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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.

The other members of the Duke team were Mark Newman, M.D.,
and Barbara Philips-Bute, Ph.D.

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