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FDA advisory panel votes in favor of broadened rosuvastatin indication for CVD primary prevention, elevated CRP
December 15, 2009 | Michael O'Riordan
Gaithersburg, MD (updated December 16, 2009) - The Food and Drug Administration (FDA) Endocrinologic and Metabolic Drugs Advisory Committee voted 12 to 4 today, with one abstention, in favor of broadening the indication for rosuvastatin (Crestor, AstraZeneca) to include patients with normal LDL-cholesterol levels but who are at low to moderate risk for cardiovascular disease based on other risk factors, most notably elevated levels of high-sensitivity C-reactive protein (hs-CRP).
Specifically, the advisory panel felt there was sufficient evidence of benefit to justify the risks of prescribing rosuvastatin in men >50 years old and women >60 years old who had fasting LDL-cholesterol levels <130 mg/dL, hs-CRP >2.0 mg/dL, triglycerides <500 mg/dL, and no prior history of cardiovascular or cerebrovascular disease or of coronary heart disease risk equivalents.
The decision is based on the results of Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), presented last year at the American Heart Association (AHA) 2008 Scientific Sessions and published in the New England Journal of Medicine [1].
The JUPITER study, previously reported by heartwire, shook up the field of primary prevention when investigators, led by Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA), showed that the treatment of apparently healthy patients, those who would not currently qualify for statin therapy based on US guidelines, reduced their risk of cardiovascular disease morbidity and mortality by 44% with rosuvastatin.
Strictly JUPITER or global risk assessment
Discussing the decision, panel member Dr Thomas Wang (Massachusetts General Hospital, Boston), who voted in favor of the expanded indication, said the JUPITER evidence was very compelling and that based on the patient population defined by the entry criteria, "there was a clear evidence of benefit with the drug."
"I believe there are patients in this study who really shouldn't receive this drug, and that needs careful consideration."
Dr William Hiatt (University of Colorado, Denver) also voted yes but expressed some discomfort in giving the drug to everyone who met the entry criteria in the JUPITER trial. However, he said that if the panel voted no and the FDA decided against the expanded indication, the drug would continue to be used off-label because it would be unethical to withhold it given evidence of benefit. Also, he said that future placebo-controlled statin trials are unlikely to be done.
"I would strongly advise the FDA, though, of a couple of things," said Hiatt. "First of all, I think defining the population that would be appropriate for extended use of the statin drug needs to be carefully portrayed in the labeling and marketing materials. . . . Second, I believe there are patients in this study who really shouldn't receive this drug, and that needs careful consideration and some kind of restrictive labeling and perhaps advertising, so that it doesn't become a global recommendation."
Like Hiatt, many panel members expressed concerns about expanding the patient population for statin therapy. As previously reported by heartwire, one recent estimate, based on data from the Health and Nutrition Examination Survey (NHANES 1999-2004), suggests that nearly one in five middle-aged adults would be eligible for statins based on the JUPITER criteria [2].
During the daylong advisory hearing, panel members remained uncertain about the possibility of allowing an indication based on age and elevated CRP levels alone. In JUPITER, age was the lone cardiovascular risk factor, in addition to elevated CRP, in 25% of patients, while nearly 50% of patients had at least one other risk factor, such as smoking or hypertension, and more than 20% had at least three risk factors.
In a post hoc subgroup analysis, the benefit of treatment was observed only in those who met the age and elevated-CRP criteria, with at least one additional risk factor. Among patients who strictly qualified for treatment based on age and CRP only, the reduction in the primary end point was not statistically significant. Similarly, when the data were sliced up to examine the benefit based on Framingham Risk Score (FRS), there was no significant treatment benefit observed in patients with <10% risk.
Speaking to the panel, Ridker said that he doesn't expect every patient with elevated hs-CRP levels to be put on a statin. "What we're looking for here is a clinical, thoughtful, middle-of-the-ground balance," he said.
Presenting more data, Ridker showed there was no statistically significant reduction in the primary end point among those with <5% risk based on Framingham, but there was a reduction observed among those with a risk between 5% and 10%. Among those with <5% risk, he is "very comfortable" recommending diet, exercise, and smoking cessation rather than prescribing a statin.
While panel members debated the relative value of the post hoc analysis, especially since JUPITER benefited all subgroups, including women and ethnic populations, some felt the absence of benefit in low-risk patients was relevant, given that statin therapy carries the potential for harm. Others, including Dr Christopher Newton-Cheh (Massachusetts General Hospital, Boston), who voted in favor of the expanded indication, noted the debate is embedded in the larger discussion of clinical guidelines and whether doctors should simply be using age and CRP to prescribe statin therapy, as some likely will, or whether global risk assessment should be used. Newton-Cheh said JUPITER becomes an obsolete study if the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) decides to use global risk assessment in the next set of guidelines.
Consideration of the risks
Despite the benefit observed in JUPITER—the trial was stopped after 1.9 years based on recommendations from an independent data monitoring board—the advisory panel wrestled with the risk/benefit profile, particularly as it related to statistically significant increases in the number of deaths due to gastrointestinal disorders and investigator-reported diabetes mellitus among those treated with rosuvastatin. In addition, 18 drug-treated patients in JUPITER reported a "confusional state," compared with four in the placebo arm, although there was no overall difference in neurologic or psychiatric adverse events.
"The biggest adverse effect is not being treated."
Most panel members felt the gastrointestinal and neurologic adverse effects were likely due to chance. The 27% increase in risk of diabetes observed in JUPITER is likely real, however, although probably a class effect, according to panel members. Dr Michael Criqui (University of California, San Diego), who voted in favor of the expanded indication, expressed concern about the short study duration, especially since the treatment benefit would be front-loaded relative to the metabolic risks. Had the study run to completion, investigators would have been better able to fully assess the magnitude of diabetes mellitus in those treated with rosuvastatin. He noted that treatment is going to be started in relatively young patients who will take the drug lifelong.
Overall, however, the advisory panel felt that the vascular benefits of treatment exceeded these risks, particularly the risk of diabetes.
"The biggest adverse effect is not being treated," said panel member Dr Thomas Bersot (Gladstone Institute of Cardiovascular Disease, San Francisco, CA).
Panel member Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA), who voted a "cautious yes" in favor of the expanded indication, said that his vote should not be construed as an endorsement of hs-CRP as a risk factor, particularly since he remains uncertain about its risk prediction potential and response to treatment.
Ridker said that a simple screening and treatment protocol based on the JUPITER study would prevent 250 000 strokes, MIs, revascularizations, and cardiovascular deaths in the US alone over a five-year period.
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