FDA Panel Recommends Crestor to Prevent Heart Attacks in Healthy People
Crestor Use in Those Without Heart Disease Shows Some Benefits; Not Without Risk
By PEGGY PECK Dec. 16, 2009
The joke in the world of heart disease is that "they should put statins in the water," but to a U.S. Food and Drug Administration advisory panel that has recommended giving statins to "healthy" people, it's no joke.
The panel voted 12 to four with one abstention to recommend that the potent statin Crestor (rosuvastatin) be approved to prevent heart attacks in people who have no history of heart disease and don't fit the traditional profile of an "at risk" population.
The FDA is not obligated to follow the advisors recommendations, but it often does. If it did so this time, it would mark a first -- a drug normally used to lower dangerously high LDL (bad) cholesterol in people with a history of heart disease or risk factors to develop heart attacks or strokes would be approved for the prevention of heart attacks in healthy people.
The new label as recommended by the advisors would state that the drug should be given to men age 50 or older and women age 60 or older who have LDL cholesterol of less than 130 mg/L and triglycerides of less than 500 mg/L if -- and this too is a first -- the patient also had an elevated blood level of C-reactive protein, a marker for inflammation.
The committee's vote was immediately seized upon by cardiologists who characterized it using terms ranging from "great news" to "courageous."
"If the FDA accepts this recommendation, it will expand the number of Americans eligible for statin therapy by millions," said Dr. Steven Nissen, chair of cardiovascular medicine at the Cleveland Clinic.
Dr. James Stein of the University of Wisconsin School of Medicine and Public Health called the vote "very significant," adding that if approved, "it will also, have the (possibly) unintended consequence of increasing highly sensitive CRP testing in the U.S."
Dr. Cam Patterson, a professor at the University of North Carolina School of Medicine, agreed with Stein. "It's been difficult to find a compelling reason to order CRP levels on patients," Patterson said. "This is some guidance from the FDA about how to take high CRP levels into account, and that is good news."
And Patterson predicts that clinicians will see this as a signal to use other statins for this population as well. Although the panel vote dealt only with the Crestor label, Patterson said pointed out that another popular statin -- Lipitor -- will be available as a generic in 18 months. "It will be tough to justify paying a premium price for Crestor when another high potency statin is available at a much cheaper price."
The basis for the new indication was the JUPITER study of almost 18,000 men and women, average age 66. All patients in the study had no history of heart disease, but did have an elevated level of the marker called CRP.
Patients in the study took 20 mg of Crestor or a sugar pill placebo for 1.9 years. At the end of that time, the patients taking Crestor had an average LDL cholesterol of 55 mg/dL-- down from 109 mg/dL when they started the study.
And compared with patients who took the placebo, the Crestor patients had a 44 percent reduction in heart attacks, stroke, need for surgery or stenting to open clogged arteries, or death from heart disease.
For every 25 people treated with Crestor, a heart attack, stroke, or death was prevented.
Those results, according to Dr. Melvyn Rubenfire of the University of Michigan, were a "home run for JUPITER" but it is not clear if the results would be same with another statin.
Noting that the panel's vote was a "somewhat courageous decision", Rubenfire said the "issue now is how the FDA, physicians, and insurers approach the results. That is, 'are all statins the same?' The robustness of the results are unique to Crestor."
But there were some risks associated with Crestor, including 13 deaths due to gastrointestinal disorders in study subjects taking rosuvastatin, and 18 patients reported a "confused state" while taking the drug.
The most troubling adverse event, however, was an uptick in investigator reported new onset diabetes mellitus in the treatment arm, 2.8 percent versus 2.5 percent, or an increased risk of 27 percent.
Although the advisory committee agreed that the benefit of rosuvastatin outweighed the risk, it said that patients should be carefully monitored for diabetes and they admonished the manufacturer to "carefully define the target population in marketing materials."
Crestor is marketed by AstraZeneca, which also sponsored the JUPITER trial.
Prescribing Information (PDF)
The following serious adverse reactions are discussed in greater detail in other sections of the label:
•Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis). [see WARNINGS AND PRECAUTIONS]
•Liver enzyme abnormalities [see WARNINGS AND PRECAUTIONS]
In the CRESTOR controlled clinical trials database (placebo or active-controlled) of 5,394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were:
The most commonly reported adverse reactions (incidence ≥ 2%) in the CRESTOR controlled clinical trial database of 5,394 patients were:
Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Adverse reactions reported in ≥ 2% of patients in placebocontrolled clinical studies and at a rate greater than or equal to placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks.
Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria [see WARNINGS AND PRECAUTIONS]; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities.
In the METEOR study, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of CRESTORtreated subjects versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea [see Clinical Studies]
Adverse reactions reported in ≥ 2% of patients and at a rate greater than or equal to placebo are shown in Table 2.
Pediatric patients 10 to 17 years of age:
In a 12-week controlled study in boys and postmenarchal girls, the safety and tolerability profile of CRESTOR 5 to 20 mg daily was generally similar to that of placebo [see Clinical Studies and Use in Special Populations, Pediatric Use].
However, elevations in serum creatine phosphokinase (CK) > 10 x ULN were observed more frequently in rosuvastatin compared with placebo-treated children. Four of 130 (3%) children treated with rosuvastatin (2 treated with 10 mg and 2 treated with 20 mg) had increased CK > 10 x ULN, compared to 0 of 46 children on placebo.
The following adverse reactions have been identified during post-approval use of CRESTOR: arthralgia, hepatic failure, hepatitis, jaundice and memory loss. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Special warnings about Crestor
Use Crestor with caution if you have a history of liver problems, if you have any symptoms associated with liver disease, or if you drink large amounts of alcohol. In rare cases, cholesterol-lowering drugs like Crestor have caused liver damage. To guard against such problems, your doctor will perform blood tests before you start taking the drug and again after 12 weeks. As therapy continues, you may have your blood tested periodically or whenever the doctor increases your dose.
There is a small chance that Crestor may cause damage to muscle tissue. Be especially cautious if you have any predisposing risk factors for muscle damage, including kidney problems or an under-active thyroid, or if you're past middle age. Promptly report to your doctor any unexplained muscle pain, tenderness, or weakness, especially if you also have a fever or you just generally do not feel well.
Use Crestor with caution if you have kidney problems. Studies have shown that the drug may affect kidney function, especially at higher doses. If your doctor finds evidence of this after routine testing, you may need to have your dosage lowered.
Be sure to tell the doctor if your ancestry is Japanese or Chinese, since these groups have been known to metabolize Crestor differently than others.
Crestor may be associated with abnormal lab test results, including tests for liver and thyroid function and blood sugar levels. If you're having any lab work done, be sure to let the doctor know you're taking Crestor.
The safety and effectiveness of Crestor have not been established in children.