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FDA Approves Crestor to Reduce Stroke, Heart Attack Risk

FDA Approves Crestor to Reduce Stroke, Heart Attack Risk

Approval based on JUPITER study which evaluated Crestor in a previously unstudied population

WILMINGTON, Del., Feb. 8 /PRNewswire-FirstCall/ -- AstraZeneca today announced that the US Food and Drug Administration (FDA) has approved Crestor (rosuvastatin calcium) to reduce the risk of stroke, myocardial infarction (heart attack) and arterial revascularization procedures in individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease (CVD) based on age (men greater than or equal to 50 and women greater than or equal to 60), high-sensitivity C-reactive protein (hsCRP) greater than or equal to 2 mg/L, and the presence of at least one additional CVD risk factor, such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease.

The FDA approval was based on data from the landmark JUPITER (Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin) study which evaluated the impact of Crestor 20 mg on reducing major CVD events in a previously unstudied population. In JUPITER, Crestor significantly reduced the relative risk of heart attack by 54% (p<0.001), stroke by 48% (p=0.002), and arterial revascularization by 46% (p<0.001) vs. placebo.

"Not only is this approval a significant milestone for AstraZeneca, but it is also important for the patients who could now benefit from Crestor therapy under this approved indication," said Howard Hutchinson, MD, Chief Medical Officer, AstraZeneca. "This new indication adds to the significant body of evidence physicians use to evaluate Crestor as a treatment option."

Important Safety Information from the JUPITER Study

A higher percentage of rosuvastatin-treated patients vs. placebo-treated patients (6.6% and 6.2%, respectively) discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation.

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Crestor. In JUPITER, there was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) vs. patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c > 6.5% at the end of the trial was significantly higher in rosuvastatin-treated vs. placebo-treated patients.

The most common adverse reactions reported were myalgia (7.6% vs. 6.6%), arthralgia (3.8% vs. 3.2%), constipation (3.3% vs. 3.0%), and nausea (2.4% vs. 2.3%) for Crestor vs. placebo, respectively.

About JUPITER

In the JUPITER study, the effect of Crestor on the occurrence of major CVD events was assessed in 17,802 men (greater than or equal to 50 years) and women (greater than or equal to 60 years) who had no clinically evident CVD, LDL-C levels <130 mg/dL and hsCRP levels greater than or equal to 2 mg/L. The study population had an estimated baseline coronary heart disease risk of 11.6% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL-C levels (23%), cigarette smoking (16%), or a family history of premature CHD (12%). Study participants had a median baseline LDL-C of 108 mg/dL and hsCRP of 4.3 mg/L. Study participants were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean duration of 2 years. The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in rosuvastatin-treated subjects.

In a post-hoc subgroup analysis of JUPITER subjects (n=1405; rosuvastatin=725, placebo=680) with a hsCRP greater than or equal to 2 mg/L and no other traditional risk factors (smoking, BP greater than or equal to 140/90 mmHg or taking antihypertensives, low HDL-C) other than age, after adjustment for high HDL-C, there was no significant treatment benefit with rosuvastatin treatment.

Results from JUPITER were originally presented in November 2008 at the American Heart Association's Annual Scientific Sessions, and published in the New England Journal of Medicine.

JUPITER is a part of AstraZeneca's extensive GALAXY clinical trials program, designed to address important unanswered questions in statin research. Currently, more than 65,000 patients have been recruited from 55 countries worldwide to participate in the GALAXY Program.

About Crestor (rosuvastatin calcium)

In addition to today's approval, Crestor is indicated as an adjunct to diet to reduce elevated Total-C, LDL-C, ApoB, non-HDL-C, and TG levels and to increase HDL-C in patients with primary hyperlipidemia and mixed dyslipidemia. Crestor is also indicated as an adjunct to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C and LDL-C to target levels.

Important Safety Information

Crestor is contraindicated in patients with a known hypersensitivity to any component of this product, in patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels, in women who are pregnant or may become pregnant, and in nursing mothers.

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Crestor. These risks can occur at any dose level, but are increased at the highest dose (40 mg).

Crestor should be prescribed with caution in patients with predisposing factors for myopathy (eg, age greater than or equal to 65 years, inadequately treated hypothyroidism, renal impairment). The risk of myopathy during treatment with Crestor may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, lopinavir/ritonavir, or atazanavir/ritonavir.

Therapy with Crestor should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected. All patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

It is recommended that liver enzyme tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. Should an increase in ALT or AST of >3 times ULN persist, reduction of dose or withdrawal of Crestor is recommended.

Crestor should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease.

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Crestor.

In the controlled clinical trials database, the most common adverse reactions were headache (3.7%), myalgia (3.1%), abdominal pain (2.6%), asthenia (2.5%), and nausea (2.2%).

The dose range for Crestor is 5 to 40 mg orally once daily. The usual starting dose is 10-20 mg. Patients initiating Crestor therapy or switching from another statin should begin treatment with Crestor at the appropriate starting dose. After initiation or upon titration of Crestor, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted accordingly. Crestor 40 mg should be used only for those patients not achieving their LDL-C goal with 20 mg.

Please see accompanying full Prescribing Information. If you have any questions concerning Crestor, please contact AstraZeneca at 1-800-237-8898. Crestor is a registered trademark of the AstraZeneca group of companies.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of prescription medicines. As a leader in gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease medicines, AstraZeneca generated global revenues of US $32.8 billion in 2009. In the United States, AstraZeneca is a $14.8 billion dollar healthcare business.

For more information about AstraZeneca in the US or our AZ&Me(TM) Prescription Savings programs, please visit: www.astrazeneca-us.com.

SOURCE AstraZeneca

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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:

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

Characteristic Criteria
No clinically evident heart disease All patients
Increased age men > 50 years or women > 60 years
Elevation in high-sensitivity C-reactive Protein > 2 mg/L
LDL-C level <130 mg/dL

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.

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:

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.

Posted: February 2010

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