Four nonvitamin K antagonist oral anticoagulants (NOACs) are approved for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF).
Aims
In this review, we assemble available evidence for the best management of ischemic and hemorrhagic stroke patients in the context of NOAC use.
Summary of review
NOACs provide predictable anticoagulation with fixed dosages. The direct thrombin inhibitor dabigatran and direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban are all noninferior to warfarin for the prevention of ischemic stroke and systemic embolism and are associated with reduced incidence of intracranial hemorrhage. While these agents offer treatment options for NVAF patients, they also present challenges specific to the clinician managing cerebrovascular disease patients.
Conclusions
We summarize available evidence and current approaches to the initiation, dosing, monitoring and potential reversal of NOACs in stroke patients.
ConnollySJEzekowitzMDYusufS. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med2009; 361: 1139–1151.
2.
PatelMRMahaffeyKWGargJ. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med2011; 365: 883–891.
3.
GrangerCBAlexanderJHMcMurrayJJ. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med2011; 365: 981–992.
4.
GiuglianoRPRuffCTBraunwaldE. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med2013; 369: 2093–2104.
5.
FurieKLGoldsteinLBAlbersGW. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke2012; 43: 3442–3453.
6.
HeidbuchelHVerhammePAlingsM. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace2015; 17: 1467–1507.
7.
DienerHCConnollySJEzekowitzMD. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol2010; 9: 1157–1163.
8.
EastonJDLopesRDBahitMC. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol2012; 11: 503–511.
9.
HankeyGJPatelMRStevensSR. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol2012; 11: 315–322.
10.
KernanWNOvbiageleBBlackHR. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke2014; 45: 2160–2236.
11.
MacleLCairnsJAAndradeJG. The 2014 Atrial Fibrillation Guidelines Companion: a practical approach to the use of the Canadian Cardiovascular Society Guidelines. Can J Cardiol2015; 31: 1207–1218.
12.
CammAJLipGYDe CaterinaR. 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. Eur Heart J2012; 33: 2719–2747.
13.
JanuaryCTWannLSAlpertJS. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol2014; 64: e1–e76.
14.
ELIQUIS® (apixaban) tablets for oral use. Full prescribing information. Princeton, NJ, USA/NY, NY, USA: Bristol-Myers Squibb Company/Pfizer Inc, 2015.
SAVAYSA™ (edoxaban) tablets for oral use. Full prescribing information. Parsippany, NJ, USA: Daiichi Sankyo Inc., 2015.
18.
AgenoWGallusASWittkowskyA. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest2012; 141: e44S–e88S.
19.
WuCMMcLaughlinKLorenzettiDLHillMDMannsBJGhaliWA. Early risk of stroke after transient ischemic attack: a systematic review and meta-analysis. Arch Intern Med2007; 167: 2417–2422.
20.
International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19, 435 patients with acute ischaemic stroke. Lancet1997; 349: 1569–1581.
21.
PaciaroniMAgnelliGMicheliSCasoV. Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke2007; 38: 423–430.
22.
LansbergMGO'DonnellMJKhatriP. Antithrombotic and thrombolytic therapy for ischemic stroke: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest2012; 141: e601S–e636S.
23.
MonteagudoMFernández-DíazEGarcía-GarcíaJAyo-MartínÓHernández-FernándezFSeguraT. Efficacy, safety and tolerability of rivaroxaban for the secondary prevention of stroke in patients with atrial fibrillation in clinical practice. Future Neurol2015; 10: 529–536.
24.
ShibazakiKKimuraKAokiJSajiNSakaiK. Early initiation of new oral anticoagulants in acute stroke and TIA patients with nonvalvular atrial fibrillation. J Neurol Sci2013; 331: 90–93.
25.
KateMGioiaLBuckB. Dabigatran therapy in acute ischemic stroke patients without atrial fibrillation. Stroke2015; 46: 2685–2687.
26.
GioiaLCKateMSivakumarL. Early rivaroxaban use after cardioembolic stroke may not result in hemorrhagic transformation: a prospective magnetic resonance imaging study. Stroke2016; 47: 1917–1919.
27.
ToyodaKArihiroSTodoK. Trends in oral anticoagulant choice for acute stroke patients with nonvalvular atrial fibrillation in Japan: the SAMURAI-NVAF study. Int J Stroke2015; 10: 836–842.
28.
BaeHJeongDDohJLeeKYunIByunB. Recurrence of bleeding in patients with hypertensive intracerebral hemorrhage. Cerebrovasc Dis1999; 9: 102–108.
29.
BiffiAAndersonCDBatteyTW. Association between blood pressure control and risk of recurrent intracerebral hemorrhage. JAMA2015; 314: 904–912.
30.
HillMDSilverFLAustinPCTuJV. Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke2000; 31: 123–127.
31.
DagerWEGosselinRCKitchenSDwyreD. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother2012; 46: 1627–1636.
32.
HelinTAPakkanenALassilaRJoutsi-KorhonenL. Laboratory assessment of novel oral anticoagulants: method suitability and variability between coagulation laboratories. Clin Chem2013; 59: 807–814.
33.
CukerASiegalDMCrowtherMAGarciaDA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol2014; 64: 1128–1139.
34.
HawesEMDealAMFunk-AdcockD. 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 Haemost2013; 11: 1493–1502.
35.
BarrettYCWangZFrostCShenkerA. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost2010; 104: 1263–1271.
36.
HillarpAGustafssonKMFaxalvL. Effects of the oral, direct factor Xa inhibitor apixaban on routine coagulation assays and anti-FXa assays. J Thromb Haemost2014; 12: 1545–1553.
37.
SamamaMMContantGSpiroTE. Laboratory assessment of rivaroxaban: a review. Thromb J2013; 11: 11.
38.
CukerAHusseinzadehH. Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review. J Thromb Thrombolysis2015; 39: 288–294.
39.
EbnerMPeterASpencerC. Point-of-care testing of coagulation in patients treated with non-vitamin K antagonist oral anticoagulants. Stroke2015; 46: 2741–2747.
40.
WhiteleyWNSlotKBFernandesPSandercockPWardlawJ. Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies. Stroke2012; 43: 2904–2909.
41.
JauchECSaverJLAdamsHPJr.. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke2013; 44: 870–947.
ShahjoueiSTsivgoulisGBavarsad ShahripourRJonesGMAlexandrovAVZandR. Safety of intravenous thrombolysis among stroke patients taking new oral anticoagulants—case series and systematic review of reported cases. J Stroke Cerebrovasc Dis2015; 24: 2685–2693.
44.
KateMSzkotakAWittAShuaibAButcherK. Proposed approach to thrombolysis in dabigatran-treated patients presenting with ischemic stroke. J Stroke Cerebrovasc Dis2014; 23: 1351–1355.
45.
DemaerschalkBMKleindorferDOAdeoyeOM. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke2016; 47: 581–641.
46.
PowersWJDerdeynCPBillerJ. 2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke2015; 46: 3020–3035.
47.
HolbrookASchulmanSWittDM. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest2012; 141: e152S–e184S.
48.
SteinerTPoliSGriebeM. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomized trial. Lancet Neurol2016; 2016: 566–573.
49.
DentaliFMarchesiCGiorgi PierfranceschiM. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost2011; 106: 429–438.
BabiloniaKTrujilloT. The role of prothrombin complex concentrates in reversal of target specific anticoagulants. Thromb J2014; 12: 8.
52.
MarluRHodajEParisAAlbaladejoPCracowskiJLPernodG. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost2012; 108: 217–224.
53.
EerenbergESKamphuisenPWSijpkensMKMeijersJCBullerHRLeviM. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation2011; 124: 1573–1579.
54.
PRAXBIND® (idarucizumab) injection, for intravenous use. Full prescribing information. Ridgefield, CT, USA: Boehringer Ingelheim Pharmaceuticals, Inc., 2015.
55.
Praxbind (Idarucizumab). Summary of product characteristics. Germany: Boehringer Ingelheim Pharmaceuticals, Inc. Biberach an der Riss, 2015.
Praxbind® solution for injection/infusion. Consumer medicine information. North Ryde, NSW, Australia: Boehringer Ingelheim Pty Limited, 2016.
58.
PollackCVJr.ReillyPAEikelboomJ. Idarucizumab for dabigatran reversal. N Engl J Med2015; 373: 511–520.
59.
HerrmannRThomJWoodAPhillipsMMuhammadSBakerR. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost2014; 111: 989–995.
60.
LeviMMooreKTCastillejosCF. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost2014; 12: 1428–1436.
61.
ZahirHBrownKSVandellAG. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation2015; 131: 82–90.
62.
CrowtherMLuGConleyP. Reversal of factor Xa inhibitors-induced anticoagulation in healthy subjects by andexanet alfa. Crit Care Med2014; 42: A1469.
63.
SiegalDMCurnutteJTConnollySJ. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med2015; 373: 2413–2424.
64.
AnsellJEBakhruSHLaulichtBE. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med2014; 371: 2141–2142.
