Results of a major trial released this month show that the use of the statin rosuvastatin (trade name Crestor) reduced the incidence of fatal and nonfatal stroke by 48 percent, compared with use of a placebo, and lowered the incidence of heart attack. Rosuvastatin lowers the level of general inflammation in the body as well as lowering LDL or “bad” cholesterol, the study showed.
The results of the study, called Jupiter (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin), appear in the Nov. 9 New England Journal of Medicine and were presented the same day during the American Heart Association Winter Session in New Orleans.
The overall results (heart-related as well as stroke) were so striking that the study, planned for four years, was stopped after less than two. It was deemed unfair to deprive the equal-risk placebo group of the chance to benefit from statin treatment.
Not your average statin test group
What made the study unique was that the nearly 18,000 participants were not the usual candidates for statins: Their LDL cholesterol levels were below the number where statin treatment would normally be prescribed for heart disease and they had no history of cardiovascular events (such as heart attack, heart failure or stroke). But they all had somewhat elevated scores on a test of general inflammation in the body, the high-sensitivity C-reactive protein test (hs-CRP). Clinical reports and other research suggest that inflammation is important in atherosclerosis, where fatty deposits build up in the inner lining of arteries, which can lead to heart attack and stroke.
People in the group taking rosuvastatin saw their LDL levels drop by an average of 50 percent and their hs-CRP levels drop an average of 37 percent. In the rosuvastatin group, 30 people had nonfatal strokes, compared with 58 in the placebo group. Three people had fatal strokes in the rosuvastatin group; six did in the placebo group. (See the New England Journal for all outcomes, including striking results for those with heart-related conditions.)
Connecting the dots: inflammation, stroke, statins
The study confirms “the critical piece of information that statins lower the chance of stroke because they lower inflammation as well as cholesterol,” says Paul Ridker of Brigham and Women's Hospital and Harvard Medical School, who led the trial. “Hs-CRP could be an even stronger predicator of stroke than it is of heart attack,” he says—significant because LDL, an important indicator for heart attack, is not a very good one for stroke. (The hs-CRP test used in this study is manufactured by Siemens; Ridker is co-inventor and holds the patents, along with Brigham and Women’s Hospital. Ridker has reported financial support from Crestor manufacturer/marketer AstraZeneca, as well as nine other pharmaceutical companies.)
Steven C. Cramer, associate professor of neurology at the University of California, Irvine, who was not involved in the study says he finds the result exciting because it “supports the idea that inflammation is a unifying component of many of the different stroke mechanisms.” Treatments to reduce heart attacks can be less effective for stroke because strokes can have such diverse causes, such as those originating in arteries of widely varying diameters. This study is “a powerful finding that could affect thinking about primary prevention for stroke,” he says. “Taking this medication is a clear, high-impact thing one can do.”
Looking ahead: More hs-CRT testing? More statin use?
Two questions the study raises are whether hs-CRP testing should be more widespread and whether statins should be more widely prescribed.
Current American Heart Association guidelines suggest that hs-CRP should not be an initial test but used only when other tests suggest a person has heightened risk. That could soon change. Jupiter was one of three major studies presented at the AHA Winter Session that together provided “the strongest evidence to date that a simple blood test for high-sensitivity C-reactive protein is a useful marker for cardiovascular disease,” according to a statement by Elizabeth G. Nabel, director of the National Heart, Lung, and Blood Institute. “Together, these studies show great promise in helping clinicians better identify and treat individuals at risk for cardiovascular disease—potentially saving millions more lives,” Nabel wrote.
Weighing benefits, risk and cost
Although Jupiter’s relative numbers regarding stroke are impressive, the drug appeared to help a small fraction of the participants. In an editorial in the New England Journal of Medicine, Mark A. Hlatky, professor of health research and policy and of cardiovascular medicine at Stanford, noted that for every 120 participants who took the drug for nearly two years, one participant’s heart attack or stroke was prevented.
“The appropriate size of the orbit of statin therapy depends on the balance between the benefits of treatment and its long-term safety and cost,” Hlatky warned. “Long-term safety is clearly important in considering committing low-risk subjects without clinical disease to 20 years or more of drug treatment.”
Another important question is whether the relatively costly rosuvastatin is the only statin that can yield the benefits reflected in the Jupiter study or if more of the current generation of statins would have the same effect. The dosage used for the study cost $3.45 a day. Justin Zivin, professor of neuroscience at the School of Medicine of the University of California, San Diego, said the Jupiter results show great potential “if it is a class effect [statins] not specific-drug effect [rosuvastatin].” It may well be class effect, he says, considering that previous studies using other statins, such as Lipitor, showed comparable results, but further study is needed.
In balancing costs, Richard Frackowiak, professor of cognitive neurology at University College London, argues that one must consider not only the fatality rate for strokes but also the economic effects of permanent disability from stroke and the cost of chronic care. “It is the prevention of stroke that may well provide a good economic reason for treating everyone with raised CRP,” he says.