New Safety Concerns Over Crestor

June 15, 2004 -- Safety problems with the widely used cholesterol drug Crestor have prompted European regulators to tighten prescription guidelines, but experts warn U.S. physicians may not be fully aware of the potentially deadly hazards for some of the more than 1 million American users of the drug.

Higher doses of Crestor, one of a family of cholesterol-lowering drugs known as statins, could increase risk of myopathy, a potentially life-threatening muscle disease that can affect the heart. In Europe, the drug's maker, AstraZeneca, changed the medication's label to warn doctors of the risk after cases of myopathy were reported there.

AstraZeneca notes these patients were already predisposed to having muscle disease. With the new label, patients who are prescribed Crestor must begin taking the drug at 10 milligrams. Dose increases to 20 milligrams or 40 milligrams — 40 milligrams being the highest dose available — will only be allowed if necessary, such as with patients with severely high cholesterol who are not at risk for muscle disease.

"It really relates to the issue of starting dose," explains Dr. Steven Nissen, vice-chairman of cardiology at The Cleveland Clinic Foundation. "If a person has high cholesterol you start at a higher dose. Now EU [the European Union] says don't ever start Crestor at a higher dose."

In the United States, the Food and Drug Administration is still reviewing reports it has received on the drug's association with muscle disease. But they do not currently have plans to change the U.S. labeling, stating, "these risk factors and many of the recommendations for how to minimize the risk of myopathy are already captured in the FDA-approved label."

Heeding the Warning

Doctors feel that the label change in Europe will affect how they prescribe Crestor. "I will avoid using the 40 milligrams, whereas in the past, I would put them on the top dose available," says Dr. Joe Breault, senior staff physician in Family Medicine at Ochsner Clinic Foundation in New Orleans, La.

Doctors agree side effects can occur with any cholesterol-lowering drug, including statins.

"Even though we know that there is contraindication in statins we may not pay attention to it in daily life. This warning will make us aware of it. It's a benefit of regulations." Breault says.

Dr. Michael Fleming, president of the American Academy of Family Physicians, also feels this new information will make him look at the drug even more closely. Fleming, who monitors FDA reports and is aware of the Crestor warning, says the warning makes him "more skittish about using it as opposed to other drugs."

Dr. Scott Grundy, director for the Center for Human Nutrition at the University of Texas Southwestern Medical Center in Dallas, attributes the greater risk of myopathy to the drug's high potency.

"Crestor is our most potent statin and thus it may well carry a higher risk for severe myopathy at high doses than other statins." says Grundy.

Dr. Peter Schulman of the University of Connecticut School of Medicine agrees. "Crestor is clearly a bit more of a potent cholesterol-lowering drug than any of its competitors such as Lipitor and Zocor," says Schulman. "And at every dose range from low to middle to high dose, it has about a 10 percent lowering advantage over Lipitor, its closest competitor in terms of lipid improvement."

Wary from the Start

While some doctors may be changing the way they dispense Crestor, there are some who have been wary of the drug since its introduction in the United States in 2003.

These physicians are what Dr. Scott Fields, professor and vice chair of family medicine at Oregon Health and Science University in Portland, Ore., calls "slow adopters." Fields feels the rapidly changing landscape of medical science and technology challenges physicians to make changes in how they practice medicine.

"When a new medicine hits the market there are things that occur when open to wider use," explains Fields. "As such, some physicians hold back with using new medications and technology and wait it out to see what happens."

In the case of Crestor, Fields says when measured against other statins that have been on the market for a long time, Crestor's marginal economic and medical benefits are small.

"Currently there is no outcome evidence showing decrease in cardiac events or mortality," says Dr. Daniel McCarter, director of clinical affairs at the University of Virginia Department of Family Medicine in Nellysford, Va. "Therefore I see no reason to start using it."

With the label change, some doctors are reminded of the problems surrounding Baycol, a statin that was pulled from the market in 2001 due to reports it caused fatal muscle disease.

"I had hundreds of patients on Baycol. All of a sudden it was removed from the market. So, currently with the possible prospect of another market withdrawal, I will be more prepared and I am sure most physicians will be more cautious in prescribing Crestor from now on." says Dr. Albert Levy, clinical assistant professor of medicine at Mount Sinai School of Medicine in New York City.

But doctors such as Sidney Alexander, director of the Lipid Clinic at the Lahey Clinic Medical Center in Burlington, Mass., does not see Crestor following in Baycol's footsteps. Alexander, who prescribes Crestor, starts his own patients at 5 milligrams.

"The drug is safe when used properly. Baycol was associated with a high incidence of myopathy. At lower doses it [Crestor] is fine so it's not like Baycol." says Alexander.

Still Safe and Effective

Despite the revised drug label, AstraZeneca asserts the drug is still a safe and effective treatment, adding, "there is no change in the overall safety profile of Crestor, which remains similar to that of all other currently marketed statins."

Adds Gary Bruell, AstraZeneca's director of cardiovascular public affairs, "There was not a problem with the product. The problem was with the prescribing patterns of the product. We have not seen any instance of prescribing patterns here which mirror those that occurred in Europe."

The FDA affirms Crestor is safe when used accordingly, reminding doctors to carefully read and follow the product label.

And despite the reports, experts still believe statins are one of the safest and needed classes of drugs available.

"Their effect in cardiovascular disease is outstanding," says Dr. Neil Brooks, medical director of Vernon Manor Health Care Facility in Vernon, Conn. "This is a case in which the benefits are far greater than the harms."

"Statin drugs save lives," says Nissen. "What we are talking about is a subtle question of the starting dose and if each of the other drugs on the market is the same or not. They [statins] help more people than they hurt. These are extremely safe drugs."

Sixty-one countries have approved Crestor, with more than 2 million patients worldwide taking the drug.