Dr. Fayad part of stroke prevention trial published in NEJM

Pierre Fayad, M.D.

UNMC’s Pierre Fayad, M.D., was the local principal investigator on the largest clinical trial ever conducted on stroke patients, the PROFESS Study. Results from the study are published in two separate articles in the current edition of the New England Journal of Medicine.

The trial — which was held at 695 medical centers in 35 countries and involved more than 20,000 patients — was sponsored by the pharmaceutical company, Boehringer Ingelheim. It evaluated the effectiveness of two drugs — Aggrenox and telmisartan (an angiotensin receptor-blocker) — for secondary stroke prevention. Patients who experience a stroke or a transient ischemic attack (TIA) are at highest risk to have another stroke.

Preventing a second stroke is critical to improving outcomes and preventing disability. Stroke is the third leading cause of death after heart disease and cancer, and a leading cause of disability in adults. More than 780,000 strokes happen every year in the United States, with one stroke affecting someone every 40 seconds. There is a stroke-related death every three to four minutes.

In the case of Aggrenox, an anti-platelet drug combining aspirin and extended-release dipyridamole, Dr. Fayad said the study found it to be no more effective at preventing stroke than clopidogrel, an anti-platelet drug commonly used in heart disease and stroke prevention.

“In that regard, the results came out as a complete surprise to what the study was expected to demonstrate,” said Dr. Fayad, Reynolds Centennial Professor and chairman of neurological sciences at UNMC and director of the Stroke Center at The Nebraska Medical Center. “That is where we all derive value and benefit from well designed and performed clinical trials. You start with an idea and you test it in a clinical trial, but can never predict where the results will take you.

NEJM articles Click here to see the NEJM article on the study regarding Aggrenox and here to see the article regarding telmisartan.

“In this case, even though the idea behind the study was proven wrong, acquiring that knowledge will empower physicians in better directing and deciding on the treatment of their patients to prevent stroke.”

Stroke experts became intrigued with Aggrenox after it significantly outperformed aspirin in terms of secondary stroke prevention in two independent clinical trials. In an earlier trial, clopidogrel — which also is known commercially as Plavix — proved only slightly more effective than aspirin in preventing strokes.

This led many experts to assume that Aggrenox should greatly outperform Clopidogrel in terms of stroke prevention.

“It’s like the Cubs beating the Yankees 3-2, and then the Dodgers beating the Yankees 6-2,” Dr. Fayad said, “The logic would lead many people to believe that the Dodgers would then beat the Cubs because they had beaten a common opponent worse than the Cubs did.”

But the results of the latest trial showed these logical assumptions to be wrong.

“This trial shows the previous assumptions about Aggrenox’s superiority did not hold up to the test and that maybe other factors were at play in the trials comparing these drugs to aspirin,” Dr. Fayad said.

The trial also looked at the role the anti-hypertension drug telmisartan may play in stroke prevention. Scientific experiments suggested that such drugs can help maintain the inner lining the blood vessels regardless of treating other factors such as hypertension. Investigators wondered whether the drug could be used to reduce strokes even if the patient didn’t have elevated blood pressures.

“Even though the idea behind the study was proven wrong, acquiring that knowledge will empower physicians in better directing and deciding on the treatment of their patients to prevent stroke.” Pierre Fayad, M.D.

In a special design, and in addition to comparing Aggrenox to clopidogrel, patients enrolled in this study also took telmisartan or placebo regardless of whether they had high-blood pressure or not. The results were disappointing in the absence of significant stroke risk reduction by telmisartan.

Toward the end of the study, there was a trend for a decreased risk of stroke, heart attacks and diabetes in patients who took telmisartan, but the differences were not significant enough to draw meaningful conclusions about such benefits, Dr. Fayad said.

This could have been because not enough patients were tested or that the trial did not follow patients long enough on the treatment to show the drug’s true impact, he said.

“Although this trial didn’t seem to indicate that taking any of the drugs we tested was better than clopidogrel or placebo at preventing strokes, the trial did open up new ideas and questions about stroke prevention that may lead to further trials and advances in the field,” Dr. Fayad said.

All faculty members in the UNMC Department of Neurological Sciences were subinvestigators in the medical center portion of the study, which was coordinated locally through the Clinical Trials Office at the Nebraska Medical Center by Mary Adolphson and her colleagues.