Alain Bel1, Wasseem Borik1, Simon Davidson2, Jean-Marie Helies3, Lev Stimmer4, Stephen Fremes5, Steven Zelenkofske6, Christopher Rusconi6, John Alexander7, David Alexander8, Philippe Menasché9, John Pepper10. 1. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou Department of Cardiovascular Surgery, Paris, France. 2. Department of Haematology, Royal Brompton Hospital, London, UK. 3. Molecular Imaging Research Center, Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France. 4. Molecular Imaging Research Center, Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France CEA-INSERM U986, Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France. 5. Department of Cardiovascular Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. 6. Regado Biosciences, Basking Ridge, NJ, USA. 7. Cardiovascular Thrombosis, Duke Clinical Research Institute, Durham, NC, USA. 8. Department of Cardiothoracic Surgery, Royal Brompton Hospital, London, UK. 9. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou Department of Cardiovascular Surgery, Paris, France Université Paris Descartes, Sorbonne Paris Cité; INSERM U 970, Paris, France. 10. Department of Cardiothoracic Surgery, Royal Brompton Hospital, London, UK j.pepper@rbht.nhs.uk.
Abstract
OBJECTIVES: Heparin and protamine are standard for anticoagulation and reversal for cardiopulmonary bypass (CPB). The REGADO biosciences protocol 1 (REG1) anticoagulant system, consisting of the Factor IXa (FIXa)-inhibitor pegnivacogin and its reversal agent (anivamersen), has been studied in patients undergoing coronary catheterization and in CPB in sheep and pigs. Prior to first human use in CPB, we wanted to test the safety and efficacy of REG1 in a primate model. METHODS: Fourteen baboons undergoing 2 h of CPB followed by 1 h of reperfusion were studied. Three received heparin/protamine and 11 received 1 of 2 doses of pegnivacogin followed by anivamersen. Thrombin-generating capacity was tested in additional in vitro experiments. RESULTS: Targeted drug levels and near-complete FIXa inhibition were achieved. Bypass was run uneventfully in all animals without any clotting in the circuit and bleeding was minimal in the two groups. However, in contrast to heparin-treated baboons, those receiving pegnivacogin/anivamersen displayed thrombi in the bypass cannulae upon cannulation and kidney cortical infarcts. Inter-species comparisons revealed that in the presence of high levels of FIXa inhibition, tissue factor-mediated thrombin generation in baboons was much higher than that in other species. CONCLUSIONS: These data highlight the limitations of the baboon model for assessing factor-specific coagulation inhibitors during CPB. The justification for Phase 1 human studies using REG1 for CPB is unclear.
OBJECTIVES:Heparin and protamine are standard for anticoagulation and reversal for cardiopulmonary bypass (CPB). The REGADO biosciences protocol 1 (REG1) anticoagulant system, consisting of the Factor IXa (FIXa)-inhibitor pegnivacogin and its reversal agent (anivamersen), has been studied in patients undergoing coronary catheterization and in CPB in sheep and pigs. Prior to first human use in CPB, we wanted to test the safety and efficacy of REG1 in a primate model. METHODS: Fourteen baboons undergoing 2 h of CPB followed by 1 h of reperfusion were studied. Three received heparin/protamine and 11 received 1 of 2 doses of pegnivacogin followed by anivamersen. Thrombin-generating capacity was tested in additional in vitro experiments. RESULTS: Targeted drug levels and near-complete FIXa inhibition were achieved. Bypass was run uneventfully in all animals without any clotting in the circuit and bleeding was minimal in the two groups. However, in contrast to heparin-treated baboons, those receiving pegnivacogin/anivamersen displayed thrombi in the bypass cannulae upon cannulation and kidney cortical infarcts. Inter-species comparisons revealed that in the presence of high levels of FIXa inhibition, tissue factor-mediated thrombin generation in baboons was much higher than that in other species. CONCLUSIONS: These data highlight the limitations of the baboon model for assessing factor-specific coagulation inhibitors during CPB. The justification for Phase 1 human studies using REG1 for CPB is unclear.
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