A dose-determining trial of heparinase-I (Neutralase™) for heparin neutralization in coronary artery surgery

Heparinase-I, a specific heparin-degrading enzyme, may represent an alternative to protamine. We explored the dose of heparinase-I for efficacy and safety in patients undergoing coronary artery surgery. At the conclusion of cardiopulmonary bypass, subjects received 5, 7, or 10 mug/kg of open-label heparinase-I instead of protamine. Activated clotting time (ACT) and its difference from a contemporaneous heparin-free sample (Delta ACT) at 3 min before and 3, 6, and 9 min after heparinase-I determined reversal efficacy. After surgery, we recorded hourly chest tube drainage. Systemic and pulmonary arterial blood pressure and cardiac output measurements before and immediately after heparinase-I were used to evaluate hemodynamic safety. Coagulation measurements included anti-factor Xa and anti-factor IIa activities. Forty-nine patients from seven institutions participated: 12 received 5 mug/ kg, 21 received 7 mug/kg, 4 received two doses of 7 mug/ kg, 8 received 10 mug/kg, and 4 received two doses of 10 mug/kg. Treatment groups did not differ demographically. Median Delta ACT 9 min later was 11, 7, and 4 s for the 5,7, and 10 mug/kg groups, respectively. No adverse hemodynamic changes occurred with heparinase-I administration. The authors conclude that heparinase-I effectively restored the ACT after cardiopulmonary bypass. This effect appeared to be dose dependent.