Mar. 9, 1999 NEW ORLEANS-- Just how do doctors figure out if a new drug for heart disease is effective? Most trials look at whether the drug reduces the number of deaths and heart attacks in group of patients taking it, compared to patients who don't.
But what if the drug turns a large heart attack, one that could potentially kill the patient, into a smaller heart attack that does less damage? Under the traditional way of testing medicines, the drug wouldn't be deemed effective, because it didn't reduce the number of heart attacks.
And that's far from an academic matter, say researchers at Duke University Medical Center, who argue that the way cardiology trials are conducted should be changed.
"Just counting the number of heart attacks may be the wrong way to measure a drug's effectiveness," says Dr. John Alexander, who prepared the results of his analysis for presentation Sunday at the annual scientific sessions of the American College of Cardiology.
"The fact that we may be able to reduce the size of myocardial infarction (MI) without necessarily reducing the incidence may be very important clinically," said Alexander, a cardiologist at the Duke Clinical Research Institute (DCRI).
Alexander based his findings on a close examination of data from the recently completed 10,948-patient PURSUIT trial of the drug eptifibatide (Integrilin), which was funded by the drug manufacturer, COR Therapeutics Inc., of San Francisco. He and his team found that while the drug slightly reduced the number of myocardial infarctions, it also reduced the size of MIs, possibly by converting larger ones into smaller ones.
Like many studies in heart disease, PURSUIT used the occurrence of an MI -- the death of heart muscle from the sudden loss of blood supply -- as a key part of the principal measurement of whether or not the patient benefited from the therapy. Since not all MIs are clear-cut, however, a committee of cardiologists not involved in the patient's care must determine whether or not an MI actually occurred, based on a review of enzyme levels, ECG tests and other clinical data.
After the trial was completed, the Duke researchers later went back and looked at the peak blood levels of an enzyme called creatine kinase-MB (CK-MB), which is released into the bloodstream by dying heart muscle cells. As more heart muscle dies, more CK-MB enters the bloodstream, making it a biochemical marker for the size of an MI.
They found that patients who received the drug eptifibatide tended to have smaller MIs, as measured by peak levels of CK-MB. More than 35 percent of patients who received eptifibatide had the lowest levels of CK-MB, compared to 29 percent for a placebo. At the highest levels of CK-MB in the blood, 38 percent received eptifibatide, 44 percent got the placebo. According to Alexander, several studies are in the planning stages at the DCRI incorporating the use of continuous endpoints that take into account MI size. The DCRI, which is made up of more than 700 cardiologists and other researchers, maintains the world's largest databank of cardiovascular disease. The fact that fewer people are dying from heart attacks during clinical trials places certain limitations on researchers, he said. For a study to have statistical significance using death as its only endpoint, more than 50,000 patients would need to be enrolled.
"Since this is not very practical, we have essentially been using MI as a surrogate for death," Alexander said. "This enables us to study the effects of drugs using a more manageable number of patients to achieve statistical significance."
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