For the first time since statins have been regularly used, a large study has found that another type of cholesterol-lowering drug can protect people from heart attacks and strokes.
The finding can help millions at high risk of heart attacks who cannot tolerate statins or do not respond to them sufficiently. And it helps clarify the role of LDL cholesterol, the dangerous form. Some had argued that statins reduced heart attack risk not just by lowering LDL levels but also by reducing inflammation. The new study indicates that the crucial factor is LDL, and the lower the levels, the better.
The six-year study, reported Monday at the annual meeting of the American Heart Association, involved 18,000 people who had had heart attacks or episodes of chest pain so severe they went to a hospital. They were randomly assigned to take a statin or a combination of a statin and the alternative drug to further reduce LDL levels.
Both groups ended up with very low LDL levels — those taking the statin, simvastatin, had an average LDL of 69, and those taking simvastatin and the other drug, ezetimibe, or Zetia, in a combination pill sold as Vytorin, had an average LDL of 54. No clinical trial had ever asked what happened when LDL levels get below 70 because, said Dr. Robert Califf, a Duke cardiologist and the study chairman, "many people were nervous about going this low and imagined a lot of possible toxicities."
Statins lower LDL by preventing it from being made. Ezetimibe lowers LDL by preventing cholesterol from being absorbed in the gut.
The drugs were so effective that there were few cardiac events among the participants, but eventually a difference emerged. There were 6.4 percent fewer cardiac events — heart disease deaths, heart attacks, strokes, bypass surgeries, stent insertions and hospitalizations for severe chest pain — in those assigned to take Vytorin. The amount corresponded to what was predicted from the extra degree of cholesterol lowering with the combination drug.
Those results translate into 2,742 events in those taking simvastatin and 2,572 in those taking the combination drug. That means, said Dr. Christopher Cannon, a principal investigator and cardiologist at Brigham and Women's Hospital, that two out of every 100 people who would have had a heart attack or stroke by taking the statin avoided those outcomes by taking the combination drug.
And, Dr. Califf said, the study found no side effects from ezetimibe — no excess cancer, no muscle aches, no headaches. "It looks like placebo," he said.
The study was sponsored by Merck, the maker of Vytorin, but the investigators had the right to publish what they wanted, with final say over what they wrote.
"Fantastic," said Dr. Sekar Kathiresan of the Broad Institute and Massachusetts General Hospital who studies the genetics of heart disease but had no part in the study. "A truly spectacular result for patients."
Dr. Harlan M. Krumholz, a Yale cardiologist not associated with the study, said he wished there was a peer-reviewed journal article instead of a presentation of the results at a meeting — the data analysis was completed just last week — but, assuming the result holds up, "this is the result we were hoping for."
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At the same time, and by sheer coincidence, two other groups of researchers reported genetic studies that supported the trial's conclusions. One, led by Dr. Brian A. Ference of Wayne State University School of Medicine found that gene mutations mimicking the effect of ezetimibe and ones mimicking the effect of statins had the same effect on heart disease risk for a given reduction in cholesterol. The implication, he said, is that "lowering cholesterol with ezetimibe, or a statin, or both, should each lower the risk of heart disease by about the same amount."
The other, led by Dr. Kathiresan, examined mutations that disabled one copy of the cholesterol absorption gene, producing the same effect as ezetimibe. The result was a 50 percent reduction in cholesterol absorption — the same as produced by ezetimibe — and an LDL reduction of 12 milligrams per deciliter of blood, also the same amount as produced by ezetimibe. The mutation, which gave people the equivalent of a lifelong exposure to ezetimibe, reduced the heart attack rate by 50 percent.
The study's results are making many wonder about the latest cholesterol guidelines, which did not mention any drug other than a statin. And instead of providing goals for cholesterol levels, they simply advised those at high risk to take a statin.