The new criteria for Crestor was approved by the FDA last month, after the agency reviewed a clinical study which showed a small reduction of strokes, heart attacks and other “cardiovascular events” among people taking the statin, compared with patients taking a placebo. According to the Times, the international study involved nearly 18,000 people who had low cholesterol readings and an elevated level of inflammation in the body as measured by a test called high-sensitivity C-reactive protein , or CRP.
The new Crestor label says it may be prescribed for apparently healthy people if they are older — men 50 and over and women 60 and over — and have one risk factor like smoking or high blood pressure, along with elevated inflammation in the body indicated by the CRP test. According to the Times, an estimated 6.5 million healthy people in the U.S. could now be considered candidates for Crestor. AstraZeneca, which makes the drug, plans to launch a big advertising blitz next month touting the statin's preventative benefits.
But do those benefits outweigh the drugs' risks? According to the Times, maybe not. Like all drugs, statins such as Crestor have side effects. Muscle aches are a common complaint of people taking statins, and patients taking the drugs have to be checked periodically to make sure their liver enzymes aren't elevated.
Most disturbing, one recent study in The Lancet found that treating healthy people with statins like Crestor could raise a person’s risk of developing Type 2 diabetes by nine percent. According to The Times, that study was based on an analysis of most of the major clinical studies of statins. It included unpublished data and the results of the clinical study that the FDA reviewed before approving expanded use of Crestor. Because of the findings, the FDA did require AstraZeneca to add the diabetes risk to the Crestor label.
The Times article also raised questions about the CRP test used to determine if a healthy person is a candidate for Crestor. For one thing, there is no agreement in the medical community that inflammation is a direct cause of cardiovascular problems.
According to the Times, the study the FDA reviewed prior to approving the expanded use of Crestor was led by Paul M. Ridker, a Harvard medical professor and cardiologist at Brigham and Women’s Hospital. When Ridker convinced AstraZeneca to pay for his study, it had already been rejected by the National Institutes of Health and at least two other companies.
Ridker is also the inventor of the CRP test. According to the Times, he receives undisclosed amounts of royalties from the CRP test.
Ridker told the Times his study found a 55 percent reduction in heart attacks, a 48 percent reduction in stroke, and a 45 percent reduction in angioplasty bypass surgery in healthy people treated with Crestor. But critics of the study point out that these claims may be misleading because the patients were so healthy that they had little risk to begin with.
As the Times points out, the 55 percent relative difference in heart attacks between the two groups translates to only 0.2 percentage points in absolute terms — or 2 people out of 1,000. In real numbers, 500 people would need to be treated with Crestor for a year to avoid one usually survivable heart attack. One cardiologist told the Times that while the difference seen in Ridker's study was statistically significant, it wasn't clinically significant.
Crestor was approved by the Food & Drug Administration (FDA) in 2003. It is a member of a drug class called statins, which lower so-called "bad" cholesterol, otherwise known as LDL cholesterol. Although Crestor's cholesterol lowering ability was already established, the CORONA study was the first to explore whether Crestor improved patient outcomes in heart failure patients.
The CORONA study was conducted with 5,000 heart failure patients in Europe, Russia and South Africa. All of the study participants where over 60-years-old, and all suffered from ischemic heart failure, a type of heart failure caused by coronary artery disease. This type of heart failure weakens the heart's ability to pump blood efficiently. During the study, all of the patients continued their usual heart medications, but half added Crestor to their regimens. Most patients in the study participated for three years.
While the Crestor patients did have reduce levels of LDL -"bad"- cholesterol and an inflammatory marker called C-reactive protein, as well as reduced heart-related hospitalizations, these benefits did not translate to a lower death rate from heart failure in the Crestor patients. After 33 months of treatment, 692 Crestor patients had heart attacks, strokes or died of heart complications. Of those taking a placebo in place of Crestor, 732 suffered the same problems. The small difference between the two groups is not considered to be statistically significant.
Crestor's August 2003 FDA approval came after a delay because of safety concerns. During Crestor's clinical trials, seven cases of the potentially fatal, muscle-destroying condition Rhabdomyolysis occurred. Rhabdomyolysis is a serious disorder that causes kidney damage resulting from toxic effects of the contents of muscle cells. These studies also linked Crestor with cases of kidney abnormalities not seen with other statins. The FDA decided to approve Crestor but at lower dosages. However, records from the FDA and health agencies in Canada and Britain show life-threatening Crestor side effects occur even at those lower doses. In 2005, the FDA issued a public health advisory to further explain the risks and benefits of Crestor. The drug now carries a new label that includes new recommended doses for patients at a higher risk of muscle damage, including Asian patients.
Although there is a risk of rhabdomyolysis (severe muscle damage) with all statin drugs, critics maintain that Crestor is, by far, the most likely to cause this condition. Public Citizen maintains that its analysis of adverse events reported to the FDA between September 2003 and September 2004 linked Crestor to incidents of rhabdomyolysis at a rate 6.2 times higher than all other statin drugs combined. The FDA has acknowledged that Crestor does pose a greater risk to Asian patients as well as patients with severe kidney disease and those taking cyclosporine. As a result, a warning to that effect was added to the Crestor label in March of this year.
Now, however, a study published in the American Heart Association journal Circulation (online 5/23/05) claims that, as among the statins, even though the incidence of rhabdomyolysis is relatively low, "Crestor has a poorer safety profile." Whether this will change the FDA s opinion as to the safety of the drug or cause it to require a more serious warning to be placed on the label remains to be seen.