Methylene blue, hexadimethrine, vancomycin, and heparinase I are among drugs tested for heparin neutralization [115, 117, 118]. None of these drugs has proved equivalent to protamine in its safety pro le for reversal of heparin after CPB. One of these drugs, heparinase I, was compared with protamine in a multi- center, randomized, prospective trial; heparinase I had an inferior safety pro le after reversal of heparin at the end of CPB that was a result of increased transfusion and prolonged hospital stay in the heparinase group compared with the protamine group [118]. At this time, protamine is considered the gold standard for reversal of heparin anticoagulation. If protamine cannot be used, there are not enough data to make a recommendation regarding safety and ef cacy of any of the alternative heparin reversal agents. Class IIb Recommendation  Anticoagulation reversal when using heparin alter- natives and direct thrombin inhibitors: For patients requiring anticoagulation with bivalirudin who have excessive bleeding after CPB, a combination of modi ed ultra ltration, hemodialysis, and the administration of recombinant factor VIIa with blood product replacement may be considered to improve hemostasis in these extreme situations. (Level of Evidence C) Conclusion The ideal anticoagulation strategy for cardiac surgery with CPB in patients who cannot take heparin does not exist. Heparin and protamine remain the gold standard for anticoagulation therapy. A small subset of patients requires heparin alternatives for the conduct of CPB. Bivalirudin seems to offer the safest heparin alternative in this setting. This drug has a short half-life of approxi- mately 25 minutes. Nonetheless, coagulopathy occurs in bivalirudin-treated patients. There is no well-de ned reversal agent for bivalirudin, and patients with coagul- opathy and excessive bleeding require unusual in- terventions for hemorrhage control. 