Common Heart Surgery Drug Potentially Dangerous

NEW ORLEANS - Protamine, a drug used for more than 40 years immediately after coronary artery bypass surgery to return thinned blood to its normal state, has been shown to have more potential negative side effects than previously appreciated, according to Duke University Medical Center researchers.

Although they found that small blood pressure changes that often occur with protamine's use are associated with increased mortality, they do not advocate any change in the clinical use of the drug. However, they do emphasize that their findings should spur development of alternatives for protamine.

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

Since protamine's approval in the early 1960s, no drug has been approved by the Food and Drug Administration (FDA) to reverse the properties of heparin.

"Without protamine to effectively reverse the properties of heparin, bypass surgery would not have reached the successful point where it is today," said Duke anesthesiologist Ian Welsby, M.D., who presented the results of the Duke study today (March 25, 2003) at the 77th Clinical and Scientific Congress of the International Anesthesia Research Society.

"We have long known that an extremely small proportion of bypass patients have severe allergic reactions to protamine, including sharp blood pressure changes and cardio-vascular collapse," Welsby continued. "We, however, wanted to see if smaller changes in blood pressure in response to protamine were related to any adverse effect on the outcomes of these patients."

Duke anesthesiologists have developed a system that continually records blood pressures of patients during and after surgery. For this study, they retrospectively analyzed the data on 6,921 patients who underwent bypass surgery at Duke. They studied the minute-by-minute fluctuations in blood pressure for the 30 minutes after the administration of protamine and compared them to the blood pressure immediately before the protamine dose. They then correlated the degree of blood pressure change with the incidence of patient deaths while still in the hospital.

"We found a significant association between drops in pressure and mortality," Welsby said.

Specifically, 19 percent of the patients had average blood pressure drops of 20 percent or more during the 30-minute period, and this was significantly associated with in-hospital death, Welsby said. Furthermore, each incremental decrease in blood pressure, as defined in the study, translated into an additional 30 percent greater chance of in-hospital death.

"While 1 to 5 percent of patients will exhibit an allergic reaction to protamine, we showed that smaller reactions are much more common, and that protamine, independent of other factors, is associated with a higher risk of mortality," Welsby said.

In addition to its effects on blood pressure, protamine can also depress heart function, activate certain immune responses, and lead to pulmonary hypertension. It has a high positive electrical charge, while heparin has a high negative charge, so they "cancel" each other out, permitting the body to clear the combined agents quickly.

"As much as protamine has helped treat patients with coronary artery disease, these results demonstrate that blood pressure changes related to protamine once considered minor may be associated with more complications than we thought," said Duke anesthesiologist Mark Stafford-Smith, M.D., senior member of the research team.

"People are beginning to recognize that while protamine certainly has its benefits, it does have potential downsides as well," Stafford-Smith continued. "However, 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."

Both Welsby and Stafford-Smith agree more research is needed. In light of these findings it might be time to intensify the search for a potential alternative to protamine, or better understand the mechanisms of its action, they said.

The study was funded by Biomarin Pharmaceuticals, Novato, Calif., which is developing a drug to potentially reverse the anticoagulation properties of heparin. Stafford-Smith is the principal investigator of an ongoing Phase III trial for the new agent, which works by "cutting" the heparin molecule into small inactive fragments.

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