Organ-specific bleeding patterns of anticoagulant therapy: lessons from clinical trials

Thomas Vanassche; Jack Hirsh; John W. Eikelboom; Jeffrey S. Ginsberg

doi:10.1160/th14-04-0346

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 112(05): 918-923
DOI: 10.1160/th14-04-0346

Theme Issue Article

Schattauer GmbH

Organ-specific bleeding patterns of anticoagulant therapy: lessons from clinical trials

Thomas Vanassche

¹Population Health Research Institute, Thrombosis and Atherosclerosis Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada

,

Jack Hirsh

¹Population Health Research Institute, Thrombosis and Atherosclerosis Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada

,

John W. Eikelboom

¹Population Health Research Institute, Thrombosis and Atherosclerosis Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada

,

Jeffrey S. Ginsberg

¹Population Health Research Institute, Thrombosis and Atherosclerosis Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada

› Author Affiliations

Abstract

Summary

Anticoagulants are effective at preventing and treating thrombosis, but can cause bleeding. For decades, vitamin K antagonists (VKAs) have been the only available oral anticoagulants. The development of non-VKA oral anticoagulants (NOACs), which inhibit either factor Xa or thrombin stoichiometrically, has provided alternatives to VKAs for several indications. The results of recent large-scale randomised controlled trials comparing NOACs with VKAs for the prevention of stroke in patients with non-valvular atrial fibrillation (AF) have produced some unexpected results. As a group, NOACs showed similar efficacy as warfarin, but a reduced risk of major bleeding. The reduction in bleeding with NOACs was greatest with intracranial hemorrhage. In contrast, the relative risk of gastro-intestinal bleeding was increased with some NOACs. In this review, we explore the potential mechanisms as well as the implications of these organ-specific bleeding patterns.

Keywords

Venous thrombosis - stroke prevention - thrombosis

Full Text

References

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 van Walraven C, Hart RG, Singer DE. et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. J Am Med Assoc 2002; 288: 2441-2448.
3 De Caterina R, Husted S, Wallentin L. et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013; 110: 1087-1107.
4 Connolly SJ, Eikelboom J, Joyner C. et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-817.
5 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
6 Giugliano RP, Ruff CT, Braunwald E. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093-2104.
7 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
8 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
9 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955-962.
10 Wallentin L, Lopes RD, Hanna M. et al. Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation. Circulation 2013; 127: 2166-2176.
11 Gallego P, Roldan V, Marin F. et al. Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation. Thromb Haemost 2013; 110: 1189-1198.
12 Wan Y, Heneghan C, Perera R. et al. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review. Circulation Cardiovasc Qual Outcom 2008; 1: 84-91.
13 Witt DM, Delate T, Hylek EM. et al. Effect of warfarin on intracranial haemorrhage incidence and fatal outcomes. Thrombosis Res 2013; 132: 770-775.
14 Piccini JP, Hellkamp AS, Lokhnygina Y. et al. Relationship between time in therapeutic range and comparative treatment effect of rivaroxaban and warfarin: results from the ROCKET AF trial. J Am Heart Assoc 2014; 3: e000521.
15 Gulati G, Hevelow M, George M. et al. International normalized ratio versus plasma levels of coagulation factors in patients on vitamin K antagonist therapy. Arch Pathol Lab Med 2011; 135: 490-494.
16 Dale B, Eikelboom JW, Weitz JI. et al. Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial haemorrhage and myocardial infarction?. J Thrombosis Thrombol 2013; 35: 295-301.
17 Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nature Rev Neurosci 2006; 7: 41-53.
18 Fisher MJ. Brain regulation of thrombosis and haemostasis: from theory to practice. Stroke 2013; 44: 3275-3285.
19 Poels MM, Vernooij MW, Ikram MA. et al. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke 2010; 41 (Suppl. 10) S103-S106.
20 Lee SH, Ryu WS, Roh JK. Cerebral microbleeds are a risk factor for warfarin-related intracerebral haemorrhage. Neurology 2009; 72: 171-176.
21 Ueno H, Naka H, Ohshita T. et al. Association between cerebral microbleeds on T2*-weighted MR images and recurrent haemorrhagic stroke in patients treated with warfarin following ischemic stroke. Am J Neuroradiol 2008; 29: 1483-1486.
22 Foerch C, Arai K, Jin G. et al. Experimental model of warfarin-associated intra-cerebral haemorrhage. Stroke 2008; 39: 3397-3404.
23 Illanes S, Zhou W, Heiland S. et al. Kinetics of hematoma expansion in murine warfarin-associated intracerebral haemorrhage. Brain Res 2010; 1320: 135-142.
24 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.
25 Lauer A, Pfeilschifter W, Schaffer CB. et al. Intracerebral haemorrhage associated with antithrombotic treatment: translational insights from experimental studies. Lancet Neurol 2013; 12: 394-405.
26 Desai J, Granger CB, Weitz JI. et al. Novel oral anticoagulants in gastroenterology practice. Gastrointest Endoscopy 2013; 78: 227-239.
27 Bathala MS, Masumoto H, Oguma T. et al. Pharmacokinetics, biotrans-formation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metabol Disp 2012; 40: 2250-2255.
28 Blech S, Ebner T, Ludwig-Schwellinger E. et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metabol Disp 2008; 36: 386-399.
29 Raghavan N, Frost CE, Yu Z. et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metabol Disp 2009; 37: 74-81.
30 Weinz C, Schwarz T, Kubitza D. et al. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metabol Disp 2009; 37: 1056-1064.
31 Eikelboom JW, Wallentin L, Connolly SJ. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123: 2363-2372.