By Federal Drug Administration Monday, February 8, 2010

Questions and Answers for Healthcare Professionals: CRESTOR and the JUPITER Trial

Q1. What is FDA announcing today?

A. FDA is approving a new indication for the cholesterol lowering medication CRESTOR (rosuvastatin). CRESTOR will now be indicated for the primary prevention of cardiovascular disease to reduce the risk of stroke, heart attack, and the risk of arterial revascularization procedures (including coronary artery bypass graft, or bypass grafting of a peripheral artery or carotid artery, or angioplasty or stent placement) in individuals who have no clinically evident heart disease but are at an increased risk of heart disease due to the combined effect of the following risk factors:

• Age (> 50 years in men; > 60 years in women), and
• An elevated high-sensitivity C-reactive protein level (> 2 mg/L), and
• Presence of at least one additional cardiovascular risk factor (e.g., high blood pressure, low HDL-C, smoking, or a family history of premature heart disease).

CRESTOR is in a class of drugs called "statins." Statins work by stopping an enzyme called HMG-CoA reductase from making cholesterol. High cholesterol is a known risk factor for heart attacks and strokes.

Q2. How is this new indication different than CRESTOR's previous approved indication(s)?

A. CRESTOR already has an approved indication to lower cholesterol and triglycerides in combination with diet and exercise in patients with high cholesterol and/or triglycerides, and an indication to slow the progression of atherosclerosis. This is the first time CRESTOR has been approved for use in the prevention of heart disease in individuals with "normal" low-density lipoprotein (LDL) cholesterol levels and no clinically evident heart disease.

Q3. What information is today's approval based on?

A. The approval is based on results from a trial called the Justification for the Use of statins in Prevention: an Intervention Trial Evaluation Rosuvastatin (JUPITER). The trial compared the safety and the effectiveness of CRESTOR 20 mg versus placebo in the time to first occurrence of cardiovascular events (cardiovascular death, nonfatal heart attack, nonfatal stroke, hospitalization for unstable angina, and arterial revascularization). This trial included approximately 18,000 individuals with no clinically evident heart disease and low-density lipoprotein (LDL) cholesterol levels below 130 mg/dL. Table 1 below summarizes the eligibility criteria for individuals in the JUPITER trial.

Table 1. Eligibility criteria for the JUPITER trial

The overall trial results showed that CRESTOR treated individuals had a lower risk of suffering a major cardiovascular event compared to individuals receiving a placebo, with a 44% relative reduction in risk. Based on these results, the JUPITER trial was stopped early after only two years. Further review of the data found that the main benefit in individuals receiving CRESTOR was derived from a lowered risk of non-fatal heart attack, non-fatal stroke and arterial revascularization. There was no statistically significant reduction seen for cardiovascular death or hospitalization for unstable angina in individuals receiving CRESTOR compared to those receiving a placebo.

Q4. Based on the results of the JUPITER trial, should everyone with an elevated hsCRP use CRESTOR or another statin drug?

A. No. Healthcare professionals must interpret the results of the JUPITER trial with caution. The results from the JUPITER trial do not support the use of CRESTOR in all patients with an elevated hsCRP. For example, there was no evidence that CRESTOR provided benefit in individuals with an elevated hsCRP but no traditional cardiovascular risk factors, which include high blood pressure, low HDL-C, smoking, or a family history of premature coronary heart disease.

The JUPITER trial studied a large number of people, approximately 18,000, and the percentage of people who had a major cardiovascular event was small, 2.8% for individuals receiving a placebo and 1.6% for individuals receiving CRESTOR. Additionally, the following limitations of the JUPITER trial make interpreting the association between an elevated hsCRP and CRESTOR use difficult.

• Of the approximately 90,000 individuals screened to participate in the JUPITER trial, approximately 26,000, or 28%, were excluded because their hsCRP was < 2 mg/L.
• The JUPITER trial did not allow for comparison between individuals with an hsCRP < 2 mg/L to those with an hsCRP > 2 mg/L.
• The JUPITER trial did not establish a particular goal of therapy for CRESTOR with respect to hsCRP levels.

Based on the limitations above, CRESTOR should only be used for the primary prevention of cardiovascular disease to reduce the risk of heart attack, stroke, or arterial revascularization procedures in individuals without clinically evident coronary heart disease who meet the following criteria:

• Men > 50 years old or women > 60 years old, and
• hsCRP > 2 mg/L, and
• Presence of at least one additional cardiovascular disease risk factor such as high blood pressure, low HDL-C, smoking, or a family history of premature coronary heart disease.

Q5. Did any safety concerns arise during the JUPITER trial?

A. The JUPITER trial confirmed the known safety profile of statins, including muscle-related adverse events and increases in liver transaminases. There were slightly more patients who discontinued CRESTOR compared to placebo due to adverse reactions; with myalgia (muscle pain) being the most common adverse reaction leading to discontinuation of CRESTOR.

An unexpected safety finding in the JUPITER trial was an increase in the number of individuals receiving CRESTOR compared to those receiving a placebo who developed diabetes. Previous meta-analyses have suggested that this is an effect of all statin drugs and is not unique to CRESTOR. It is important to note that an analysis of individuals in the JUPITER trial who had impaired fasting glucose at baseline did show a 34% reduction in major cardiovascular events with the use of CRESTOR.

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