Changing the cardiovascular prevention game

Commentators on the presidential debates in the fall of 2008 were often asked whether they had spotted any "game changers"—something the candidates said or did that would alter the course of the election. A few days after Election Day, many doctors (especially cardiologists) were talking about a game changer in how we go about preventing heart attacks and strokes.

They were reacting to results from a large clinical trial that showed cardiovascular events were cut in half by taking a powerful statin drug among people whose "bad" LDL cholesterol levels were fine, according to current guidelines, and in no need of lowering. What's more, the results suggested that a test for C-reactive protein (CRP), a marker for inflammation, could be used to flag people who might benefit from this unorthodox use of statins.

In the short run, more doctors are likely to order CRP tests, which cost $20 and are readily available. We'll probably also see an uptick in statin prescriptions. A 2009 update of prevention and cholesterol guidelines will go a long way toward determining how soon—and in exactly what way—routine medical practice will change.

In the longer run, these results could usher in a new era of cardiovascular disease prevention based on CRP testing and inflammation. There are real concerns, though, about cost: Will the additional tests and statin prescriptions prevent enough heart attacks, strokes and cardiovascular procedures to make the additional expense worth it?

Stopped early

True to its name, JUPITER (that's short for Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) was huge: nearly 18,000 people from 26 countries volunteered to participate. The study population included women (just under 40 percent), blacks (13 percent), and Hispanics (13 percent), so it was more diverse than many other important clinical trials. Men had to be age 50 or older and women, 60 or older, so these were people entering the prime years for heart attack and stroke.

The entry criteria included a relatively low LDL level (less than 130 mg/dL) and a relatively high CRP (2 mg/L, a notch below the 3 mg/L standard for high CRP used by the American Heart Association).

Half of the volunteers were randomly assigned to take a 20-mg pill of rosuvastatin (Crestor) daily, twice the usual starting dose. The other half took a placebo pill. AstraZeneca, the London-based pharmaceutical company that makes Crestor, funded the study, but the investigators say the company had no role in the analysis of the results. The lead investigator, Paul Ridker, M.D., and his hospital, Harvard-affiliated Brigham and Women's Hospital in Boston, have the patent rights on the CRP test.

JUPITER was scheduled to last four years but was stopped about halfway through, in March 2008, when an interim analysis showed that people taking the rosuvastatin had markedly fewer major cardiovascular events (heart attack, stroke, hospitalization for angina, etc.) than people taking the placebo pills.

Full analysis of the data was consistent with the interim look. The median LDL levels of the people taking rosuvastatin plunged by 50 percent (from 108 to 54 mg/dL), and their CRP levels fell by 37 percent. And compared with those taking the placebo pills, people taking rosuvastatin were 54 percent less likely to have a heart attack, 48 percent less likely to have a stroke, and 44 percent less likely to experience a serious cardiovascular event of any kind.

But these relative effects are best judged in the context of how many actual cardiovascular problems were averted. By design, the JUPITER was a study of a relatively low-risk population—there were only 393 serious cardiovascular events among all 18,000 participants. That means even a large relative change isn't going to translate into impressive absolute numbers. Indeed, the researchers calculated that 95 people needed to take rosuvastatin for two years to prevent just one serious cardiovascular event.

The data collected on adverse reactions didn't show problems with side effects like muscle weakness—a growing concern about statins—although there was a slight suggestion that rosuvastatin might increase the risk of developing diabetes.

What's next

One of the big unanswered questions now is whether other statins will have the same effect as rosuvastatin. If cheap, generic statins do, that will dramatically alter the cost considerations.

The JUPITER results come on the heels of others that have demonstrated benefits from lowering LDL to previously unheard of levels. We don't propose throwing in the towel on lifestyle changes, but as a practical matter, that may mean millions more of us will be advised to take statins. More than ever, we will need close monitoring for long-term side effects.

If CRP testing takes off, the JUPITER results may, indeed, change the focus of cardiovascular disease prevention from reducing cholesterol to quelling inflammation. Researchers have known that inflammation is an integral part of atherosclerosis but it's been unclear how, exactly, to put that knowledge to practical use. Broader use of CRP testing may be one way to start.