Biotech Values

[DewDiligence]

Value of Cholesterol Targets Is Disputed

[“Treating to goal” is virtually an article of faith in the pharma industry; if this concept were to become discredited, the ramifications would be enormous.]

http://www.nytimes.com/2006/10/17/health/17chol.html

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October 17, 2006
By RONI RABIN

A provocative review paper published this month has raised questions about the aggressive cholesterol-lowering recommendations made two years ago by a government panel.

The panel, the National Cholesterol Education Program, urged patients at risk for heart disease to reduce sharply their harmful LDL cholesterol and to try to reach specific, very low levels.

Though the authors of the new paper, published in the Oct. 3 issue of Annals of Internal Medicine, endorse the use of cholesterol-lowering statins, they say there is not enough solid scientific evidence to support the target numbers for LDL cholesterol set forth by the government panel.

The authors’ argument challenges mainstream medical thinking and the consensus among most cardiologists that the lower the cholesterol is, the better.

Until 2004, an LDL cholesterol level of less than 130 milligrams a deciliter was considered low enough. But the updated guidelines recommend that high-risk patients reduce their level even more — to less than 100 — while patients at very high risk are given “the option” of reducing LDL cholesterol to less than 70. Patients often have to take more than one cholesterol-lowering drug to achieve those targets.

“This paper is not arguing that there is strong evidence against the LDL targets, but rather that there’s no evidence for them,” said Dr. Rodney A. Hayward, a study author, adding that this was largely because of the way clinical trials had been devised and carried out.

“If you’re going to say, ‘Take two or three drugs to get to these levels,’ you need to know you’re doing more benefit than harm,” said Dr. Hayward, who is director of the Veterans Affairs Center for Health Services Research and Development and a professor at the University of Michigan Medical School. He said he was particularly concerned because there was little long-term safety data about the drug combinations used to lower cholesterol.

Several scientists who participated in developing the panel’s guidelines acknowledged that the scientific evidence to support the goal recommendation of less than 70 was not as strong as it could be. But, they said, it is also a weaker recommendation.

“This is not a ‘Thou shalt,’ ” said Dr. James I. Cleeman, coordinator of the cholesterol education program. “It is not a hard and fast rule, and the evidence for it is not as strong.”

But, Dr. Cleeman said, there is “very very strong evidence” that patients who get their cholesterol under 100 benefit from a lower risk of coronary disease.

“There is tremendous evidence that LDL cholesterol causes heart disease; it’s not just along for the ride,” he said. “And no matter how we lower LDL — with drugs, a statin or other, surgery or diet or other means — the degree of lowering coronary risk is proportional to the degree of LDL lowering.”

“Do we know the final number that should be the LDL goal?” he asked. “That would be discussable.”

Clinical trials have demonstrated that statin use is beneficial and that high doses are more effective in patients at high risk than lower doses, the paper says. But statins have effects other than just lowering cholesterol, Dr. Hayward noted; they have anticlotting and anti-inflammatory effects, and the dose level may be more important than the LDL level achieved by the patient.

“As far as we know, statins are like aspirin,” he said. “Doctors tell patients to take an aspirin a day, but we don’t go back and check how much it thins their blood.”

Still, panels that develop guidelines cannot wait until all the scientific evidence is in, said Dr. David J. Gordon, special assistant for clinical studies at the National Heart, Lung and Blood Institute’s division of cardiovascular diseases. “They can’t meet and come out with a statement that says, ‘The evidence isn’t airtight, so we’ll give you recommendations in 10 years.’ ”

Dr. Gordon said the authors of the new paper had a point. “You could make the argument that if somebody has a heart attack, just give them a statin,” he said. “There is certainly an argument to be made for that.”

Dr. Sidney C. Smith Jr., a professor of medicine at the University of North Carolina who was involved in the updated guidelines and is a former president of the American Heart Association, said the trends in studies of LDL levels and heart disease “continue to suggest that lower is better.”

But, Dr. Smith said, “we don’t know, as you get into the lower levels of LDL, that the benefit continues.” He added, “That’s why we need additional studies.”

Dr. Hayward and the other authors of the review paper, Dr. Timothy P. Hofer and Dr. Sandeep Vijan, said they examined all the studies that assessed the relationship between LDL cholesterol and cardiovascular outcomes in patients with LDL levels less than 130. But, they wrote, they were unable to identify studies that provided evidence that achieving a specific LDL target level was important in and of itself, independent of other factors, and that studies that had tried to do so had major flaws.

Dr. Vincenza Snow, the director of clinical programs and quality of care for the American College of Physicians, wrote a paper in 2004 that reached similar conclusions.

“All the lipid-lowering trials that have been done have tested a dose of a statin as opposed to either another dose of a statin or another drug,” Dr. Snow said. “They have never designed a trial to treat to a target.” All this treating to a target is not supported by the evidence. The evidence supports putting someone on a certain dose of a statin.”

Patients respond differently to statins, with some achieving more success in cholesterol reduction than others, Dr. Snow said. But, she said, “our goal is not necessarily to get to a certain level of cholesterol, but to decrease heart attacks and strokes, and you can reduce that risk with a certain dose of statin.”
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