Unanswered questions and research priorities to optimise stroke prevention in atrial fibrillation with the new oral anticoagulants

Graeme J. Hankey

doi:10.1160/TH13-09-0741

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 111(05): 808-816
DOI: 10.1160/TH13-09-0741

Theme Issue Article

Schattauer GmbH

Unanswered questions and research priorities to optimise stroke prevention in atrial fibrillation with the new oral anticoagulants

Graeme J. Hankey

¹School of Medicine and Pharmacology, The University of Western Australia, Nedlands, Perth, Australia

²Department of Neurology, Sir Charles Gairdner Hospital, Nedlands, Perth, Australia

› Author Affiliations

Abstract

Summary

This review article discusses the following, as yet unanswered, questions and research priorities to optimise patient management and stroke prevention in atrial fibrillation with the new direct oral anticoagulants (NOACs): 1. In patients prescribed a NOAC, can the anticoagulant effects or plasma concentrations of the NOACs be measured rapidly and reliably and, if so, can “cut-off points” between which anticoagulation is therapeutic (i.e. the “therapeutic range”) be defined? 2. In patients who are taking a NOAC and bleeding (e.g. intracerebral haemorrhage), can the anticoagulant effects of the direct NOACs be reversed rapidly and, if so, can NOAC-associated bleeding and complications be minimised and patient outcome improved? 3. In patients taking a NOAC who experience an acute ischaemic stroke, to what degree of anticoagulation or plasma concentration of NOAC, if any, can thrombolysis be administered safely and effectively? 4. In patients with a recent cardioembolic ischaemic stroke, what is the optimal time to start (or re-start) anticoagulation with a NOAC (or warfarin)? 5. In anticoagulated patients who experience an intracranial haemorrhage, can anticoagulation with a NOAC be re-started safely and effectively, and if so when? 6. Are the NOACs effective and safe in multimorbid geriatric people (who commonly have atrial fibrillation and are at high risk of stroke but also bleeding)? 7. Can dose-adjusted NOAC therapy augment the established safety and efficacy of fixed-dose unmonitored NOAC therapy? 8. Is there a dose or dosing regimen for each NOAC that is as effective and safe as adjusted-dose warfarin for patients with atrial fibrillation who have mechanical prosthetic heart valves? 9. What is the long-term safety of the NOACs?

Keywords

Clinical trials - direct antithrombin agents - coagulation inhibitors - stroke prevention

Full Text

References

References
1 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
2 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
3 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
4 Camm AJ, Lip GY, De Caterina R. et al. ESC Committee for Practice Guidelines-CPG; Document Reviewers. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association. Europace 2012; 14: 1385-1413.
5 Skanes AC, Healey JS, Cairns JA. et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012; 28: 125-136.
6 Ageno W, Gallus AS, Wittkowsky A. et al. Oral anticoagulant therapy: Anti-thrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e44S-88S.
7 Gong IY, Kim RB. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol 2013; 29: S24-33.
8 Reilly PA, Lehr T, Haertter S. et al. The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischaemic Stroke and Major Bleeding in Atrial Fibrillation Patients in the RE-LY Trial. J Am Coll Cardiol. 2013 Epub ahead of print.
9 PRADAXA (dabigatran etexilate mesylate). Product information. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT: Available at: http://www.boehringer-ingelheim.ca/content/dam/internet/opu/ca_EN/documents/humanhealth/product_monograph/Pradax-pm.pdf Accessed August 15, 2013.
10 Pare G, Eriksson N, Lehr T. et al. Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation 2013; 127: 1404-1412.
11 Xarelto (rivaroxaban). Product information. Bayer AG, Leverkusen. Germany: Available at: http://www.bayer.ca/files/Xarelto%20English%2012APR2013.pdf Accessed August 15, 2013.
12 Eliquis (apixaban). Product information. Bristol-Myers Squibb Co. Princeton, NJ: Available at: http://www.pfizer.ca/en/our_products/products/monograph/313 Accessed August 15, 2013.
13 Mani H, Kasper A, Lindhoff-Last E. Measuring the anticoagulant effects of target specific oral anticoagulants-reasons, methods and current limitations. J Thromb Thrombolysis 2013; 36: 187-194.
14 Harenberg J, Giese C, Marx S. et al. Determination of dabigatran in human plasma samples. Semin Thromb Haemost 2012; 38: 16-22.
15 Douxfils J, Dogné JM, Mullier F. et al. Comparison of calibrated dilute thrombin time and aPTT tests with LC-MS/MS for the therapeutic monitoring of patients treated with dabigatran etexilate. Thromb Haemost 2013; 110: 543-549.
16 Hawes EM, Deal AM, Funk-Adcock D. et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013; 11: 1493-1502.
17 Antovic JP, Skeppholm M, Eintrei J. et al. Evaluation of coagulation assays versus LC-MS/MS for determinations of dabigatran concentrations in plasma. Eur J Clin Pharmacol. 2013 Epub ahead of print.
18 Harenberg J, Erdle S, Marx S. et al. Determination of rivaroxaban in human plasma samples. Semin Thromb Haemost 2012; 38: 178-184.
19 Harenberg J, Marx S, Weiss C. et al. Report of the Subcommittee of Control of Anticoagulation on the determination of the anticoagulant effects of rivaroxaban. J Thromb Haemost 2012; 10: 1433-1436.
20 Douxfils J, Tamigniau A, Chatelain B. et al. Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban. Thromb Haemost 2013; 110: 723-731.
21 Douxfils J, Chatelain C, Chatelain B. et al. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 2013; 110: 283-294.
22 Stangier J, Feuring M. Using the HAEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23: 138-143.
23 Barrett YC, Wang Z, Frost C. et al. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104: 1263-1271.
24 Mani H, Rohde G, Stratmann G. et al. Accurate determination of rivaroxaban levels requires different calibrator sets but not addition of antithrombin. Thromb Haemost 2012; 108: 191-198.
25 Samama MM, Contant G, Spiro TE. et al. Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost 2012; 107: 379-387.
26 Hylek EM, Go AS, Chang Y. et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349: 1019-1026.
27 Odén A, Fahlén M, Hart RG. Optimal INR for prevention of stroke and death in atrial fibrillation: a critical appraisal. Thromb Res 2006; 117: 493-449.
28 Reilly PA, Lehr T, Haertter S. et al. The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischaemic Stroke and Major Bleeding in Atrial Fibrillation Patients in the RE-LY Trial. J Am Coll Cardiol. 2013 Epub ahead of print.
29 Schiele F, van Ryn J, Canada K. et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121: 3554-3562.
30 Lu G, DeGuzman FR, Hollenbach SJ. et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19: 446-451.
31 Portola Pharmaceuticals. Phase 2 Healthy Volunteer Study to Evaluate the Ability of PRT064445 to Reverse the Effects of Several Blood Thinner Drugs on Laboratory Tests. 2012 Available at: http://clinicaltrials.gov/show/NCT01758432 Accessed August 20, 2013.
32 Al-Shahi Salman R. Haemostatic drug therapies for acute spontaneous intracerebral haemorrhage. Cochrane Database Syst Rev 2009; 04: CD005951.
33 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.
34 Zhou W, Zorn M, Nawroth P. et al. Haemostatic therapy in experimental intracerebral haemorrhage associated with rivaroxaban. Stroke 2013; 44: 771-778.
35 Eerenberg ES, Kamphuisen PW, Sijpkens MK. et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: 1573-1579.
36 Dinkelaar J, Molenaar PJ, Ninivaggi M. et al. In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban. J Thromb Haemost 2013; 11: 1111-1118.
37 Marlu R, Hodaj E, Paris A. et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108: 217-224.
38 Rybinnik I, Mullen MT, Messe S. et al. Treatment of Acute Stroke in Patients on Dabigatran: A Survey of US Stroke Specialists. J Stroke Cerebrovasc Dis. 2013 Epub ahead of print.
39 Hart RG, Diener HC, Yang S. et al. Intracranial haemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke 2012; 43: 1511-1517.
40 Becattini C, Vedovati MC, Ageno W. et al. Incidence of arterial cardiovascular events after venous thromboembolism: a systematic review and a meta-analysis. J Thromb Haemost 2010; 08: 891-897.
41 Jauch EC, Saver JL, Adams Jr. HP. et al. Guidelines for the early management of patients with acute ischaemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44: 870-947.
42 Brown SG, Macdonald SP, Hankey GJ. Do risks outweigh benefits in thrombolysis for stroke?. Br Med J 2013; 347: f5215.
43 Whiteley WN, Slot KB, Fernandes P. et al. Risk factors for intracranial haemorrhage in acute ischaemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies. Stroke 2012; 43: 2904-2909.
44 Miedema I, Luijckx GJ, De Keyser J. et al. Thrombolytic therapy for ischaemic stroke in patients using warfarin: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2012; 83: 537-540.
45 Xian Y, Liang L, Smith EE. et al. Risks of intracranial haemorrhage among patients with acute ischaemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator. J Am Med Assoc 2012; 307: 2600-2608.
46 Mazya MV, Lees KR, Markus R. et al. for the SITS investigators. Safety of IV thrombolysis for ischaemic stroke in patients treated with warfarin. Ann Neurol. 2013 Epub ahead of print.
47 Chong CA, Chiu L. Dabigatran and acute stroke thrombolysis. Cerebrovasc Dis 2010; 30: 202.
48 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.
49 Casado Naranjo I, Portilla-Cuenca JC, Jimenez Caballero PE. et al. Fatal intra-cerebral haemorrhage associated with administration of recombinant tissue plasminogen activator in a stroke patient on treatment with dabigatran. Cerebrovasc Dis 2011; 32: 614-615.
50 Matute MC, Guillan M, Garcia-Caldentey J. et al. Thrombolysis treatment for acute ischaemic stroke in a patient on treatment with dabigatran. Thromb Haemos 2011; 106: 178-179.
51 Lee VH, Conners JJ, Prabhakaran S. Intravenous thrombolysis in a stroke patient taking dabigatran. J Stroke Cerebro Dis 2012; 21: 916. e11-12.
52 Marrone LC, Marrone AC. Thrombolysis in an ischaemic stroke patient on dabigatran anticoagulation: a case report. Cerebrovasc Dis 2012; 34: 246-247.
53 Sangha N, El Khoury R, Misra V. et al. Acute ischaemic stroke treated with intravenous tissue plasminogen activator in a patient taking dabigatran with radiographic evidence of recanalization. J Stroke Cerebrovasc Dis 2012; 08: 917. e5-e8.
54 Pfeilschifter W, Abruscato M, Hövelmann S. et al. Thrombolysis in a stroke patient on dabigatran anticoagulation: case report and synopsis of published cases. Case Rep Neurol 2013; 05: 56-61.
55 Jayathissa S, Gommans J, Harper P. Stroke thrombolysis in patients taking dabigatran. Intern Med J 2013; 43: 826-828.
56 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.
57 Sun L, Zhou W, Ploen R. et al. Anticoagulation with dabigatran does not increase secondary intracerebral haemorrhage after thrombolysis in experimental cerebral ischaemia. Thromb Haemost 2013; 110: 153-161.
58 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.
59 Gliem M, Hermsen D, van Rooijen N. et al. Secondary intracerebral haemorrhage due to early initiation of oral anticoagulation after ischaemic stroke: an experimental study in mice. Stroke 2012; 43: 3352-3357.
60 Moey AW, Koblar SA, Chryssidis S. et al. Endovascular therapy after stroke in a patient treated with dabigatran. Med J Aust 2012; 196: 469-471.
61 Müller P, Topakian R, Sonnberger M. et al. Endovascular thrombectomy for acute ischaemic stroke patients anticoagulated with dabigatran. Clin Neurol Neurosurg. 2013 Epub ahead of print.
62 Broderick JP, Palesch YY, Demchuk AM. et al. Interventional Management of Stroke (IMS) III Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013; 368: 893-903.
63 Ciccone A, Valvassori L, Nichelatti M. et al. SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischaemic stroke. N Engl J Med 2013; 368: 904-913.
64 Kidwell CS, Jahan R, Gornbein J. et al. MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischaemic stroke. N Engl J Med 2013; 368: 914-923.
65 Paciaroni M, Agnelli G, Micheli S. et al. Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke 2007; 38: 423-430.
66 Diener HC. Pro: “The novel oral anticoagulants should be used as 1st choice for secondary prevention in patients with atrial fibrillation”. Thromb Haemost 2013; 110: 493-495.
67 Stöllberger C, Finsterer J. Contra: “New oral anticoagulants should not be used as 1st choice for secondary stroke prevention in atrial fibrillation”. Thromb Haemost 2013; 110: 496-500.
68 Lindley RI, Wardlaw JM, Sandercock PA. et al. Frequency and risk factors for spontaneous haemorrhagic transformation of cerebral infarction. J Stroke Cerebrovasc Dis 2004; 13: 235-246.
69 Paciaroni M, Agnelli G, Corea F. et al. Early haemorrhagic transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results of a prospective multicenter study. Stroke 2008; 39: 2249-2256.
70 Lee JH, Park KY, Shin JH. et al. Symptomatic haemorrhagic transformation and its predictors in acute ischaemic stroke with atrial fibrillation. Eur Neurol 2010; 64: 193-200.
71 Alvarez-Sabín J, Maisterra O, Santamarina E. et al. Factors influencing haemorrhagic transformation in ischaemic stroke. Lancet Neurol 2013; 12: 689-705.
72 Lip GY, Nieuwlaat R, Pisters R. et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest 2010; 137: 263-272.
73 Olesen JB, Lip GY, Hansen ML. et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: a nationwide cohort study. Br Med J 2011; 342: d124.
74 Albertsen IE, Rasmussen LH, Overvad TF. et al. Risk of Stroke or Systemic Embolism in Atrial Fibrillation Patients Treated With Warfarin: A Systematic Review and Meta-analysis. Stroke 2013; 44: 1329-1336.
75 Phan TG, Koh M, Wijdicks EF. Safety of discontinuation of anticoagulation in patients with intracranial haemorrhage at high thromboembolic risk. Arch Neurol 2000; 57: 1710-1713.
76 Passero S, Burgalassi L, D’Andrea P. et al. Recurrence of bleeding in patients with primary intracerebral haemorrhage. Stroke 1995; 26: 1189-1192.
77 Hill MD, Silver FL, Austin PC. et al. Rate of stroke recurrence in patients with primary intracerebral haemorrhage. Stroke 2000; 31: 123-127.
78 Hanger HC, Wilkinson TJ, Fayez-Iskander N. et al. The risk of recurrent stroke after intracerebral haemorrhage. J Neurol Neurosurg Psychiatr 2007; 78: 836-840.
79 Azarpazhooh MR, Nicol MB, Donnan GA. et al. Patterns of stroke recurrence according to subtype of first stroke event: the North East Melbourne Stroke Incidence Study (NEMESIS). Int J Stroke 2008; 03: 158-164.
80 Zia E, Engström G, Svensson PJ. et al. Three-year survival and stroke recurrence rates in patients with primary intracerebral haemorrhage. Stroke 2009; 40: 3567-3573.
81 O’Donnell HC, Rosand J, Knudsen KA. et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral haemorrhage. N Engl J Med 2000; 342: 240-245.
82 Biffi A, Sonni A, Anderson CD. et al. International Stroke Genetics Consortium. Variants at APOE influence risk of deep and lobar intracerebral haemorrhage 2010; Ann Neurol 2010; 68: 934-943.
83 Biffi A, Anderson CD, Jagiella JM. et al. International Stroke Genetics Consortium. APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study. Lancet Neurol 2011; 10: 702-709.
84 Viswanathan A, Rakich SM, Engel C. et al. Antiplatelet use after intracerebral haemorrhage. Neurology 2006; 66: 206-209.
85 Berwaerts J, Webster J. Analysis of risk factors involved in oral-anticoagulant-related intracranial haemorrhages. QJM 2000; 93: 513-521.
86 Arakawa S, Saku Y, Ibayashi S. et al. Blood pressure control and recurrence of hypertensive brain haemorrhage. Stroke 1998; 29: 1806-1809.
87 Arima H, Anderson C, Omae T. et al. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) Collaborative Group. Effects of blood pressure lowering on intracranial and extracranial bleeding in patients on antithrombotic therapy: the PROGRESS trial. Stroke 2012; 43: 1675-1677.
88 Hylek EM, Evans-Molina C, Shea C. et al. Major haemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007; 115: 2689-2696.
89 Huhtakangas J, Löppönen P, Tetri S. et al. Predictors for recurrent primary intra-cerebral haemorrhage: a retrospective population-based study. Stroke 2013; 44: 585-590.
90 Reinecke H, Brand E, Mesters R, Schäbitz WR, Fisher M, Pavenstädt H, Breithardt G. Dilemmas in the management of atrial fibrillation in chronic kidney disease. J Am Soc Nephrol 2009; 20: 705-711.
91 Olesen JB, Lip GY, Kamper AL. et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012; 367: 625-635.
92 Lovelock CE, Cordonnier C, Naka H. et al. Antithrombotic drug use, cerebral microbleeds, and intracerebral haemorrhage: a systematic review of published and unpublished studies. Stroke 2010; 41: 1222-1228.
93 Biffi A, Halpin A, Towfighi A. et al. Aspirin and recurrent intracerebral haemorrhage in cerebral amyloid angiopathy. Neurology 2010; 75: 693-698.
94 Apostolakis S, Lane DA, Guo Y. et al. Performance of the HAEMORR(2)HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation: the AMADEUS (evaluating the use of SR34006 compared to warfarin or acenocoumarol in patients with atrial fibrillation) study. J Am Coll Cardiol 2012; 60: 861-867.
95 Majeed A, Kim YK, Roberts RS. et al. Optimal timing of resumption of warfarin after intracranial haemorrhage. Stroke 2010; 41: 2860-2866.
96 Hawryluk GW, Austin JW, Furlan JC. et al. Management of anticoagulation following central nervous system haemorrhage in patients with high thromboembolic risk. J Thromb Haemost 2010; 08: 1500-1508.
97 RESTART Trial. Available at: http://www.restarttrial.org/about.html Accessed September 3, 2013.
98 Gathier CS, Algra A, Rinkel GJ. et al. Long-Term Outcome after Anticoagulation-Associated Intracerebral Haemorrhage with or without Restarting Antithrombotic Therapy. Cerebrovasc Dis 2013; 36: 33-37.
99 Hylek EM, D’Antonio J, Evans-Molina C. et al. Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke 2006; 37: 1075-1080.
100 Fang MC, Go AS, Hylek EM. et al. Age and the risk of warfarin-associated haemorrhage: the anticoagulation and risk factors in atrial fibrillation study. J Am Geriatr Soc 2006; 54: 1231-1236.
101 Carroll K, Majeed A. Comorbidity associated with atrial fibrillation: a general practice-based study. Br J Gen Pract 2001; 51: 884-886. 889-891.
102 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.
103 Coresh J, Selvin E, Stevens LA. et al. Prevalence of chronic kidney disease in the United States. J Am Med Assoc 2007; 298: 2038-2047.
104 Berthold HK. New oral anticoagulants for the prevention of stroke. Open questions in geriatric patients. Z Gerontol Geriatr 2012; 45: 498-504.
105 Eikelboom JW, Connolly SJ, Brueckmann M. et al. the RE-ALIGN Investigators. Dabigatran versus Warfarin in Patients with Mechanical Heart Valves. N Engl J Med. 2013 Epub ahead of print.
106 Kaeberich A, Reindl I, Raaz U. et al. Comparison of unfractionated heparin, low-molecular-weight heparin, low-dose and high-dose rivaroxaban in preventing thrombus formation on mechanical heart valves: results of an in vitro study. J Thromb Thrombolysis 2011; 32: 417-425.
107 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.
108 Mant J, Hobbs FD, Fletcher K. et al. BAFTA investigators. Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007; 370: 493-503.
109 Connolly SJ, Wallentin L, Ezekowitz MD. et al. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation 2013; 128: 237-243.
110 Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013; 368: 1272-1274.
111 Larsen TB, Rasmussen LH, Skjøth F. et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013; 61: 2264-2273.
112 Sørensen R, Gislason G, Torp-Pedersen C. et al. Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study. Br Med J Open. 2013 Epub ahead of print.
113 Kakkar AK, Mueller I, Bassand JP. et al. International longitudinal registry of patients with atrial fibrillation at risk of stroke: Global Anticoagulant Registry in the FIELD (GARFIELD). Am Heart J 2012; 163: 13-19. e1.