ATLANTA -- After reviewing the data from four of the largest multi-center randomized clinical trials of new heart disease drugs, Duke University Medical Center researchers have found significant differences in heart attack rates reported by physicians who actually provide the patient care and the physician committees responsible for later determining whether a heart attack actually occurred.
The Duke researchers said these differences, which occurred in up to one-fifth of the cases, increased the perceived benefits of the drug being tested in one trial and decreased the perceived benefits of the drug in the other three trials. While these differences of opinion had no effect on patient care, the researchers believe that the results should help them refine the way future trials are designed and carried out.
Most large clinical trials use clinical events committees (CEC) to review case records to ensure that all the physicians at participating hospitals follow the same guidelines. CECs are usually composed of cardiology fellows and attending cardiologists and their rulings are final.
Differences of opinion have become common as large multi-center trials use more subtle measurements, or endpoints, to determine the effectiveness of a particular treatment.
"It is very important for us involved in clinical trial design to understand why such significant differences between the physicians and the committees exist, and to make changes," said Duke cardiologist Dr. Kenneth Mahaffey. "Because physicians treat their patients differently from hospital to hospital, and from country to country in clinical trials, we need to have a systematic way of reporting heart attacks in these patients."
In the 1980s, death was a common measurement for clinical trials, an endpoint that leaves no room for disagreement among physicians, the researchers said.
"However, in the 1990s, we started using such endpoints as recurrent infarction (heart attack) to determine whether or not a drug was effective," Mahaffey said. "While most cases of reinfarction are obvious, in up to about 20 percent of the cases, there were differences of opinion whether or not reinfarction actually occurred in the clinical trials, which is similar to what physicians see every day in practice."
Mahaffey prepared the results of the Duke study for presentation Tuesday at the 47th annual scientific session of the American College of Cardiology.
The four trials reviewed by the Duke researchers were called EPIC, IMPACT-II, GUSTO-IIb and PURSUIT. Researchers from the Cleveland Clinic coordinated the EPIC trial, the other three were coordinated by the Duke Clinical Research Institute, of which Mahaffey is a member.
In the EPIC trial, for example, physicians in the field reported that 9 percent of their patients has suffered a reinfarction, but upon further review by the CEC, the rate turned out to be 8.3 percent. For the other three trials, the effect was reversed:
- IMPACT-II: Physicians reported 5.5 percent rate; the CEC 9.2 percent.
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GUSTO-IIb: Physicians reported 8.4 percent; the CEC 8.9 percent
- PURSUIT: Physicians reported 8 percent; the CEC 14.2 percent.
As an example of how disagreements could occur, Mahaffey cited the case of a patient who is rushed to an emergency room with a heart attack and is enrolled in a trial. A few hours later, the patient experiences some chest pain with some EKG and blood enzyme changes.
"Did that patient have another heart attack? Not all cardiologists would agree," Mahaffey said. "So we must come up with ways we formulate our definitions to ensure that everyone is following the same guidelines. We're now looking at changes that can be applied worldwide in the trials we're now designing."
While the outcomes of these trials are important to the companies whose drugs are being tested, they have no influence once the trial begins.
"The companies, of course, have input in the overall design of the actual trial, but once it begins, CECs are completely independent. As a matter of policy, CEC members are blinded to the treatment assigned to each patient."
The study was supported by the Duke Clinical Research Institute. Joining Mahaffey in the study were, from Duke, Dr. Barbara Tardiff, Dr. Christopher Granger, Dr. Kerry Lee, Dr. Robert Harrington and Dr. Robert Califf. Dr. Eric Topol, from the Cleveland Clinic, also participated.