In a study that will likely change medical practice, researchers reported that Crestor, a cholesterol-fighting statin made by AstraZeneca (AZN), reduced the risk of heart attack, stroke, and cardiovascular disease by a surprisingly robust 45% in people who do not have high cholesterol. The patients did have high levels of a protein associated with arterial inflammation that is not routinely measured.
Medical experts said the results, released Nov. 9 at the American Heart Association (AHA) meeting in New Orleans, will almost certainly expand the market for statins, already the world's best-selling drugs. They also will likely spark demand for a controversial and costly test for high-sensitivity C-reactive protein (CRP), a marker for inflammation, which has some practitioners worried about the cost/benefit of extrapolating the research to the general population.
The much anticipated study—named Jupiter and paid for by AstraZeneca—enrolled 17,802 subjects in 26 countries, selecting men over 50 and women over 60. All had low levels of LDL cholesterol levels—which would normally argue against putting them on a statin—and no history of cardiovascular disease. However, they did have high levels of CRP (BusinessWeek.com, 4/15/08), often associated with heart disease. Half the subjects were given placebos and the other half 20 milligrams daily of Crestor, one of the most powerful statins.
Cholesterol Isn't the Only Culprit
The Crestor group had 54% fewer heart attacks than the placebo subjects, as well as 48% fewer strokes, and 20% fewer deaths. The study was originally meant to track all patients for five years, but the results were so robust that it was terminated after a median follow-up of 1.9 years. In March an independent panel of observers halted it because they considered the effects of the drug to be so beneficial that it would have been unethical to keep the control group on a placebo.
About half the trial subjects were at moderate to high risk of heart disease because of smoking, being overweight, or other risk factors. But it was striking that—among those at low risk—there was a 37% reduction in heart attacks and other events, said Dr. Paul Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham & Women's Hospital in Boston and lead investigator on Jupiter. The Jupiter trial feeds into a growing sense in the cardiovascular community that heart disease is a result of far more than high cholesterol, particularly since half of all heart attacks and strokes occur in apparently healthy people with normal levels of LDL cholesterol. Ridker first reported in 2001 an apparent link between CRP and heart disease, and Jupiter is the first large-scale trial to test the hypothesis.
The study also contributes to the conviction of some cardiovascular specialists that even patients with low LDL cholesterol should consider measures to prevent heart disease. However, plenty of medical experts at the AHA meeting were clearly worried that patients and doctors both will overreact to the Jupiter study by prescribing costly drugs and tests whether or not they're needed. "I know everyone in my practice is going to come in in the next few weeks and ask if they should go on a statin after this, or be tested for CRP," said Dr. Sharonne Hayes, director of the Women's Health Clinic at the Mayo Clinic in Rochester, Minn.
Not Necessarily Just Crestor
Dr. Timothy Gardner, president of the AHA, emphasized the study was not designed to determine whether the lowered risk was due to a reduction in CRP or in LDL cholesterol. Since statins lower both measures, "the findings cannot determine whether lowering cholesterol, reducing inflammation, or a combination of both is responsible for the effects seen" in Jupiter. The AHA issued a statement Nov. 9 reaffirming its recommendation that controlling cholesterol is critical for prevention of heart disease.
A CRP blood test costs $50 to $80, and Crestor is $3.95 per pill. There are far cheaper generic statins available, and Pfizer's (PFE) Lipitor, the best-selling statin, is due to go off patent in 2011. Dr. Gordon Tomaselli, chief of cardiology at Johns Hopkins, said that, although no similar study has been done or is being planned with other statins, probably the entire class of drugs has some effect on CRP.
Currently the AHA recommends a CRP test only when a doctor is unsure whether to treat a patient (BusinessWeek, 1/17/08) at intermediate risk of heart disease. The underlying assumption to that recommendation is that patients at low risk do not need treatment—but Jupiter could change that equation. "Can our society afford to put millions more people on an expensive drug, and screen them with an expensive test, when the money might better be used elsewhere?" asks Hayes. "We have to think long and hard about that."
Women and Minorities Tested
Dr. Andrew Tonkin, head of cardiovascular research at Monash University in Melbourne, Australia, cautioned that the actual number of heart attacks and other cardiovascular events was low, even in the study participants that were taking placebos. There were 83 cardiac events of all types in the Crestor group, an 0.9% actual risk, compared with 157, or 1.8%, in the placebo group. "You would have to treat 180 people for two years to prevent one death," he said.
The Crestor therapy did appear to be very safe, however, mitigating concerns that an increase of patients on statins will lead to unforeseen consequences. The investigators found little or no difference between the Crestor and placebo groups on most side effects, including muscle soreness, often associated with statins. There was a small increase in diabetes in the Crestor group, an effect observed in most statins, and one case of rhabdomyolysis, a rare and dangerous muscle disease also associated with statin use. The statin group had a lower rate of cancer, but Tonkin said there would need to be a 5-to-20-year follow-up to accurately determine the risk of increased cancer.
The Jupiter study was also notable because it included large numbers of women and minorities, groups often overlooked in heart disease trials. The results were the same for all subgroups in the trial, no matter their gender or ethnicity. Crestor's sales rose 28% in the third quarter, according to AstraZeneca, and Wall Street analysts estimate that Jupiter could end up doubling Crestor's sales by 2015, to $6.3 billion. AstraZeneca's stock has climbed 45% since Jupiter was halted last March.
Arnst is a senior writer for BusinessWeek based in New York.
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