FDA sets stage for Tuesday’s Crestor (rosuvastatin) advisory panel

The FDA has released briefing information for next Tuesday’s advisory panel meeting to consider an expanded indication for rosuvastatin (Crestor). The proposed expanded indication is based on the results of JUPITER and reads as follows:

“For the prevention of cardiovascular disease in adult patients with an increased risk of cardiovascular disease based on the presence of cardiovascular disease risk markers such as an elevated hsCRP level, age, hypertension, low HDL-C, smoking or a family history of premature coronary heart disease, CRESTOR is indicated to:

  • reduce the risk of total mortality
  • reduce the risk of cardiovascular death
  • reduce the risk of stroke
  • reduce the risk of myocardial infarction
  • reduce the risk of arterial revascularization
  • reduce the risk of unstable angina”

The FDA review ask the panel members to “keep in mind that an estimated 6 million middle-aged and older men and women in the United States satisfy the JUPITER hsCRP and LDL-C entry criteria.”

The FDA review generally accepts the efficacy conclusions from JUPITER, but raises several safety issues, though it appears unlikely that these will be strong enough to derail the expanded indication.

Here is the main efficacy conclusion of the review:

Treatment with rosuvastatin in subjects with no clinically evident cardiovascular disease, a LDL-C of <130 mg/dL, hsCRP ≥2 mg/L, and at least one other major ATP-III risk factor resulted in a 44% reduction in time to major cardiovascular events defined as the composite of cardiovascular death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, and revascularization.

The safety review noted an imbalance of gastrointestinal side effects, including 13 deaths in the rosuvastatin group versus 1 in the placebo group, though the FDA reviewers concluded that this was “a chance finding.” Perhaps more problematic is the finding of a 27% increase in investigator-reported diabetes, as well as a post-hoc analysis of development of diabetes occurring in 15.3% of the rosuvastatin group versus 12.% of the placebo group.

The FDA review asks the advisory committee members to vote on the 4 following questions:

  1. In the JUPITER clinical trial, there were 13 deaths due to gastrointestinal disorders in the treatment arm versus one in the placebo arm. Please comment on the significance of this imbalance.
  2. In the JUPITER clinical trial, there were 18 patients who reported a confusional state in the treatment arm versus four in the placebo arm. Please comment on the significance of this imbalance.
  3. In the JUPITER clinical trial, there was a statistically significant increase in investigator-reported diabetes mellitus in the treatment arm versus the placebo arm; 2.8% versus 2.3%, respectively with a hazard ratio of 1.27 (95% CI 1.05, 1.53; p=0.015). Please comment on the significance of this imbalance.
  4. Has the sponsor provided sufficient evidence of a favorable benefit-to-risk profile for rosuvastatin for the primary prevention of cardiovascular disease (CVD) in middle-to-older aged, low-to-moderate CVD risk individuals with levels of LDL-C <130 mg/dL and hsCRP ≥2 mg/L?

Although the committee evaluating the new indication for rosuvastatin is the Endocrinologic and Metabolic Drugs Advisory Committee, CardioBrief readers will be intrigued to learn that controversial Cardiovascular and Renal Drugs Advisory Committee member Sanjay Kaul, who was famously “uninvited” from last February’s prasugrel panel, will be a voting member on Tuesday. In the past, Kaul has been highly critical of JUPITER, as we reported last April. Discussing  a highly critical comment by Salim Yusuf and colleagues in the Lancet about JUPITER, Kaul told CardioBrief:

Yusuf et al. make many important points that I concur with. The results of the recently published AURORA trial in patients on hemodialysis add to the observations described by Yusuf et al in their commentary. As in CORONA and GISSI-HF trials, treatment with rosuvastatin reduced LDL levels as well as hsCRP (11% compared to 37% in JUPITER), without impacting cardiovascular outcomes. So why should treatment with rosuvastatin result in a cardiovascular outcome benefit in primary prevention, but not in secondary prevention? A likely explanation is that truncated trials are notorious for producing implausibly large (“too good to be true”) treatment effects. Such “random high” observations seen at early time points invariably “regress to the mean” (truth) upon longer follow-up. There are numerous examples of this phenomenon in the clinical trial literature. This then begs the question whether JUPITER should have been stopped early. In my opinion, trials should ideally be stopped for safety or futility concerns, not for “implausibly large” treatment effects. Event the all-cause mortality benefit appears to be driven by cancer mortality, likely a spurious observation. This has important implications for interpretation of overall benefit-risk. It is likely that benefit of statin therapy in JUPITER was overestimated and risk underestimated due to early stopping, suboptimal compliance and enrollment of highly selective population. Moreover, increased risk of incident diabetes in statin arm appears to be worrisome. Finally, not being able to know the long-term safety of “ultra-low LDL” levels is quite frankly a lost opportunity.

In conclusion, to paraphrase Victor Montori and Gordon Guyatt et al. (JAMA 2005), “overly sanguine estimates of treatment effect can result in misleading benefit-risk ratios, misguided policy decisions and practice recommendations, and suboptimal clinical practice”.

You can read more about the FDA briefing materials here:

Here are links to the original FDA documents:

December 15, 2009 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee:


  1. Long-term safety of this drug can be seen in 3 RCT: CORONA, GISSI-HF, AURORA. All of these were extremely sick patients on multiple medications, with high mortality rates. If impaired safety was present, it might have come out in one of these trials (liver, muscle, renal, neurological). In contrast, atorvastatin and simvastatin have not been tested in such circumstances.


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