Antithrombotic Treatment at Onset of Stroke with Atrial Fibrillation,Functional Outcome,and Fatality: A Systematic Review and Meta-Analysis

Abstract

Background

In atrial fibrillation–associated stroke, conflicting data exist regarding association between therapeutic vitamin K-antagonist anticoagulation (International Normalized Ratio 2–3) and early death and functional outcome, and few data exist relating to late outcome in ischemic and haemorrhagic atrial fibrillation–stroke.

Aim

We performed a systematic review and meta-analysis of oral anticoagulation at stroke onset, death and functional outcome.

Methods

We performed a systematic review, searching multiple sources. Studies were included if outcomes in atrial fibrillation–associated stroke were reported stratified by pre-stroke antithrombotic status, with documented International Normalized Ratio at onset. Outcomes were survival and good functional outcome (modified Rankin score 0–2) at discharge/30 days, and at one-year.

Results

Of eight studies (3552 patients) in ischemic stroke, International Normalized Ratio ≥ 2 compared with other treatments (International Normalized Ratio < 2, antiplatelet, or no anti-thrombotic) was associated with good outcome [pooled odds ratio 1·9 (95% confidence interval) 1·5–2·5, P < 0·001] and improved survival at 30 days discharge (pooled odds ratio for death 0·4, confidence interval 0·2–0·5, P < 0·001). The net benefit remained after inclusion of haemorrhagic stroke (odds ratio for good outcome 1·89, confidence interval 1·45–2·46, P < 0·001). At one-year, improved functional outcome for International Normalized Ratio ≥ 2 (pooled odds ratio 1·7, confidence interval 1·0–2·7, P = 0·04) and survival (odds ratio for death 0·5, confidence interval 0·4–0·8, P = 0·001) were also observed.

Conclusions

Therapeutic International Normalized Ratio at stroke onset was associated with early and late improved survival and functional recovery suggesting sustained benefit for warfarin anticoagulation for stroke outcome in atrial fibrillation patients. Long-term outcome data following stroke in patients taking new oral anticoagulants is required.

Keywords

anticoagulation atrial fibrillation prevention stroke warfarin

Get full access to this article

View all access options for this article.

References

Wolf

Abbott

Kannel

. Atrial Fibrillation as an independent risk factor for stroke: The Framingham study. Stroke 1991; 22: 983–8.

Hylek

Phillips

. Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001; 285: 2370–5.

Arsava

Gungor

. Admission International Normalized Ratio and acute infarct volume in ischemic stroke. Ann Neurol 2008; 64: 499–506.

Hannon

Sheehan

Kelly

. Stroke associated with atrial fibrillation — incidence and early outcomes in the North Dublin Population Stroke Study. Cerebrovasc Dis 2010; 29: 43–9.

Gatellari

Goumas

Aitken

Worthington

. Outcomes for patients with ischaemic stroke and atrial fibrillation: The PRISM study (A Program of Research Informing Stroke Management). Cerebrovasc Dis 2011; 32: 370–82.

Feinberg

Blackshear

Laupacis

Kronmal

Hart

. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995; 155: 469–73.

Hart

Pearce

Aguilar

. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have had nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: 857–67.

Prasad

Kaplan

Passman

. New frontiers for stroke prevention in atrial fibrillation. Cerebrovasc Dis 2012; 33: 199–208.

Ufer

. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010; 103: 572–85.

10.

Crowther

Warkentin

. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost 2009; 7: 107–10.

11.

Heusler

Konieczny

Endres

Villringer

Heuschmann

. Impact of anticoagulation before stroke on stroke severity and long term survival. Int J Stroke 2012; 7: 544–50.

12.

Åsberg

Eriksson

Henriksson

Terént

. Reduced risk of death with warfarin — results of an observational nationwide study of 20 442 patients with atrial fibrillation and ischaemic stroke. Int J Stroke 2013; 8: 689–95.

13.

Higgins

JPT

Thompson

Deeks

Altman

. Measuring Inconsistency in Meta-analysis. BMJ 2003; 327: 557–60.

14.

Hylek

Chang

. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. NEJM 2003; 349: 1019–26.

15.

Indredavik

Rohweder

Lydersen

. Frequency and effect of optimal anticoagulation before onset of ischaemic stroke in patients with known atrial fibrillation. J Intern Med 2005; 258: 133–44.

16.

O'Donnell

Oczkowski

Fang

on behalf of the Investigators of the Registry of the Canadian Stroke Network. Pread-mission anti-thrombotic treatment and stroke severity in patients with atrial fibrillation and acute ischemic stroke: An observational study. Lancet Neurol 2006; 5: 749–54.

17.

Audebert

Schenk

Schenkel

Heuschmann

. Impact of pre-stroke oral anticoagulation on severity and outcome of ischemic stroke in patients with atrial fibrillation. Cerebrovasc Dis 2010; 29: 476–83.

18.

Schwammenthal

Bornstein

Schwammenthal

. Relation of effective anticoagulation in patients with atrial fibrillation to stroke severity and survival (from the National Acute Stroke Israeli Survey [NASIS]. Am J Cardiol 2010; 105: 411–16.

19.

Hannon

Callaly

Moore

. Improved late survival and disability after stroke with therapeutic anticoagulation for atrial fibrillation — a population study. Stroke 2011; 42: 2503–8.

20.

Tan

Noone

Hatton

. Stroke in Patients with Atrial Fibrillation on Warfarin Therapy. Irish J Med Sci 2008; 9: S336.

21.

Wakita

Yasaka

Minematsu

Yamaguchi

. Effects of anticoagulation on infarct size and clinical outcome in acute cardioembolic stroke. Angiology 2002; 53: 551–6.

22.

Flaherty

Tao

Haverbusch

. Warfarin use leads to larger intracerebral hematomas. Neurology 2008; 71: 1084–9.

23.

Sanossian

Saver

Rajajee

. Premorbid antiplatelet use and ischemic stroke outcomes. Neurology 2006; 66: 319–23.

24.

Obviagele

Buck

Liebeskind

. Prior antiplatelet use and infarct volume in ischemic stroke. J Neurol Sci 2008; 264: 140–4.

25.

Paciaroni

Agnelli

Caso

. Previous use of antithrombotic agents and neurological functional outcome at discharge in patients with ischemic stroke. J Thromb Haemost 2006; 4: 1957–61.

26.

Libman

Sharfstein

Barr

. Stroke outcome in patients already taking aspirin. J Stroke Cerebrovasc Dis 1999; 8: 423–5.

27.

Béjot

Aboa-Eboulé

De Maistre

. Pre-stroke antiplatelet therapy and early prognosis in stroke patients: The Dijon Stroke Registry. Eur J Neurol 2013; 20: 879–90.

28.

Stroup

Berlin

Morton

. Meta-analysis of observational studies in epidemiology. A proposal for reporting. JAMA 2000; 283: 2008–12.

29.

Connolly

Ezekowitz

Yusuf

. RE-LY Steering Committee and Investigator. Dabigatran versus warfarin in patients with atrial fibrillation. New Engl J Med 2009; 361: 1139–51.

30.

Patel

Mahaffey

Garg

. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883–91.

31.

Connolly

Eikelboom

Joyner

. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806–17.