Statins May Halve Heart-Attack Risk

A much-anticipated study released Nov. 9 at the American Heart Association’s annual meeting confirms what doctors have long suspected: that inflammation may be as critical a predictor for heart-disease risk as is a patient’s cholesterol score.

The study’s results suggest that using statins to treat the symptoms of inflammation, an oft-overlooked condition, may nearly halve people’s risk of future heart attack, stroke and heart-related death.

Led by Dr. Paul Ridker at Brigham and Women’s Hospital in Boston, the study tracked about 17,800 people in 26 countries. Participants included men ages 50 and older and women ages 60 and older, who had high levels of C-reactive protein (CRP) but normal cholesterol levels and no history of heart disease. Half the participants were given rosuvastatin (Crestor), and half were given a placebo daily for just under two years. The statin group reduced their CRP levels by 37%; their LDL, or bad cholesterol, levels dropped 50% to about 55 mg/dL. Among the 8,901 statin-takers, 31 suffered a heart attack and 33 suffered a stroke. When compared with the placebo group, those figures translated to a 54% lower risk of heart attack and a 48% lower risk of stroke in people taking a statin for inflammation — double the reduction of risk in patients who lower their cholesterol alone.

“This is unprecedented,” says Dr. Steven Nissen, chair of cardiovascular medicine at Cleveland Clinic, who is familiar with the study but did not participate in it. “I have never seen a result of this magnitude reduction in risk.” The results were significant enough to stop the study three years early.

Several previous studies have suggested that inflammation, independent of cholesterol levels and other well-established risk factors, is an important marker of heart disease. But while it was clear that inflammation was a key player in disease, there was no real data to prove that reducing inflammation, as measured by lower levels of the CRP marker in the blood, could prevent future cardiovascular disease in otherwise healthy patients.

“When the first studies came out, a lot of us measured CRP, then it fell out of vogue because there was nothing we could do with the result,” says Dr. Douglas Weaver, president of the American College of Cardiology (ACC).

The results of the study not only shift the state of the evidence but also herald new guidelines for the prevention of heart disease and redefine the traditional at-risk population. Many people who, for example, lack outward signs of heart disease may have high CRP levels, which could put them at silent risk for heart attack or stroke. According to the study, published also in the New England Journal of Medicine, at least 250,000 heart attacks, or about 20% of the total heart attacks suffered per year in the U.S., may be prevented by controlling inflammation. Indeed, nearly half of all heart attacks occur in people with normal cholesterol levels, a strong indicator that factors other than cholesterol and atherosclerosis — such as inflammation — are involved. “This is a new way to prevent cardiovascular events in an entirely new population that we have been missing,” says Weaver.

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Although JUPITER (Justification for the Use of Statins in the Prevention: an Intervention Trial Evaluating Rosuvastatin) was designed to study inflammation, its findings also underscore the risk of high cholesterol. The study’s statin group clearly benefited from reducing CRP, but they had also simultaneously lowered their LDL levels to nearly 50% below the government-prescribed target of 100 mg/dL. Experts say the JUPITER results may prompt serious rethinking of the current guidelines — an issue that health officials have already been debating in recent years. “I would not be surprised if, given these results, we determined that normal LDL should be lower than currently defined,” says Dr. Elizabeth Nabel, director of the National Heart, Lung and Blood Institute. Updated cholesterol guidelines are expected in 2009.

That will likely be just one of many changes in the thinking behind heart-disease prevention. JUPITER’s results shore up the contention that one heart attack is not the same as the next. Cardiologists think that cholesterol and inflammation conspire to cause heart attacks but that each person’s genes and lifestyle influence how those factors interact. Excess cholesterol causes fatty deposits to build up within heart artery walls; those plaques trigger immune and inflammatory reactions in the body that tend to increase the instability and rupture of the plaques, which causes heart attacks. How aggressive the inflammatory response is depends on a person’s genes, diet, stress levels and even exposure to chronic infections such as gum disease. So, the more active the inflammatory response, the greater the chance of ruptured plaques and heart attack. In people with elevated CRP, that means the danger lies not so much in the number of plaques (measured by cholesterol) but in how likely they are to burst (measured by CRP).

The new study suggests that screening all patients for CRP (a $10 test) as well as for cholesterol and blood pressure would not be unwise, or perhaps the test should be used for patients with indeterminate heart-disease risk, who may derive benefit from taking a statin. Longer-term trials are still needed, however, to show whether the benefits of statins outweigh their potential side effects — the drugs are relatively benign, but they are known in rare cases to cause debilitating side effects such as muscle weakness (which forced Bayer to pull its version off the market in 2001). There was no increase in side effects among JUPITER’s study group, but because the trial was terminated early, researchers don’t know whether they would have seen more adverse effects later on. It’s also not clear whether all statins can provide equal benefit, says Dr. Roger Blumenthal, director of preventive cardiology at Johns Hopkins Hospital.

Despite the questions that remain, cardiologists say the findings of JUPITER put another screening tool in the doctor’s arsenal.

“Primary-care physicians now have to add to their battery of tests — which include colonoscopy, PSA and breast exams — something for the asymptomatic older person for the prevention of heart disease that now has greater benefit than anything we have ever had in the past,” says Weaver of the ACC.

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