Blood Test, Statin Afford Potent Shield, Study Says
Monday, November 10, 2008; Page A01
A highly anticipated study has produced powerful evidence that a simple blood test can spot seemingly healthy people who are at increased risk for a heart attack or stroke and that giving them a widely used drug offers potent protection against the nation's leading killers.
In findings that could transform efforts to prevent cardiovascular disease, the study of nearly 18,000 volunteers flagged by the test in 26 countries found that a cholesterol-lowering statin slashed the risk by about half -- even if their cholesterol was normal.
"The potential public health benefits are huge," said Paul M. Ridker of the Brigham and Women's Hospital in Boston, who presented the findings yesterday at a meeting of the American Heart Association in New Orleans. "It really changes the way we have to think about prevention of heart attack and stroke."
The test measures a bodily reaction known as inflammation, reinforcing an increasingly accepted theory about the underlying biology of heart disease, which kills about 450,000 Americans each year.
"It's a breakthrough study," said Steven E. Nissen of the Cleveland Clinic, who was not involved in the research. "It's a blockbuster. It's absolutely paradigm-shifting."
Several leading authorities predicted the findings would prompt many doctors to start routinely screening middle-age patients for inflammation with the $20 test and begin prescribing the statin used in the study, or one of the less expensive generic versions, to those who get worrisome results. All such drugs reduce inflammation.
"This takes prevention to a whole new level," said W. Douglas Weaver, president of the American College of Cardiology. "Yesterday, you would not have used a statin for a patient whose cholesterol was normal. Today, you will."
Some experts, however, expressed concern about rushing millions of healthy people onto powerful drugs.
"This would be a huge expansion of the boundaries of drug therapy," said Mark A. Hlatky of Stanford University, who wrote an editorial that will accompany a paper describing the findings in the New England Journal of Medicine. "I think we need to be careful before we radically change what we do. Nothing is risk-free."
The traditional model for how heart attacks and strokes occur is that high cholesterol causes fatty buildups to slowly accumulate inside arteries supplying blood to the heart and brain. But about half of all heart attacks and strokes occur in people whose cholesterol is normal. That has raised questions about what other factors may be involved and how more deaths could be prevented.
"This has been the puzzle," Ridker said. "How do we identify these people and prevent disease in these folks?"
Evidence has been building that inflammation, part of the body's defense against infection and injuries, may play a crucial role by causing the most vulnerable plaques inside arteries to rupture, triggering blood clots that finally block blood flow. The blood test, known as the high sensitivity C-reactive protein (HSCRP) test, detects inflammation by measuring a substance in the blood called C-reactive protein. But it has remained far from clear how important or useful that information was.
In 2003, Ridker and his colleagues started prescribing either 20 milligrams of the statin Crestor or an inert placebo daily to 17,802 middle-age and elderly men and women who had what are considered safe cholesterol levels but high CRP: 2 milligrams per liter of blood or above.
The researchers planned to follow the subjects for five years, but an independent panel monitoring the study stopped the trial in March after an average follow-up of less than two years, concluding that the benefit was so striking that it would be unethical to continue withholding the real drug from those taking the placebo. But no details were released at the time.
Compared with those getting the placebo, those taking Crestor were 54 percent less likely to have a heart attack, 48 percent less likely to have a stroke, 46 percent less likely to need angioplasty or bypass surgery to open a clogged artery, 44 percent less likely to suffer any of those events and 20 percent less likely to die from any cause, the researchers reported yesterday.
"We were both shocked and elated," Ridker said.
The numbers were relatively small -- for example, 31 heart attacks in the statin group vs. 68 in the placebo group, reducing the rate from .37 to .17 per 100 person years (or 100 people living one year). But the relative reduction in risk was about double that seen in any previous study evaluating a statin, one of the most widely prescribed types of medications. The data are also the first to offer clear evidence of a benefit for women and minorities as well as men.
"These are very, very dramatic findings," said Elizabeth G. Nabel, director of the National Heart, Lung and Blood Institute, noting that two other studies presented at the meeting support the value of CRP testing.
Experts will review the data before deciding how to revise federal guidelines on CRP testing and statin treatment, Nabel said. But she and others said the results will probably have a significant impact on how doctors try to prevent heart disease.
"This really validates inflammation as being an important factor in the development and progression of heart disease, and that treating inflammation, even in the setting of a normal cholesterol level, may be very important for certain individuals," Nabel said.
Although some of the study subjects had risk factors for heart disease, such as being overweight or having high blood pressure, the findings held true even for those who had no known risks other than their high CRP levels.
"This changes medical practice in a major way," Nissen said. "People are going to flock to their doctors to get their CRP measured, and if it's elevated, they will say, 'Here's this drug you can take.' We'll save many lives and a lot of money."
Ridker said one of his colleagues predicted that an estimated 250,000 heart attacks, strokes, angioplasties or deaths from heart attacks could be prevented in the United State alone over five years,
Although there has been concern about the safety of Crestor, the researchers found no signs of significant risks. The study was funded by AstraZeneca, which makes Crestor, but the company had no influence over the analysis, Ridker said. He and his hospital receive royalties from the high-sensitivity CRP, or HSCRP, test, but other researchers said that was no reason to doubt the findings.
Whether other statins would produce similar benefits remains unproved, but other statins also reduce CRP, and experts said it was likely that they would be beneficial, though the magnitude of the benefit may be smaller.
Some skeptics, however, argued that the actual risk reduction for an individual would be very small, given the relatively low risk for most middle-age people, so the benefits easily could be outweighed by the costs of thousands more people taking tests, drugs and being monitored by doctors.
"We're already struggling to provide health services for the 46 million Americans who don't have health insurance in the United States," said John Abramson, a clinical instructor at Harvard Medical School. "This is going to drain away a lot of money from the system for little or no benefit. We know that there are lifestyle interventions that are effective."
Ridker and others, however, said that the benefit was clear.
"We could prevent a lot of heart attacks, stroke, bypass surgeries, angioplasties, and save a lot of lives," Ridker said. "To me, that's a good thing."