers found that the risk of the AERS occurred relatively earlier after the start of rosuvastatin therapy, usually within the first 12 weeks. In addition, 62 percent of the AERS occurred at the 10-milligram (mg) dose or less. Fatalities occurred in only a few cases, with death rates in patients taking rosuvastatin and simvastatin being lower than the other statins (pravastatin and atorvastatin).

Karas said post-marketing analyses like this one can help identify safety concerns that might be missed by pre-marketing trials that typically exclude patients who may be at greater risk of certain side effects but who are likely to receive a drug after it's marketed. Pre-marketing trials that assess safety or efficacy also often don't detect relatively rare adverse events.

Limitations of this study include the possibility of under-reporting the actual number of adverse events. In clinical practice, adverse events tend to be under-reported and serious events are more likely to be reported than milder ones. In addition, publicity about the removal of cerivastatin from the market may have heightened awareness of rosuvastatin's safety concerns. Karas considers the voluntary nature of the current post-marketing surveillance system to be the greatest limitation.

"One of the limitations is that the current surveillance system does not require the reporting of all the drugs that patients are taking," he said.

As a result, variations in reporting detail make it difficult to conclude what caused the side effects, particularly when other factors, such as potential drug interactions, are poorly reported.

Karas notes that the analysis reports relative risks, which are useful for comparing one drug's effects to the next. The absolute risk indicates a person's chance of actually having an adverse event. The absolute risk of AERS 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.

In an accompanying editorial, Scott Grundy, M.D., Ph.D., director of The Center for Human Nutrition and departments of clinical nutrition and internal medicine at UT Southwestern Medical Center in Dallas, stressed that the absolute risk of myopathy from rosuvastatin is low.

"Importantly, most side effects, including myopathy, disappear upon withdrawal of medication," Grundy said "It would be unfortunate for patients to quit taking statins for fear of side effects because that would increase their risk of heart attack."

He recommends a balanced, conservative approach.

"Doses of statins should not exceed those required to achieve current goals of therapy," Grundy said, adding that it seems unwise to use statins outside current cholesterol-management guidelines.

Karas also urged doctors to individualize treatment, reserving the strongest statins for patients whose cholesterol levels resist standard treatment. Most people with moderately elevated cholesterol levels respond to the time-tested drugs.

"The risks of specific statins should be weighed for each patient," Jacobs said. "In general, physicians initially should prescribe the lowest dose of statin to bring a patient's cholesterol to target levels."

Karas' co-authors are Alawi A. Alsheikh-Ali, M.D.; Marieta S. Ambrose, M.D.; and Jeffrey T. Kuvin, M.D.

http://www.americanheart.org/