Researchers report possible breakthrough in treating heart disease
Published: January 6, 2005
For years, doctors have known that there was more to heart disease than just the buildup of cholesterol in coronary arteries.
Now, researchers say they have proof that targeting another villain with statin drugs is as important in preventing heart attacks as lowering LDL cholesterol.
In two separate articles Thursday, researchers said that lowering levels of C-reactive protein, an inflammatory substance found in the blood, substantially reduced heart attacks and slowed plaque buildup in arteries.
The studies’ authors say the findings have implications for the treatment of heart disease and could accelerate the development of new heart drugs to target this inflammation.
However, doctors not associated with the research say that while the findings are compelling, more research is needed before making major changes.
Both studies looked at CRP, a substance found in the blood that is a measure - and likely a cause - of inflammation in the body, especially in coronary arteries.
More than a dozen observational studies have showed that CRP is a risk factor for heart disease, but the two new papers, appearing Thursday in the New England Journal of Medicine, are the first large clinical trial results involving CRP.
CRP can be reduced by taking cholesterol-lowering statin drugs, but also by losing weight, exercising and eating healthy.
Certain diabetes drugs, as well as some drugs that raise HDL cholesterol (the good kind), also can lower CRP.
Smoking and hormone replacement therapy raise CRP levels, which can be measured inexpensively by a simple blood test.
In recent years, CRP has emerged as a key player in coronary inflammation, a process that destabilizes the plaque sitting inside arteries.
It works something like this:
Cholesterol builds up and is oxidized inside the walls of arteries. That, in turn, results in the marshaling of immune cells that, in their effort to eliminate the oxidized cholesterol, inflame the arteries, rupturing the lining. The body tries to repair the crack, and a clot forms, resulting in a heart attack.
Among other things, CRP aggravates the immune response.
Inflammation and substances such as CRP help explain why more than half of heart attacks occur in people who have normal cholesterol levels, doctors said.
Some scientists even consider coronary artery disease as a type of autoimmune dysfunction, similar to diseases such as lupus or multiple sclerosis, in which the body is attacked by its own immune system.
In fact, statins actually may be beneficial in treating people with those diseases, said Michael Ehrenstein, a rheumatologist at University College in London who wrote an editorial accompanying the two studies.
In an interview, Ehrenstein said the two studies confirm that CRP is an independent risk factor for heart disease and that using statins to treat it is worthwhile.
This is the first large study to show that lowering CRP levels improved heart health.
Armed with the results of the two studies, researchers now say that doctors should start targeting CRP as well as cholesterol in patients with known heart disease.
“This is the first hard evidence that lowering CRP can reduce events (heart attacks),” said lead author Paul Ridker, a professor of medicine at Harvard Medical School and cardiologist at Brigham and Women’s Hospital in Boston. “You need to monitor both. It’s simply not adequate (to treat) cholesterol alone.”
Ridker’s study was a post hoc analysis involving 3,745 patients who had been hospitalized after having either a heart attack or unstable angina and were put into a clinical trial comparing two statin drugs, 80 milligrams a day of Lipitor or 40 mg of Pravachol. The study was co-funded by Bristol-Myers Squibb, the maker of Pravachol.
Ridker also is co-inventor of an approach that uses markers of inflammation in heart disease and has received funding from Dade Behring, a company that makes a CRP test.
Over a two-year period, those in the study who got their CRP down to below 2 milligrams per liter had substantially fewer heart attacks, both when their cholesterol reached optimal levels and when it did not. Getting CRP down to below 1 mg/liter was associated with even fewer heart attacks.
However, while it is a reasonable option for doctors to attempt to lower CRP in heart patients whose cholesterol is at a desirable level, the new studies should not change practice just yet, said Jon Keevil, an assistant professor of cardiovascular medicine at the University of Wisconsin-Madison.
He pointed out that the two studies involved heart patients, not people who did not have known heart disease.
“I think the CRP story is fascinating,” Keevil said. “(But) I don’t see this as a major groundbreaking change in the way we treat people.”
Lowering LDL cholesterol should remain the primary focus of doctors, said Sidney Smith, director of the Center for Cardiovascular Science and Medicine at the University of North Carolina, Chapel Hill School of Medicine.
“These are very powerful, important studies,” said Smith, a spokesman for the American Heart Association.
But, Smith said, the design of the studies was not perfect. He said he would like to see another study in which CRP is the primary target of statin therapy.
The second study, which was funded by Pfizer, the maker of the statin Lipitor, looked at a group of 502 heart patients who were put on either 80 mg of Lipitor or 40 mg of Pravachol.
Doctors at the Cleveland Clinic used an ultrasound imaging technique to see how much their artery disease had progressed over 18 months.
Those who had the biggest drops in CRP had more slowing of their artery disease, even after taking into account reductions of LDL cholesterol.
“All this time we’ve been missing something,” said lead author Steven Nissen, a cardiologist at the Cleveland Clinic. “If you don’t get CRP down as well (as LDL cholesterol), you don’t get the full benefit.”
Still, Nissen and his co-authors said their findings did not yet warrant routine screening for CRP as a way to adjust statin therapy.
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