FDA has cleared AstraZeneca's statin Crestor for wider use in preventing heart disease and related cardiovascular events, in the process validating the controversial high sensitivity C-reactive protein test as a risk marker, some experts say.

According to the new label, unveiled Feb. 8, Crestor (rosuvastatin) is now indicated for the primary prevention of cardiovascular disease to reduce the risk of stroke, heart attack, and other cardiovascular events in certain patients. Clearance applies to those with no clinically evident heart disease but who are at an increased risk due to the combined effects of the following risk factors:

1) Age (> 50 years in men; > 60 years in women);

2) An elevated high-sensitivity C-reactive protein level (> 2 mg/L); and

3) Presence of at least one additional cardiovascular risk factor, such as high blood pressure, low HDL-C, smoking, or a family history of premature heart disease.

Elevated hsCRP is a marker of inflammation thought to be predictive of heart disease. On its own, it is not a CV risk factor recognized by the U.S. Preventive Services Task Force or The Annals of Internal Medicine (¹ Also see "Crestor Advisory Meeting Weighs Value Of C-Reactive Protein Risk Marker" - Pink Sheet, 21 December, 2009.).

The upgraded label marks the first time Crestor has been approved for use in the prevention of heart disease in individuals with "normal" low-density lipoprotein cholesterol levels and no clinically evident heart disease, the FDA noted in a Q&A sheet for healthcare professionals.

The decision is important for a number of reasons. For one, it paves the way for AstraZeneca to directly market the primary prevention indication, expanding the statin-eligible patient population for Crestor by an estimated six million people.

It's also highly significant from a regulatory point of view, as it represents the first time any cholesterol-lowering drug has been approved to treat patients who don't have elevated cholesterol levels.

Decision Puts FDA imprimatur On hsCRP

Furthermore, the decision puts the "FDA imprimatur" on the use of hsCRP, according to Dr. Steven Nissen, chair of cardiovascular medicine at the Cleveland Clinic. Up to now, a "natural conservatism" among professionals has worked against the adoption of the new risk marker, despite the "good science," backing it, he said.

"The lipid community has focused singularly on cholesterol for decades. In some ways, yes, cholesterol is part of problem, but inflammation is also important," Nissen said in an interview.

The new label is supported by AstraZeneca's 18,000-patient strong JUPITER study. That trial evaluated Crestor as a preventive measure for CV events in patients who had LDL-C less than 130 mg/dL and who had elevated hsCRP levels. Overall, the study showed dramatically improved outcomes in patients treated with Crestor (² Also see "Will JUPITER Change Statin Use?" - Pink Sheet, 10 November, 2008.).

In deciding whether to recommend approval of Crestor for wider use, members of FDA's Endocrinologic and Metabolic Drugs Advisory Committee had been divided about the use of hsCRP as a qualifier for statin therapy. But in the end, they voted 12 to four for an expanded label based on the results from the JUPITER study, under conditions similar to the ones spelled out in the final label (³ Also see "Crestor Advisory Meeting Weighs Value Of C-Reactive Protein Risk Marker" - Pink Sheet, 21 December, 2009.).

The agency does a good job in evaluating claims and an FDA label could have an impact on thinking about CRP, Nissen said.

Relevance Of hsCRP Draws Scrutiny

However, some cardiologists strongly disagree with this point of view.

It has long been documented that lowering cholesterol in patients with normal cholesterol levels can have strong beneficial effects for reducing cardiovascular events, said Matthew Budhoff, cardiologist and associate professor of medicine at Harbor-UCLA Medical Center. The JUPITER study merely confirms this result and shows Crestor has a particularly potent effect on outcomes, he said.

It's unclear whether the hsCRP levels had any relevance to the findings because the study excluded almost 30 percent of the 90,000 people screened to participate in JUPITER who had an hsCRP below 2 mg/L. So it's impossible to know if patients with low levels would have had the same reduction in risk for events as those with higher levels.

"Unfortunately there is a huge knowledge gap because of the study design. If they had studied a subset and saw the same changes, then we would know if it was hsCRP or not," Budhoff said in an interview.

In Budhoff's opinion, the FDA label does not represent a validation of the hsCRP test. Rather it merely reflects the agency's standard practice of approving an indication based on the study design, he said.

Cardiologists Are "Moving Away" From hsCRP

In practice, cardiologists have been moving away from the hsCRP test because it is not specific to detecting inflammation the heart, Budhoff said. Rather it picks up inflammation throughout the body. The test has commonly been used in other specialties. For example, in pulmonology, it may be used to determine whether a patient has a cold or something more serious, like bronchitis.

But used over time, results may fluctuate and are difficult to interpret, he said.

"The vast majority [of cardiologists] I run into don't believe in CRP," Budhoff said. "A cold could cause CRP to go up."

In its Q&A for health professionals, the regulator warned that the JUPITER results should be interpreted with caution and highlighted the lack of evidence for using Crestor in all patients with an elevated hsCRP. For example, there is no evidence that the drug will help those who have an elevated hsCRP unless they also have more traditionally recognized cardiovascular risk factors.

There were also limitations in the study that "make interpreting the association between an elevated hsCRP and Crestor use difficult," FDA stated.

Treatment of people with normal cholesterol levels is also controversial. Rita Redberg, director of women's cardiovascular services at the University of California at San Francisco, commented that she was "surprised that the FDA relabeled on the basis of one study."

Early termination of the JUPITER study was viewed by some as a design flaw, she noted. Redberg concluded that she would be cautious about prescribing statin medications, which have known side effects, to patients without elevated cholesterol for the rest of their lives.

"One large study is not enough to make me comfortable prescribing statins to people who are otherwise healthy," she said.

Commercial Impact Unclear

Analysts said the commercial impact of the new label is a bit uncertain.

One downside of the label, which had been expected, is that it did not include a claim for reducing total mortality or deaths. The "Clinical Studies" section explicitly states that there were no significant treatment differences between Crestor and placebo for death due to CV causes or hospitalizations for unstable angina, noted Leerink Swann's Seamus Fernandez in a Feb. 9 note.

However, based on the JUPITER results and the label, the eligible patient population eligible for treatment might increase by 5 million to 7 million patients, Fernandez wrote.

The label means AstraZeneca representatives can now actively promote the JUPITER study and label revisions. "We believe the label revision can help sustain Crestor growth but we are skeptical that it will drive a significant uptick in prescribing," Fernandez wrote.

But results were well-publicized upon release in 2008 and global sales have already risen from $3.5 billion in 2008 to $4.5 billion in 2009.

UCSF's Redberg observed that if the company chooses to go the route of direct-to-consumer advertising for the primary prevention indication, that could have an impact on prescribing patterns. The firm's promotional plans also hinge on its success in patent litigation against eight generic firms (⁴ Also see "As Crestor Patent Trial Nears, Generic Firms Seek To Block AstraZeneca Subsidiary From Suit" - Pink Sheet, 9 February, 2010.).

- Emily Hayes (⁵ e.hayes@elsevier.com)

Crestor Label Lends Validity To Controversial C-Reactive Protein Test

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