An international trial found that the cholesterol busting drug rosuvastatin reduced heart attack and stroke in men and women with low cholesterol who had high levels of C-reactive protein but who were otherwise classed as healthy, and experts suggested this could be a class effect of all statins and not just rosuvastatin, which is marketed by AstraZeneca as Crestor.
The study involved nearly 18,000 men and women from 26 countries and was led by researchers from Brigham and Women’s Hospital (BWH), a teaching affiliate of Harvard Medical School (HMS) in Boston, Massachusetts, USA. The findings are published in the New England Journal of Medicine, NEJM and were presented on Sunday at the American Heart Association 2008 scientific meeting in New Orleans.
Dr Paul Ridker, director of the Center for Cardiovascular Disease Prevention at BWH led the landmark study, called the JUPITER trial, which focused on 17,802 patients with low cholesterol and high C-reactive protein and found that rosuvastatin reduced their risk of heart attack, stroke, and cardiovascular death by nearly fifty percent.
Ridker, who co-invented a test for C-reactive protein and who with some other members of the team also receives grants from and consults for AstraZeneca and other drug companies, said that:
“Our results are relevant for patient care and the prevention of heart attack and stroke.”
“Physicians can no longer assume that patients are at low risk for heart disease simply because they have low cholesterol,” he added.
Ridker said that patients with elevated C-reactive protein are at increased risk even if their cholesterol levels are low, and JUPITER shows evidence that a “simple and safe therapy cuts that risk and saves lives”.
Previous studies had shown that patients with increased hsCRP (high-sensitivity CRP), a sign that the body is fighting inflammation somewhere, were at high risk of heart disease, despite not showing other risk factors, and that statins lowered hsCRP levels, suggesting they had anti-inflammatory as well as cholesterol busting properties. What was missing was a trial that linked the two and showed that statins also lowered the risk of heart disease and stroke.
For the JUPITER trial, which was funded by AstraZeneca, Ridker and colleagues randomly assigned the participants, who all had low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per decilitre (3.4 mmol per litre) and high-sensitivity C-reactive protein levels of 2.0 mg per litre or higher, to receive either a daily 20 mg dose of rosuvastatin or placebo.
The cholesterol levels of the participants were at levels thought by most doctors to be within normal range: the average LDL or “bad” cholesteror was just above 100 mg/dL and the average HDL or “good” cholesterol was nearly 50 mg/dL.
The researchers tracked the incidence of heart attack, stroke, surgery for arterial revascularization to improve blood supply, admission to hospital for unstable angina, and death from cardiovascular and any cause.
The results showed that compared to the placebo group, the rosuvastatin group experienced a 54 per cent reduction in heart attack risk, 48 per cent reduction in stroke risk, 46 per cent reduction in need for bypass surgery or angioplasty, and a 20 per cent reduction in risk of death from any cause.
The researchers said these figures are twice as big as might be expected from statin therapy in patients with high cholesterol, suggesting that hsCRP is an important risk factor for cardiovascular disease.
JUPITER stands for the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin and started in 2003. It was originally planned to take 4 years but was stopped two years later because the findings were so beneficial, the researchers told the AHA meeting.
Dr Antonio Gotto, Dean of the Weill-Cornell Medical College in New York, called the trial “paradigm shifting” and said that:
“We should regularly measure hsCRP along with lipids when we determine cardiovascular risk.”
Dr Eugene Braunwald, a well known cardiologist who also based at Brigham and Women’s Hospital, agreed:
“For the cardiology world, discovering a major new risk factor as well as an effective treatment is like hitting a walk-off home run to win the World Series.”
In a press statement, the BWH team suggested routine screening for hsCRP and treating those at high risk would save considerable costs because it would result in fewer hospital admissions and expensive procedures like angioplasty and coronary artery bypass, which were reduced by nearly 50 per cent among the participants on rosuvastatin.
The trial also showed that rosuvastatin reduced the risk of cardiovascular events by 46 per cent in women compared to 42 per cent in men.
There was no difference between the groups for major adverse events, including cancer or myopathy, but there was a slight increase in diabetes incidence in the statin group, which is usual in most statin trials.
Dr Robert Glynn, statistician and study co-author, suggested that if the strategy tested in the study were applied throughout the US, it would results in 250,000 fewer heart attacks, strokes, revascularization procedures, and cardiac deaths over 5 years.
Dr James Willerson, Director of the Texas Heart Institute in Houston, said:
“JUPITER should dramatically change prevention guidelines, the bottom line here is simple — if your hsCRP is high, you should be on statin therapy regardless of your cholesterol level.”
“This is an approach we can start using tomorrow,” he added.
There has been a mixed reaction to the news, with some critics saying that the cost of using statins to reduce hsCRP as well as cholesterol would add more than 9 billion dollars to the US annual healthcare bill, said a report in the Los Angeles Times.
World sales of statins currently total more than 22 billion dollars a year, most of it in the US where some 13 million Americans take them to lower cholesterol.
“Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein.”
Ridker, Paul M, Danielson, Eleanor, Fonseca, Francisco A.H., Genest, Jacques, Gotto, Antonio M., Jr., Kastelein, John J.P., Koenig, Wolfgang, Libby, Peter, Lorenzatti, Alberto J., MacFadyen, Jean G., Nordestgaard, Borge G., Shepherd, James, Willerson, James T., Glynn, Robert J., the JUPITER Study Group.
N Engl J Med Published online November 9, 2008, in print November 20, 2008.
DOI: 10.1056/NEJMoa0807646.
Sources: NEJM, Brigham and Women’s Hospital, Los Angeles Times.
Written by: Catharine Paddock, PhD.