Cholesterol Levels Should Be Even Lower, Study Finds
GINA KOLATA / NY Times 8mar04
Lowering cholesterol far below the level that most doctors now consider adequate can substantially reduce patients' risk of having or dying from a heart attack, researchers reported today.
The findings, cardiologists say, will greatly change how doctors treat patients with heart disease and will provide the impetus to re-evaluate how low cholesterol levels should go.
The study compared high doses of one of the most powerful cholesterol-lowering drugs, Pfizer's Lipitor, to a less potent drug, Pravachol, made by Bristol-Myers Squibb, which conducted the trial.
The patients taking Lipitor were significantly less likely to have heart attacks or to require bypass surgery or angioplasty, the study found. Both drugs are statins, a class of medications that block a cholesterol-synthesizing enzyme and are often prescribed for patients with heart problems.
"This is really a big deal," Dr. David Waters, a professor of medicine at the University of California in San Francisco, said of the findings. "We have in our hands the power to reduce the risk of heart disease by a lot. It's very exciting."
National guidelines call for levels of L.D.L. cholesterol, which carries cholesterol to arteries, to be below 100 milligrams per deciliter in high-risk patients.
But the two-year study, involving 4,162 patients hospitalized for a sudden attack of chest pain from heart disease, asked whether reducing cholesterol levels far below 100 milligrams was beneficial. The study will be published in the April 8 issue of the New England Journal of Medicine, but the journal lifted its embargo on the report because the results were presented at the American College of Cardiology meetings in New Orleans.
In the study, patients were randomly assigned to take 80 milligrams a day of Lipitor, the highest available dose, or 40 milligrams of Pravachol, the highest dose when the study began. The patients' cholesterol fell within the levels specified by the national guidelines. But on Lipitor, the patients had a median L.D.L. level of 65, as compared with 95 for those who took Pravachol. (Although Pravachol is now available in an 80-milligram dose, experts say doubling the dose does not make much difference because it only reduces L.D.L. levels by an additional 6 percent.)
Within a month, the Lipitor patients started doing better than those taking Pravachol.
Dr. Eric J. Topol, a cardiologist at the Cleveland Clinic Foundation, called the findings a sea change, a term he said he had used only once before in his 20-year career.
"It's a big shake-up," Dr. Topol said. "It's a whole different viewpoint on what statins can do."
Even though the Pravachol patients would, until now, have been considered adequately treated, their rate of heart attacks, bypass surgery and angioplasty, symptoms like chest pain, and events like strokes and death was 26.3 percent, as compared with only 22.3 percent with Lipitor, a difference of 16 percent.
The death rate for Lipitor patients was 28 percent lower than for those taking Pravachol and the death rate from cardiovascular disease was 30 percent lower among the Lipitor patients.
Researchers said that they were particularly surprised because the study, sponsored by Bristol-Myers Squibb, was designed to show that Pravachol was just as effective as Lipitor. The researchers, at Harvard Medical School, specified in their contract with Bristol-Myers Squibb that they would publish the results no matter how they came out.
Heart disease experts complained that the study would not show any difference because it had only half the number of patients that would be needed and followed them for only half the time.
"A lot of people believed that lower is better," observed Dr. Daniel Rader, director of Preventive Cardiology at the University of Pennsylvania School of Medicine. "But no one thought that this would be the study to prove it."
Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, said that drug companies "never ever sponsor a trial like this that they think has a chance of going the wrong way." But, he added, "this trial backfired because in fact the differences between these two drugs are very profound."
The study was called Prove It, for Pravastatin or Atorvastatin Evaluation and Infection Therapy. But Dr. Topol said many heart disease researchers had joked that the study should be called "Prove What?"
At Bristol-Myers Squibb, the company's senior vice president of strategic and medical and external affairs, Dr. Andrew Bodnar, said, "I think we were all surprised." But, Dr. Bodnar added, "it's really really important information."
He emphasized that the findings applied only to patients like those in the study, who were hospitalized because a plaque in their coronary arteries had ruptured. When that happens, blood clots form and block blood flow to the heart. The result is sudden crushing chest pains.
Pfizer's vice president for cardiovascular products in the United States, Dr. Gary Palmer, said the results "are fantastic news" for patients like those in the study "and a reminder of how good a drug Lipitor is."
Dr. Bodnar added that it was hard to imagine that just lowering L.D.L. levels could start making a difference within a month.
"It strikes me as inescapable, given these results that there are other things at work as well," he said.
One possibility, he and others suggested, is that more intensive therapy has a greater effect in suppressing inflammation. When plaques are inflamed, they are more likely to burst open.
The study does not mean that doctors should abandon Pravachol, Dr. Bodnar said. While statins are considered very safe, and no patients in the study suffered serious or permanent harm, the Lipitor patients had more side effects.
Liver enzymes were elevated in 3.3 percent of them, as compared with 1.1 percent of Pravachol patients. When that happens, patients may have to reduce the dose of the drug or stop taking it. More Lipitor patients (3.3 percent) than Pravachol patients (2.7 percent) stopped taking their medication because of muscle aches or enzyme elevations.
Other cardiologists said the study's results applied to everyone at high risk, and some experts said they might apply to everyone whose cholesterol levels were elevated.
Dr. Christopher P. Cannon of Harvard Medical School, the study's lead author, said heart patients should leave the hospital with a high dose of a statin, something that rarely happens now. He added that the millions of Americans who have high L.D.L. levels but ignored them should do so no longer.
"Everyone needs to shift up one level in their intensity of cholesterol treatment," he said. "Currently, people will try a diet and say `Okay, okay, I've been cheating a little,' and their doctor will say, `Come back in six months,' " Dr. Cannon said. "Hopefully, this will be a wake-up call."
Dr. Eugene Braunwald, chairman of the Harvard Medical School group that conducted the study, said that people with L.D.L. levels over 100, whether or not they have symptoms of heart disease, are "accidents waiting to happen," and should get their levels down.
The study closely follows one by Pfizer reported at the American Heart Association' meeting in November and published last week in the Journal of the American Medical Association. That study, too, compared 40 milligrams of Pravachol to 80 milligrams of Lipitor in heart patients, looking at the rate that plaque grew in coronary arteries. Lipitor, the study found, halted plaque growth; Pravachol slowed but did not stop it.
But Bristol-Myers Squibb and some cardiologists cautioned that the Pfizer study, directed by Dr. Nissen, fell short of proof. The growth of plaque, they said, was not necessarily the same as a reduction in heart attacks and deaths. Without knowing what their own study would show, Bristol-Myers Squibb sent its sales force out to tell doctors to wait for its more definitive study before abandoning Pravachol.
Now, said Dr. Christie M. Ballantye, a professor of medicine at Baylor College of Medicine, it looks like the study's name is surprisingly apt.
"They did prove it," he said. "But I don't think they proved what they thought they would prove. It is remarkable."
source: http://query.nytimes.com/mem/tnt.html?tntget=2004/03/08/health/08CND-STAT.html&tntemail0=&pagewanted=print&position= 8mar04
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