Nissen Hearts Crestor Study

Here's the impression: As much as Steven Nissen, head of cardiology at the Cleveland Clinic, hates the cholesterol-lowering combo pill Vytorin (ezetemibe/simvastatin; Merck/Schering-Plough), he adores the statin Crestor (rosuvastatin), or its maker AstraZeneca, or both. The evidence is in a string of loving quotes from Nissen in the lay press about the positive results of the company's JUPITER study, which were concurrently presented at the ongoing Scientific Sessions of the AHA and published in the latest issue of the NEJM.

Nissen tells Bloomberg, "This may be the most important trial we've seen in a decade," and that the study findings are an "out-of-the-park home run."

He tells the LA Times, "It's a blockbuster. It's absolutely paradigm shifting."

He tells CNN, "This is a huge reduction, unprecedented reduction in risk occurring very quickly."

He tells Forbes, "It's potentially a game-changer."

He tells Time, "This is unprecedented...I have never seen a result of this magnitude reduction in risk. The results were significant enough to stop the study 3 years early."

He tells The Washington Post, "It's a breakthrough study," and "This changes medical practice in a major way. People are going to flock to their doctors to get their [c-reactive protein] measured and if it's elevated, they will say, 'Here, this drug you can take.' We'll save many lives and a lot of money."

He tells USA Today, "This is going to have huge repercussions. It means that men over 50 and women over 60 are going to get their [c-reactive protein] checked, and if they're high, they're going to get 20 milligrams of rosuvastatin...We know that we can reduce their risk of heart attack and stroke and angioplasty by nearly 50%. We've never seen this magnitude of risk reduction in a statin trial."

What's got Nissen (who was not a part of the JUPITER study, but who has received research support from AstraZeneca) so buzzed is that rosuvastatin 20 mg daily, when compared with placebo, reduced the relative risk of the primary endpoint, a first major cardiovascular event,* by nearly 50% in more than 17,000 men or women with nonelevated LDL levels but with high c-reactive protein (CRP) levels. The median follow-up of the study was 1.9 years, and the trial was stopped early because of the favorable results.

But despite the high relative risk reductions observed in the JUPITER study, absolute risk reductions were small:

• Rate of primary endpoint: rosuvastatin, 1.6%; placebo, 2.8% → difference, 1.2%.
• Rate of fatal or nonfatal MI: rosuvastatin, 0.35%; placebo, 0.76% → difference, 0.41%.
• Rate of fatal or nonfatal stroke: rosuvastatin, 0.37%; placebo, 0.72% → difference, 0.35%.

Patients who received rosuvastatin also demonstrated a significantly higher rate of physician-reported diabetes (but not myopathy or cancer): rosuvastatin, 3.0%; placebo, 2.4% → difference, 0.6%. Nissen's evidently nowhere near as worried about this adverse event (which undoubtedly raises CV risk) as he was about the possibly fluky cancer risk in the SEAS trial of Vytorin.  

The rationale for the JUPITER study is based on the proposed CV risk associated with high levels of CRP, an inflammatory biomarker and a proposed, independent predictor of vascular events. The lead author of the study, Paul Ridker, is coinventor of a patent (USP no. 7,030,152, along with Charles Hennekens) that describes the use of CRP to evaluate the risk of CV disease.

Other cardiologists, quoted in the press, are more cautious than Nissen about the JUPITER study results and the utility of measuring CRP.

Lori Mosca of Columbia tells Bloomberg, "This finding is clearly expanding the universe of who should receive cholesterol pills, but we need to carefully evaluate at what point it becomes cost-effective to treat the majority of people."

In an NEJM editorial, Mark Hlatky of Stanford writes, "Long-term safety is clearly important in considering committing low-risk subjects without clinical disease to 20 years or more of drug treatment," and adds that the daily cost of rosuvastatin, $3.45, is much higher than that of generic statins.

To this last point, others, like Northwestern's Robert Bonow and Public Citizen's Sidney Wolfe, believe that the JUPITER results can probably be generalized to all statins, including generic versions. AHA president Tim Gardner agrees: "This is a win for all statins," he tells the LA Times and predicts that the findings will be incorporated into practice guidelines.

Of course, the use of a statin in this context depends on the CRP level, which has a checkered history in clinical practice. "When the first [CRP] studies came out," ACC president Douglas Weaver tells Time, "a lot of us measured CRP. Then it fell out of vogue because there was nothing we could do with the result." Scott Grundy of Southwestern advises the New York Times, "CRP is not a standard test that everyone should have," and Daniel Rader of the University of Pennsylvania tells the paper, "It is an additional test that you should do if you're on the fence." Online sources (example) indicate that the cost of high-sensitivity CRP testing is approximately $50.

However, Nissen's (and AstraZeneca's) biggest buzzkill may be found in form of Sanjay Kaul from Cedars-Sinai, who tells Forbes, "I'm convinced CRP is a fad. Maybe there will be a little blip in its use, but many physicians have given up on CRP."

11/10/08 afternoon addendum: Polling results at the NEJM indicate an approximate 50-50 split among responders about whether the JUPITER results should change 1) the approach to laboratory screening and 2) the therapeutic use of statins.

* Nonfatal MI, nonfatal stroke, arterial revascularization, hospitalization for unstable angina, or confirmed death from CV causes.

ACC = American College of Cardiology; AHA = American Heart Association; CV = cardiovascular; JUPITER = Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis.

2006 photo of Steven Nissen testifying at the Hearing on Building a 21st Century FDA.