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DURHAM, N.C. -- The results of an international clinical trial led by Duke University Medical Center researchers has shown that a new drug is not a suitable replacement for protamine, a drug that has been used for more than 40 years after coronary artery bypass surgery to return thinned blood to its normal state.

While protamine is effective in reversing the blood-thinning properties of heparin, recent studies have shown that its use can cause changes in blood pressure which have been linked to increased mortality in some patients. In addition to its negative effects on blood pressure, protamine can also depress heart function, activate certain immune responses, and lead to pulmonary hypertension, the researchers said. However, they emphasized, the drawbacks of protamine do not compromise the overall success of heart bypass surgery, and patients should not be overly concerned by those drawbacks.

The latest candidate alternative to protamine is heparinase I, a compound naturally produced by Flavobacterium heparinum, a bacterium commonly found in soil and water. The bacterial enzyme from which heparinase I is derived deactivates heparin through a mechanism different than protamine.

However, the current Phase IIB/IIIA safety and efficacy trial conducted at 47 sites in the U.S, Canada and Germany, was halted early because patients receiving heparinase I had higher incidences of negative side effects, such as bleeding and infections. The trial was halted after 167 of a planned 600 patients were enrolled.

The results of the trial were published in the August, 2005, issue of the journal Anesthesiology.

"The trial was designed to determine if this new drug could work as well as protamine without its known side effects," said Mark Stafford-Smith, M.D., Duke cardiovascular anesthesiologist and lead author of the study. "However, after reviewing the safety profiles during the trial, the data safety monitoring board decided to stop the trial.

"The design of the trial was such that it not only allowed us to spot problems early in the process but gave us the confidence in our decision that heparinase I would not be a suitable replacement for protamine," Stafford-Smith continued. "However, we do need to continue our efforts to develop an effective alternative."

Protamine, a drug purified from salmon sperm, is given to patients intravenously immediately after coronary bypass surgery to counteract the effects of the anticoagulant heparin, which is infused during the procedure. Heparin prevents clots from forming in the heart-lung machine, which oxygenates and pumps blood for the body while the heart is stopped for surgery.

Since protamine's emergence in the early 1960s, no drug has been approved by the Food and Drug Administration (FDA) to reverse the properties of heparin. In fact, according to Stafford-Smith, if protamine was a newly developed drug entering today's approval process, it would not receive FDA approval.

"Patients receiving heparinase I had more postoperative bleeding complications, were more likely to have anemia and needed more transfusions than patients who received protamine," Stafford-Smith said. "Additionally, patients who received heparinase I were more likely to have longer hospital stays or experience a serious adverse event, such as bleeding or infection."

The trial was developed and coordinated by the Global Perioperative Research Organization (GPRO), a joint program of the International Anesthesia Research Society and the Duke Clinical Research Institute (DCRI). This is the first clinical trial completed by GPRO, which is directed by Mark Newman, M.D., chairman of anesthesiology at Duke and Lee Fleisher, M.D., chairman of anesthesiology at the University of Pennsylvania.

"The results of this study clearly demonstrate that more research is needed to develop a protamine alternative," Newman said. "As in the use of all medications, there must be judgments made about the risks and benefits. Because of the limited alternatives available to us at this point, the benefits of protamine still exceed the risks, at least until we find something better."

One of the strengths of heparinase I trial, both Stafford-Smith and Newman pointed out, was the use of human simulators -- a "dummy" human that reacts as humans would while undergoing surgery -- to train clinical trial workers before the trial began. Previous studies at Duke using human simulators have shown that clinical trial coordinators felt more confident in their abilities and thus had a much shorter "learning curve" at the beginning of trial.

"Because of this advanced training, the trial coordinators are more at ease and less likely to make mistakes," Newman continued. "As a result, patients participating in the trial are safer and the quality of data we receive is more consistent, which leads to better trial results."

GPRO is currently coordinating six clinical trials using this methodology.

While the search for a replacement for protamine will continue, the researchers do not want to needlessly worry patients who are considering heart surgery.

"We do not want people to become overly alarmed – bypass surgery has been incredibly successful in improving the quantity and quality of life for heart disease patients," Stafford-Smith said. "Protamine has played a role in that success."

The trial was funded by the developer of heparinase I., BioMarin Pharmaceuticals, Novato, Calif. Stafford-Smith and Newman do not have financial interests in BioMarin.

In addition to Stafford-Smith and Newman, Duke members of the team were Ian Welsby, M.D., Linda Barber, Jasmine Mathias, and James Rochon, Ph.D. Other team members were Edward Lefrak, M.D., Inova Fairfax Hospital, Virginia; Anjum Qazi, M.D., Washington Adventist Hospital, Maryland; Andreas Hoeft, M.D., University of Bonn, Germany; and Alejandro Dorenbaum, M.D., BioMarin.