A Dose-Determining Trial of Heparinase-I (Neutralase™) for Heparin Neutralization in Coronary Artery Surgery

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Abstract
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 μg/kg of open-label heparinase-I instead of protamine. Activated clotting time (ACT) and its difference from a contemporaneous heparin-free sample (ΔACT) 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 μg/kg, 21 received 7 μg/kg, 4 received two doses of 7 μg/kg, 8 received 10 μg/kg, and 4 received two doses of 10 μg/kg. Treatment groups did not differ demographically. Median ΔACT 9 min later was 11, 7, and 4 s for the 5, 7, and 10 μg/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.