FDA Expands Rosuvastatin Use to People With Normal LDL

Michael O'Riordan and Shelley Wood

February 09, 2010

Updated February 9, 2010 (Silver Spring, Maryland) — The FDA has agreed to broader labeling for rosuvastatin (Crestor, AstraZeneca), the company announced late Monday [1]. Following recommendations that the agency's advisory panel made last December, the FDA has now approved the statin for reducing the risk of stroke, myocardial infarction, and revascularization procedures in individuals who have normal low-density lipoprotein (LDL) levels and no clinically evident coronary heart disease but who do have an increased risk based on age, C-reactive protein (CRP) levels, and the presence of at least one additional cardiovascular disease risk factor.

As previously reported by heartwire, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 12 to 4 on December 15, 2009 to recommend an expansion of rosuvastatin labeling.

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 FDA's decision is based on results from the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, reported in detail by heartwire.

"Appropriately Conservative"

Although the sponsor had sought an expanded indication that mirrored the inclusion criteria of the JUPITER trial, the new label includes one additional cardiovascular risk factor, something that was not required for patients to be enrolled in the trial. During the December 2009 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.

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.

Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA), the lead investigator of JUPITER, told heartwire that the new label is "appropriately conservative," adding that hs-CRP works best for risk stratification among individuals with a 10-year Framingham risk of 5% to 20% and who might not otherwise be treated with a statin.

Similarly, Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) told heartwire that the label is faithful to the evidence because patients in JUPITER with less than two risk factors, such as those enrolled based on age and elevated hs-CRP alone, "failed to derive significant treatment benefit."

Kaul, a member of the advisory panel who voted a "cautious yes" for approval, commented that he was gratified to see the agency consider the deliberations of the advisory panel rather than rely simply on the vote count.

"The results of the JUPITER trial should not be viewed as an endorsement of CRP as a risk factor, and the FDA agreed with that," he told heartwire .

What Happens Now?

Commenting on the approval for heartwire , Dr James Stein (University of Wisconsin Medical School, Madison) noted, however, that hs-CRP is not widely used in clinical practice. He believes there may be concerns about variability between individuals or on repeat testing, which would give a false sense of risk when these values cross defined thresholds of risk. Earlier recommendations suggested testing hs-CRP twice and then taking the average to guide decisions, but any test that requires testing twice complicates clinical practice, he added.

"Also, the constant debate about the value of a high-sensitivity CRP [level] has discouraged primary-care docs from using the test," Stein told heartwire . "Having said that, there really is no new or emerging biomarker with a stronger evidence base for its value as a predictive marker than hs-CRP. And there is no other new or emerging biomarker that has a prospective, randomized, controlled trial showing that you can use it to identify a patient population that otherwise would not be treated [and] who, if treated with a statin, will have a reduction in cardiovascular events and an improvement in mortality."

From his point of view, the new label is "more liberal" than the criteria employed in the JUPITER study. Although JUPITER enrolled patients based on CRP and age and did not require patients to have an additional cardiovascular risk factor, as the expanded label now requests, the study excluded individuals on cholesterol therapy and postmenopausal hormone-replacement therapy, those with elevated liver or muscle enzyme levels, those with kidney disease, diabetes, severe hypertriglyceridemia, uncontrolled hypertension, or thyroid disease, as well as those with cancer within the past five years or drug or alcohol abuse.

"So it looks like many, many more patients than just those who could have been in JUPITER will be eligible for treatment based on the new indication," Stein told heartwire . "It is not necessarily bad. It just is not exactly the JUPITER trial entry criteria."

In a separate analysis, Stein and Dr Jon Keevil (University of Wisconsin, Madison) applied the JUPITER enrollment criteria to the 1999–2002 National Health and Nutrition Examination Surveys and reported that of 174 million US adults who were 20 to 85 years old, approximately seven million (4%) met the JUPITER inclusion criteria. Based on the label, which would include many more patients with diabetes, elevated cholesterol levels, and high blood pressure, a back-of-the-envelope calculation estimates another 16 or 17 million people eligible for treatment based on the FDA indication, he pointed out.