Neurology 85(12): 1078-1084

Potential new uses of non–vitamin K antagonist oral anticoagulants to treat and prevent stroke

Background:

Non–vitamin K antagonist oral anticoagulant (NOAC) drugs are at least equivalent to warfarin for ischemic stroke prevention in patients with atrial fibrillation and have a lower risk of intracranial hemorrhage. The role of these agents in the prevention and treatment of other types of cerebrovascular disease remains unclear.

Methods:

We reviewed the literature (randomized trials, exploratory comparative studies, and case series) on the use of NOACs in patients with atrial fibrillation, venous thromboembolism, and cerebrovascular disease independent of atrial fibrillation.

Results:

The literature on the use of NOACs for treatment and prevention of cerebrovascular disease in patients without atrial fibrillation is sparse. The potential benefit of vitamin K antagonists over antiplatelet agents for primary and secondary prevention in certain subsets of patients with cerebrovascular disease is offset by the increased risk of major and intracranial hemorrhage. Given that NOACs are equivalent to vitamin K antagonists in preventing ischemic stroke and systemic embolism in patients with atrial fibrillation with less bleeding risk, clinical trials are needed to investigate the short- and long-term use of NOACs in populations of patients with other forms of cerebrovascular disease, including those with cryptogenic stroke with or without evidence of patent foramen ovale and low ejection fraction, cervical artery dissection, large artery atherosclerosis, venous thrombosis, and stuttering lacunar stroke.

Conclusion:

There may be a role for NOACs in stroke prevention and treatment beyond atrial fibrillation. Randomized controlled trials are needed to compare NOACs to current stroke prevention and treatment strategies in certain subgroups of patients with cerebrovascular disease.

From the Department of Neurology, College of Physicians and Surgeons (S.Y., M.S.V.E.), and Department of Epidemiology, Mailman School of Public Health (M.S.V.E.), Columbia University, New York; and Department of Neurology (H.K.), Weill Cornell Medical College, New York, NY.

^{Corresponding author.}

Correspondence to Dr. Elkind: ude.aibmuloc@31esm

Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Correspondence to Dr. Elkind: ude.aibmuloc@31esmGo to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Received 2015 Mar 14; Accepted 2015 May 18.

Abstract

Background:

Methods:

Results:

Conclusion:

Abstract

Atrial fibrillation remains the only condition for which oral anticoagulation has been demonstrated in large-scale clinical trials to be effective for stroke prevention. However, anticoagulants are used in several other situations by practicing neurologists, including cervical artery dissection, cryptogenic stroke with or without patent foramen ovale (PFO), cerebral venous thrombosis (CVT), and fluctuating stroke. Anticoagulation is occasionally used in all of these cerebrovascular conditions with varying degrees of supportive evidence.¹ Non–vitamin K antagonist oral anticoagulant (NOAC) drugs have been shown to be at least noninferior to vitamin K antagonists (VKAs) in preventing ischemic stroke and systemic embolism with lower bleeding risk.²^–⁵ Furthermore, one trial showed that among patients with atrial fibrillation deemed to be ineligible to receive VKA for various reasons, including inability to comply with monitoring regimens and high risk of hemorrhage, apixaban reduced the risk of stroke with similar major bleeding risk compared with aspirin.⁶ Thus, one may logically consider the use of these agents in these other situations in which anticoagulation is often used or recommended. In this review, we discuss the potential for future use of NOACs in cerebrovascular disease.

GLOSSARY

APAS	antiphospholipid antibody syndrome
CI	confidence interval
CVT	cerebral venous thrombosis
ESUS	embolic stroke of undetermined source
HR	hazard ratio
INR	international normalized ratio
NAVIGATE ESUS	Rivaroxaban vs Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients with Recent Embolic Stroke of Undetermined Source
NOAC	non–vitamin K antagonist oral anticoagulant
NT-proBNP	N-terminal fragment of the prohormone brain natriuretic peptide
PFO	patent foramen ovale
PTAS	percutaneous angioplasty and stenting
RE-SPECT ESUS	Dabigatran Etexilate for Secondary Stroke Prevention in Patients with Embolic Stroke of Undetermined Source
VKA	vitamin K antagonist
WARCEF	Warfarin vs Aspirin in Reduced Cardiac Ejection Fraction
WARSS	Warfarin vs Aspirin Recurrent Stroke Study
WASID	Warfarin-Aspirin Symptomatic Intracranial Disease

GLOSSARY

REFERENCES

References

1. Furie KL, Kasner SE, Adams RJ, et al Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:227–276. [[PubMed][Google Scholar]
2. Patel MR, Mahaffey KW, Garg J, et al Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–891. [[PubMed][Google Scholar]
3. Connolly SJ, Ezekowitz MD, Yusuf S, et al Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151. [[PubMed][Google Scholar]
4. Granger CB, Alexander JH, McMurray JJ, et al Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–992. [[PubMed][Google Scholar]
5. Giugliano RP, Ruff CT, Braunwald E, et al Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–2104. [[PubMed][Google Scholar]
6. Connolly SJ, Eikelboom J, Joyner C, et al Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–817. [[PubMed][Google Scholar]
7. 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. [[PubMed][Google Scholar]
8. Yaghi S, Elkind MS. Cryptogenic stroke: a diagnostic challenge. Neurol Clin Pract 2014;4:386–393.
9. Hart RG, Diener HC, Coutts SB, et al Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014;13:429–438. [[PubMed][Google Scholar]
10. Sanna T, Diener HC, Passman RS, et al Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478–2486. [[PubMed][Google Scholar]
11. Gladstone DJ, Spring M, Dorian P, et al Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014;370:2467–2477. [[PubMed][Google Scholar]
12. Gladstone DJ, Dorian P, Spring M, et al Atrial premature beats predict atrial fibrillation in cryptogenic stroke: results from the EMBRACE trial. Stroke 2015;46:931–941. [[PubMed][Google Scholar]
13. Sacco RL, Ellenberg JH, Mohr JP, et al Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol 1989;25:382–390. [[PubMed][Google Scholar]
14. Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 2004;62:569–573. [[PubMed]
15. Mohr JP, Thompson JL, Lazar RM, et al A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:1444–1451. [[PubMed][Google Scholar]
16. Sacco RL, Prabhakaran S, Thompson JL, et al Comparison of warfarin versus aspirin for the prevention of recurrent stroke or death: subgroup analyses from the Warfarin-Aspirin Recurrent Stroke Study. Cerebrovasc Dis 2006;22:4–12. [[PubMed][Google Scholar]
17. January CT, Wann LS, Alpert JS, et al 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071–2104. [[PubMed][Google Scholar]
18. Tamura H, Watanabe T, Nishiyama S, et al Elevated plasma brain natriuretic peptide levels predict left atrial appendage dysfunction in patients with acute ischemic stroke. J Cardiol 2012;60:126–132. [[PubMed][Google Scholar]
19. Sinner MF, Stepas KA, Moser CB, et al B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies. Europace 2014;16:1426–1433. [Google Scholar]
20. Montaner J, Perea-Gainza M, Delgado P, et al Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke 2008;39:2280–2287. [[PubMed][Google Scholar]
21. Reddy VY, Doshi SK, Sievert H, et al Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-year follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation 2013;127:720–729. [[PubMed][Google Scholar]
22. Kamel H, Elkind MS, Bhave PD, et al Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013;44:1550–1554. [Google Scholar]
23. Kamel H, Soliman EZ, Heckbert SR, et al P-wave morphology and the risk of incident ischemic stroke in the multi-ethnic study of atherosclerosis. Stroke 2014;45:2786–2788. [Google Scholar]
24. Di Tullio MR, Sacco RL, Sciacca RR, Homma S. Left atrial size and the risk of ischemic stroke in an ethnically mixed population. Stroke 1999;30:2019–2024. [[PubMed]
25. Russo C, Jin Z, Liu R, et al LA volumes and reservoir function are associated with subclinical cerebrovascular disease: the CABL (Cardiovascular Abnormalities and Brain Lesions) Study. JACC Cardiovasc Imaging 2013;6:313–323. [Google Scholar]
26. Stahrenberg R, Edelmann F, Haase B, et al Transthoracic echocardiography to rule out paroxysmal atrial fibrillation as a cause of stroke or transient ischemic attack. Stroke 2011;42:3643–3645. [[PubMed][Google Scholar]
27. Yaghi S, Moon YP, Mora-McLaughlin C, et al Left atrial enlargement and stroke recurrence: the Northern Manhattan Stroke Study. Stroke 2015;46:1488–1493. [Google Scholar]
28. Black IW. Spontaneous echo contrast: where there's smoke there's fire. Echocardiography 2000;17:373–382. [[PubMed]
29. Longstreth WT, Jr, Kronmal RA, Thompson JL, et al Amino terminal pro-B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. Stroke 2013;44:714–719. [Google Scholar]
30. Homma S, Thompson JL, Pullicino PM, et al Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012;366:1859–1869. [Google Scholar]
31. Pullicino PM, Qian M, Sacco RL, et al Recurrent stroke in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial. Cerebrovasc Dis 2014;38:176–181. [Google Scholar]
32. Dentali F, Riva N, Crowther M, Turpie AG, Lip GY, Ageno W. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012;126:2381–2391. [[PubMed]
33. Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP. Effect of medical treatment in stroke patients with patent foramen ovale: Patent Foramen Ovale in Cryptogenic Stroke Study. Circulation 2002;105:2625–2631. [[PubMed]
34. Meissner I, Whisnant JP, Khandheria BK, et al Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC Study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc 1999;74:862–869. [[PubMed][Google Scholar]
35. Cramer SC, Rordorf G, Maki JH, et al Increased pelvic vein thrombi in cryptogenic stroke: results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) Study. Stroke 2004;35:46–50. [[PubMed][Google Scholar]
36. Gautier JC, Durr A, Koussa S, Lascault G, Grosgogeat Y. Paradoxal cerebral embolism: role of patent oval foramen [in French]. Bull Acad Nat Med 1990;174:1031–1038; discussion 1038–1040. [[PubMed]
37. Renard D, Larue A, Taieb G, Jeanjean L, Labauge P. Recurrent cerebral infarction in Klippel-Trenaunay-Weber syndrome. Clin Neurol Neurosurg 2012;114:1019–1020. [[PubMed]
38. Carroll JD, Saver JL, Thaler DE, et al Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013;368:1092–1100. [[PubMed][Google Scholar]
39. Agnelli G, Buller HR, Cohen A, et al Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699–708. [[PubMed][Google Scholar]
40. Buller HR, Prins MH, Lensin AW, et al Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–1297. [[PubMed][Google Scholar]
41. Chimowitz MI, Lynn MJ, Derdeyn CP, et al Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011;365:993–1003. [Google Scholar]
42. Derdeyn CP, Chimowitz MI, Lynn MJ, et al Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet 2014;383:333–341. [Google Scholar]
43. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005;352:1305–1316. [[PubMed][Google Scholar]
44. Gan R, Sacco RL, Kargman DE, Roberts JK, Boden-Albala B, Gu Q. Testing the validity of the lacunar hypothesis: the Northern Manhattan Stroke Study experience. Neurology 1997;48:1204–1211. [[PubMed]
45. Kawano H, Nakajima M, Inatomi Y, Yonehara T, Ando Y. Loading dose of clopidogrel in combination with other antithrombotic therapy for capsular warning syndrome. J Stroke Cerebrovasc Dis 2014;23:1265–1266. [[PubMed]
46. Meyer DM, Albright KC, Allison TA, Grotta JC. LOAD: a pilot study of the safety of loading of aspirin and clopidogrel in acute ischemic stroke and transient ischemic attack. J Stroke Cerebrovasc Dis 2008;17:26–29.
47. Tissue plasminogen activator for acute ischemic strokeThe National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581–1587. [[PubMed][Google Scholar]
48. Lyrer P, Engelter S. Antithrombotic drugs for carotid artery dissection. Cochrane Database Syst Rev 2010:CD000255. [[PubMed]
49. Menon RK, Markus HS, Norris JW. Results of a UK questionnaire of diagnosis and treatment in cervical artery dissection. J Neurol Neurosurg Psychiatry 2008;79:612. [[PubMed]
50. Caprio FZ, Bernstein RA, Alberts MJ, et al Efficacy and safety of novel oral anticoagulants in patients with cervical artery dissections. Cerebrovasc Dis 2014;38:247–253. [[PubMed][Google Scholar]
51. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol 2015;14:361–367. [[PubMed]
52. Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F; ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004;35:664–670. [[PubMed]
53. Saposnik G, Barinagarrementeria F, Brown RD, Jr, et al Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:1158–1192. [[PubMed][Google Scholar]
54. Geisbusch C, Richter D, Herweh C, Ringleb PA, Nagel S. Novel factor Xa inhibitor for the treatment of cerebral venous and sinus thrombosis: first experience in 7 patients. Stroke 2014;45:2469–2471. [[PubMed]
55. Mendonca MD, Barbosa R, Cruz ESV, Calado S, Viana-Baptista M. Oral direct thrombin inhibitor as an alternative in the management of cerebral venous thrombosis: a series of 15 patients. Int J Stroke Epub 2015 Feb 24. [[PubMed]
56. Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med 1997;127:177–185. [[PubMed]
57. Eikelboom JW, Connolly SJ, Brueckmann M, et al Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369:1206–1214. [[PubMed][Google Scholar]