JUPITER's Orbit Expands: How Far Should Preventive Statin Therapy Go?

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Are all statins created equal? Can we afford to give statins to millions more people? Are there risks for people with different types of heart disease? Do we know the very long-term risks of statin therapy? These and many other questions must be considered before large-scale cholesterol-lowering programs are adopted.

When the JUPITER trial was presented at the 2008 American Heart Association meeting, it became national news. The study showed that a new biomarker could identify seemingly healthy people at risk of heart disease and that treatment with a statin could significantly reduce the incidence of cardiovascular events. Since the trial’s release, much debate has ensued on the preventive use of statin therapy, and the potential economic effects if the findings are adopted into the clinical guidelines.

Participants in the JUPITER trial had normal cholesterol levels and elevated levels of high-sensitivity C-reactive protein (hsCRP). Subjects were randomized to either rosuvastatin (Crestor, AstraZeneca) or placebo. Researchers found that the statin group had benefitted in several areas compared to the placebo group, including reductions in heart attacks, stroke, target lesion revascularization and all-cause mortality. Lead JUPITER investigator Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, says the JUPITER trial confirms the findings of nearly two dozen previous cohort studies.

Even skeptics have been convinced. “When you perform a study in 18,000 patients with normal cholesterol but elevated hsCRP levels, and you see a 50 percent reduction in morbidity and mortality, you just can’t ignore those findings. I am now convinced that we should perform hsCRP testing in more individuals,” says Steven Nissen, MD, chair of the department of cardiovascular medicine at the Cleveland Clinic.

What is the cost?

According to estimates, the number of patients who would begin statin theapy if the guidelines change as a result of the JUPITER findings ranges from several million to more than 11 million. The figure at the top of that range comes from Erica Spatz, MD, and her group at Yale University (Circ Cardiovasc Qual Outcomes 2009;2:41-48). The figure at the lower end of the spectrum comes from the JUPITER researchers. The better question to ask, however, according to Ridker, is how many fewer cardiac events would occur and how many lives would be saved. He notes that JUPITER researchers “very conservatively estimated that more than a quarter million fewer heart attacks, strokes, bypass surgeries and cardiovascular deaths would occur in a five-year span if the JUPITER strategy is put into place.”

One caveat before the U.S. potentially embarks upon preventive statin therapy is the lack of very long-term safety studies, according to Nissen. There could be unforeseen risks in the second decade of therapy that the cardiovascular community is, as of yet, unaware, he says, and suggests the National Institutes of Health conducts such a study.

Another factor to consider regarding cost is whether there are real differences between generic and brand name statins. A recent meta-analysis found the two groups to be equivalent in several cardiovascular medication categories including statins (JAMA 2008;300:2514-2526). But not all statins are created equal, says John Kjekshus, MD, from the department of cardiology at the University of Oslo, Norway. Through clinical trialing, in particular the PROVE-IT trial, researchers learned that rosuvastatin and atorvastatin (Lipitor, Pfizer) are superior to pravastatin (Pravachol, Bristol Myers Squibb) as cholesterol-lowering drugs. Spatz suggests that starting patients with a less expensive, clinically proven statin may lead to greater adherence in the long run, given that the LDL is lowered appropriately.

Heart failure patients

In the CORONA trial, researchers found a difference in outcomes between older patients with mild heart failure who had more positive outcomes with a rosuvastatin regimen and those with more severe systolic heart failure whose death rate did not change with the regimen (N Engl J Med 2007;357:2248-2261). The CORONA researchers, led by Kjekshus, were surprised by this finding because they had expected the statins to have an effect in reducing systolic heart failure.

The statin therapy, however, did reduce the number of cardiovascular hospitalizations across all patients during a median follow-up of nearly three years. A post-hoc analysis revealed that the therapy produced a 16 percent reduction in MI and stroke, and had an effect in patients with high levels of hsCRP and patients in the lower one-third of B-type natriuretic peptide (BNP) levels, according to Kjekshus. “The hsCRP finding in the CORONA trial seems to be a link to the JUPITER trial—that patients with elevated hsCRP are at higher risk for cardiovascular events, but they seem to benefit from statin treatment,” he says, and suggests that a large randomized trial be conducted among patients with low BNP and high levels of hsCRP.

One commentary suggested that the reason researchers failed to show a reduction in vascular events with rosuvastatin in older patients with systolic heart failure “may be a reduction in coenzyme Q10, which is known to be caused by statins” (N Engl J Med 2008;358:1301). Coenzyme Q10 is important in mitochondrial electron transport and energy generation, and depletion of coenzyme Q10 in myocardial tissue has been correlated with an increased clinical severity of heart failure. Kjekshus has analyzed the effect of coenzyme Q10 levels and discovered that it is a risk factor among heart failure patients, especially those at higher risk for having an event. He expects to publish this finding later this year. He also found that statins will reduce coenzyme Q10 in the blood, but did not find any correlation between a reduction caused by rosuvastatin and an increase in cardiovascular events.

Because hospitalization was reduced for heart failure patients—for both coronary artery disease and all-cause hospitalization, Kjekshus says an argument could be made for recommending statins for this patient population. “At least those patients already on statin treatment should not stop,” he says.

JUPITER’s Ripple Effects
The JUPITER trial researchers will be rolling out a number of follow-up analyses based on the initial trial, including:
  • Whether or not the benefits in JUPITER were strictly due to cholesterol reduction, hsCRP reduction or both
  • The impact of rosuvastatin on other endpoints, such as venous thrombosis
  • The number-needed-to-treat data