Anticoagulation with dabigatran does not increase secondary intracerebral haemorrhage after thrombolysis in experimental cerebral ischaemia

Summary

Dabigatran etexilate (DE) has recently been introduced for stroke prevention in atrial fibrillation, but management of acute ischaemic stroke during therapy with DE is a challenge. Thrombolysis is contrain-dicated because of a presumed increased risk of intracerebral haemorrhagic complications. We studied in different ischaemia models whether DE increases secondary haemorrhage after thrombolysis. C57BL/6 mice were anticoagulated with high-dose DE or warfarin. After 2 hour (h) or 3 h transient filament MCAO, rt-PA was injected. At 24 h after MCAO, secondary haemorrhage was quantified using a macroscopic haemorrhage score and haemoglobin spectrophotometry. Post-ischaemic blood-brain-barrier (BBB) damage was assessed using Evans blue. To increase the validity of findings, the duration of anticoagulation was prolonged in mice (5 x DE over 2 days), and the effect of DE after thrombolysis was also examined in thromboembolic MCAO in rats. Pretreatment with warfarin resulted in significantly more secondary haemorrhage (mean haemorrhage score 2.6 ± 0.2) compared to non-anticoagulated animals (1.7 ± 0.3) and DE (9 mg/kg, 1.6 ± 0.3) in 2 h ischaemia. Also after a 3 h period of ischaemia, haemorrhage was more severe in animals anticoagulated with warfarin compared to 9 mg/kg DE and non-anticoagulated control. Prolonged or enteral dabigatran pretreatment led to identical results. Also, thrombolysis after thromboembolic MCAO in rats did not induce more severe bleeding in DE-treated animals. Mice pretreated with warfarin had higher BBB permeability and increased activation of matrix-metalloproteinase 9. In conclusion, DE does not increase the risk of secondary haemorrhage after thrombolysis in various rodent models of ischaemia and reperfusion. The implications of this finding for stroke patients have to be determined in the clinical setting.

Keywords

Cerebral ischaemia - oral anticoagulation - thrombolysis - haemorrhage

• References

• 1 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: 857-867.
• 2 Waldo AL, Becker RC, Tapson VF. et al. Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation. J Am Coll Cardiol 2005; 46: 1729-1736.
• 3 Garcia D, Libby E, Crowther MA. The new oral anticoagulants. Blood 2010; 115: 15-20.
• 4 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
• 5 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
• 6 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
• 7 Steiner T, Petersson J, Al-Shahi RSalman. et al. European research priorities for intracerebral haemorrhage. Cerebrovasc Dis 2011; 32: 409-419.
• 8 Watanabe M, Siddiqui FM, Qureshi AI. Incidence and management of ischaemic stroke and intracerebral haemorrhage in patients on dabigatran etexilate treatment. Neurocrit Care 2012; 16: 203-209.
• 9 Adams Jr. HP, del Zoppo G, Alberts MJ. et al. Guidelines for the early management of adults with ischaemic stroke: A guideline from the american heart association/american stroke association stroke council, clinical cardiology council, cardiovascular radiology and intervention council, and the atherosclerotic peripheral vascular disease and quality of care outcomes in research interdisciplinary working groups: The american academy of neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 2007; 115: e478-534.
• 10 Hacke W, Kaste M, Bluhmki E. et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischaemic stroke. N Engl J Med 2008; 359: 1317-1329.
• 11 Lees KR, Bluhmki E, von Kummer R. et al. Time to treatment with intravenous alteplase and outcome in stroke: An updated pooled analysis of ecass, atlantis, ninds, and epithet trials. Lancet 2010; 375: 1695-1703.
• 12 Wahlgren N, Ahmed N, Davalos A. et al. Thrombolysis with alteplase for acute ischaemic stroke in the safe implementation of thrombolysis in stroke-monitoring study (sits-most): An observational study. Lancet 2007; 369: 275-282.
• 13 Prabhakaran S, Rivolta J, Vieira JR. et al. Symptomatic intracerebral haemorrhage among eligible warfarin-treated patients receiving intravenous tissue plasminogen activator for acute ischaemic stroke. Arch Neurol 2010; 67: 559-563.
• 14 Pfeilschifter W, Spitzer D, Pfeilschifter J, Steinmetz H, Foerch C. Warfarin anticoagulation exacerbates the risk of haemorrhagic transformation after rt-pa treatment in experimental stroke: Therapeutic potential of pcc. PLoS One 2011; 06: e26087.
• 15 Sun L, Zhou W, Ploen R. et al. Rapid reversal of anticoagulation prevents excessive secondary haemorrhage after thrombolysis in a thromboembolic model in rats. Stroke 2011; 42: 3524-3529.
• 16 Illanes S, Zhou W, Schwarting S. et al. Comparative effectiveness of haemostatic therapy in experimental warfarin-associated intracerebral haemorrhage. Stroke 2011; 42: 191-195.
• 17 Zhou W, Schwarting S, Illanes S. et al. Haemostatic therapy in experimental intracerebral haemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011; 42: 3594-3599.
• 18 Longa EZ, Weinstein PR, Carlson S. et al. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989; 20: 84-91.
• 19 Sun L, Marti HH, Veltkamp R. Hyperbaric oxygen reduces tissue hypoxia and hypoxia-inducible factor-1 alpha expression in focal cerebral ischaemia. Stroke 2008; 39: 1000-1006.
• 20 Toomey JR, Valocik RE, Koster PF. et al. Inhibition of factor ix(a) is protective in a rat model of thromboembolic stroke. Stroke 2002; 33: 578-585.
• 21 Sun L, Zhou W, Heiland S. et al. A translationally relevant thromboembolic stroke model for the study of secondary haemorrhage after thrombolysis in rats. Brain Res 2011; 1368: 346-354.
• 22 Sun L, Zhou W, Mueller C. et al. Oxygen therapy reduces secondary haemorrhage after thrombolysis in thromboembolic cerebral ischaemia. J Cereb Blood Flow Metab 2010; 30: 1651-1660.
• 23 Pfeilschifter W, Bohmann F, Baumgarten P. et al. Thrombolysis with recombinant tissue plasminogen activator under dabigatran anticoagulation in experimental stroke. Ann Neurol 2012; 71: 624-633.
• 24 Illanes S, Zhou W, Heiland S. et al. Kinetics of hematoma expansion in murine warfarin-associated intracerebral haemorrhage. Brain Res 2010; 1320: 135-142.
• 25 Bederson JB, Pitts LH, Tsuji M. et al. Rat middle cerebral artery occlusion: Evaluation of the model and development of a neurologic examination. Stroke 1986; 17: 472-476.
• 26 Swanson RA, Morton MT, Tsao-Wu G. et al. A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 1990; 10: 290-293.
• 27 Choudhri TF, Hoh BL, Solomon RA. et al. Use of a spectrophotometric haemoglobin assay to objectively quantify intracerebral haemorrhage in mice. Stroke 1997; 28: 2296-2302.
• 28 Wang X, Lee SR, Arai K. et al. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med 2003; 10: 1038.
• 29 Bohmann F, Mirceska A, Pfeilschifter J. et al. No influence of dabigatran anticoagulation on haemorrhagic transformation in an experimental model of ischaemic stroke. PLoS One 2012; 07: e40804.
• 30 Lauer A, Cianchetti FA, Van Cott EM. et al. Anticoagulation with the oral direct thrombin inhibitor dabigatran does not enlarge hematoma volume in experimental intracerebral haemorrhage. Circulation 2011; 124: 1654-1662.
• 31 De Smedt A, De Raedt S, Nieboer K. et al. Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with dabigatran. Cerebrovasc Dis 2010; 30: 533-534.
• 32 Matute MC, Guillán M, García-Caldentey J. et al. Thrombolysis treatment for acute ischaemic stroke in a patient on treatment with dabigatran. Thromb Haemost 2011; 106: 178-179.
• 33 Casado INaranjo, Portilla-Cuenca JC, Jiménez PECaballero. et al. Fatal intracerebral haemorrhage associated with administration of recombinant tissue plasminogen activator in a stroke patient on treatment with dabigatran. Cerebrovasc Dis 2011; 32: 614-615.
• 34 Fang MC, Chang Y, Hylek EM. et al. Advanced age, anticoagulation intensity, and risk for intracranial haemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004; 141: 745-752.
• 35 Bleeding during antithrombotic therapy in patients with atrial fibrillation. The stroke prevention in atrial fibrillation investigators. Arch Intern Med 1996; 156: 409-416.
• 36 Rosand J, Eckman MH, Knudsen KA. et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral haemorrhage. Arch Intern Med 2004; 164: 880-884.
• 37 Steiner T, Rosand J, Diringer M. Intracerebral haemorrhage associated with oral anticoagulant therapy: Current practices and unresolved questions. Stroke 2006; 37: 256-262.
• 38 Cheng T, Petraglia AL, Li Z. et al. Activated protein C inhibits tissue plasminogen activator-induced brain haemorrhage. Nat Med 2006; 12: 1278-1285.