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Thromb Haemost 2017; 117(07): 1448-1454
DOI: 10.1160/TH16-12-0961
Stroke, Systemic or Venous Thromboembolism
Schattauer GmbH

Cessation of oral anticoagulation is an important risk factor for stroke and mortality in atrial fibrillation patients

José Miguel Rivera-Caravaca
1   Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
,
Vanessa Roldán
2   Department of Hematology and Clinical Oncology, Hospital Universitario Morales Meseguer, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
,
María Asunción Esteve-Pastor
1   Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
,
Mariano Valdés
1   Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
,
Vicente Vicente
2   Department of Hematology and Clinical Oncology, Hospital Universitario Morales Meseguer, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
,
Gregory Y. H. Lip   *
3   University of Birmingham Institute of Cardiovascular Sciences, City Hospital, University of Birmingham, Birmingham, UK
4   Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
,
Francisco Marín   *
1   Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain
› Author Affiliations Financial Support: This work was supported by ISCIII and FEDER (PI13/00513 and P14/00253), Fundación Séneca (grant number: 19245/PI/14), RD12/0042/0050.
Further Information

Publication History

Received: 29 December 2016

Accepted after major revision: 23 February 2017

Publication Date:
28 November 2017 (online)

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Summary

Oral anticoagulation (OAC) is highly effective preventing stroke and mortality in AF, but withdrawal is common in the elderly, when high bleeding risk and when are difficulties achieving an optimal time in therapeutic range (TTR). We analysed the rate of OAC cessation, predisposing factors to cessation and the relation to clinical outcomes in a large ‘real world’ cohort of AF patients over a long follow-up period. Consecutive non-valvular AF outpatients clinically stables for six months were recruited. Rates of cardiovascular events, major bleeding and mortality were recorded and related to OAC cessation. We included 1361 patients (48.7 % male; aged 76, IQR 71–81), followed-up for a median of 6.5 years. During follow-up, 244 patients suffered thrombotic events, 250 suffered from major bleeding and 551 patients died. 10 % of patients stopped OAC. After OAC withdrawal, there were 36 thromboembolic events (22 strokes), 10 major bleedings and 75 deaths. OAC cessation was independently associated with adverse cardiovascular events (HR 1.45; 95 % CI 1.01–2.08), stroke/TIA (HR 1.85; 1.17–2.94) and all-cause mortality (HR 1.30; 1.02–1.67). Independent predictors of OAC cessation were age ≥80 (HR 2.29; 1.60–3.29), previous coronary artery disease (HR 0.32; 0.15–0.71), major bleeding (HR 5.00; 3.49–7.15), heart failure (HR 2.38; 1.26–4.47), cancer (HR 5.24; 3.25–8.44) and renal impairment developed during follow-up (HR 2.70; 1.26–5.75). In conclusion, in non-valvular AF patients, cessation of OAC was independently associated with the risk of stroke, adverse cardiovascular events and mortality. Bleeding events and some variables associated with higher bleeding risk are responsible for OAC cessation.

Note: The review process for this manuscript was fully handled by Christian Weber, Editor in Chief.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Atrial fibrillation - anticoagulants - stroke - haemorrhage - mortality

* Joint senior authors.


 

  • References

  • 1 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22: 983-988.
    CrossrefPubMedGoogle Scholar
  • 2 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.
    CrossrefPubMedGoogle Scholar
  • 3 Ogilvie IM, Welner SA, Cowell W. et al. Characterization of the proportion of untreated and antiplatelet therapy treated patients with atrial fibrillation. Am J Cardiol 2011; 108: 151-161.
    CrossrefPubMedGoogle Scholar
  • 4 Waldo AL, Becker RC, Tapson VF. et al. Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation. J Am Coll Cardiol 2005; 46: 1729-1736.
    CrossrefPubMedGoogle Scholar
  • 5 Wilke T, Groth A, Mueller S. et al. Oral anticoagulation use by patients with atrial fibrillation in Germany. Adherence to guidelines, causes of anticoagulation under-use and its clinical outcomes, based on claims-data of 183,448 patients. Thromb Haemost 2012; 107: 1053-1065.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Gallagher A, Setakis E, Plumb J. et al. Risk of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost 2011; 106: 968-977.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Morgan CL, McEwan P, Tukiendorf A. et al. Warfarin treatment in patients with atrial fibrillation: observing outcomes associated with varying levels of INR control. Thromb Res 2009; 124: 37-41.
    CrossrefPubMedGoogle Scholar
  • 8 Wan Y, Heneghan C, Perera R. et al. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review. Circ Cardiovasc Qual Outcomes 2008; 1: 84-91.
    CrossrefPubMedGoogle Scholar
  • 9 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Lip GY, Laroche C, Popescu MI. et al. Improved outcomes with European Society of Cardiology guideline-adherent antithrombotic treatment in high-risk patients with atrial fibrillation: a report from the EORP-AF General Pilot Registry. Europace 2015; 17: 1777-1786.
    CrossrefPubMedGoogle Scholar
  • 11 Chao TF, Liu CJ, Tuan TC. et al. Impact on Outcomes of Changing Treatment Guideline Recommendations for Stroke Prevention in Atrial Fibrillation: A Nationwide Cohort Study. Mayo Clinic Proc 2016; 91: 567-574.
    CrossrefPubMedGoogle Scholar
  • 12 Fauchier L, Villejoubert O, Clementy N. et al. Causes of deaths and influencing factors in patients with atrial fibrillation. Am J Med 2016 ; Epub ahead of print.
    PubMedGoogle Scholar
  • 13 Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-694.
    CrossrefPubMedGoogle Scholar
  • 14 Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med 1989; 87: 144-152.
    CrossrefPubMedGoogle Scholar
  • 15 Gallego P, Roldan V, Marín 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Lip GY, Fauchier L, Freedman SB. et al. Atrial fibrillation. Nat Rev Dis Primers 2016; 2: 16016.
    CrossrefPubMedGoogle Scholar
  • 17 Massera D, Wang D, Vorchheimer DA. et al. Increased risk of stroke and mortality following new-onset atrial fibrillation during hospitalization. Europace 2016 ; Epub ahead of print.
    PubMedGoogle Scholar
  • 18 Pipilis A, Farmakis D, Kaliambakos S. et al. Anticoagulation therapy in elderly patients with atrial fibrillation: results from the Registry of Atrial Fibrillation To Investigate the Implementation of New Guidelines (RAFTING). J Cardiovasc Med 2016 ; Epub ahead of print.
    PubMedGoogle Scholar
  • 19 Poli D, Antonucci E, Grifoni E. et al. Bleeding risk during oral anticoagulation in atrial fibrillation patients older than 80 years. J Am Coll Cardiol 2009; 54: 999-1002.
    CrossrefPubMedGoogle Scholar
  • 20 Chang SS, Dong JZ, Ma CS. et al. Current Status and Time Trends of Oral Anticoagulation Use Among Chinese Patients With Nonvalvular Atrial Fibrillation: The Chinese Atrial Fibrillation Registry Study. Stroke 2016 ; Epub ahead of print.
    PubMedGoogle Scholar
  • 21 Lefebvre MC, St-Onge M, Glazer-Cavanagh M. et al. The Effect of Bleeding Risk and Frailty Status on Anticoagulation Patterns in Octogenarians With Atrial Fibrillation: The FRAIL-AF Study. Can J Cardiol 2016; 32: 169-176.
    CrossrefPubMedGoogle Scholar
  • 22 Lip GY, Clementy N, Pericart L. et al. Stroke and major bleeding risk in elderly patients aged >/=75 years with atrial fibrillation: the Loire Valley atrial fibrillation project. Stroke 2015; 46: 143-150.
    CrossrefPubMedGoogle Scholar
  • 23 Savarese G, Rosano GMC, McMurray J. et al. Efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation and heart failure: a meta-analysis of phase III clinical trials. J Am Coll Cardiol Heart Fail 2016; 4: 870-880.
    PubMedGoogle Scholar
  • 24 Hamon M, Lemesle G, Tricot O. et al. Incidence, source, determinants, and prognostic impact of major bleeding in outpatients with stable coronary artery disease. J Am Coll Cardiol 2014; 64: 1430-1436.
    CrossrefPubMedGoogle Scholar
  • 25 Miyamoto K, Aiba T, Arihiro S. et al. Impact of renal function deterioration on adverse events during anticoagulation therapy using non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Heart Vess 2015; 1-10.
    PubMedGoogle Scholar
  • 26 Weitz JI, Eikelboom J. Incorporating edoxaban into the choice of anticoagulants for atrial fibrillation. Thromb Haemost 2016; 115: 257-270.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Limdi NA, Nolin TD, Booth SL. et al. Influence of Kidney Function on Risk of Supratherapeutic International Normalized Ratio-Related Hemorrhage in Warfarin Users: A Prospective Cohort Study. Am J Kidney Dis 2015; 65: 701-709.
    CrossrefPubMedGoogle Scholar
  • 28 Melloni C, Shrader P, Carver J. et al. Management and outcomes of patients with atrial fibrillation and cancer: the ORBIT-AF Registry. J Am Coll Cardiol 2016 ; Epub ahead of print.
    PubMedGoogle Scholar
  • 29 Lee Y-J, Park J-k, Uhm J-S. et al. Bleeding risk and major adverse events in patients with cancer on oral anticoagulation therapy. Intern J Cardiol 2016; 203: 372-378.
    CrossrefPubMedGoogle Scholar
  • 30 Hsu JC, Maddox TM, Kennedy KF. et al. Oral anticoagulant therapy prescription in patients with atrial fibrillation across the spectrum of stroke risk: Insights from the ncdr pinnacle registry. JAMA Cardiol 2016; 1: 55-62.
    CrossrefPubMedGoogle Scholar
  • 31 Medi C, Hankey GJ, Freedman SB. Stroke risk and antithrombotic strategies in atrial fibrillation. Stroke 2010; 41: 2705-2713.
    CrossrefPubMedGoogle Scholar
  • 32 Roldan I, Marin F. On the Way to a Better Use of Anticoagulants in Nonvalvular Atrial Fibrillation. Proposed Amendment to the Therapeutic Positioning Report UT/V4/23122013. Revista Espanol Cardiol 2016; 69: 551-553.
    PubMedGoogle Scholar
  • 33 Chai-Adisaksopha C, Hillis C, Monreal M. et al. Thromboembolic events, recurrent bleeding and mortality after resuming anticoagulant following gastrointestinal bleeding. A meta-analysis. Thromb Haemost 2015; 114: 819-825.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Staerk L, Lip GY, Olesen JB. et al. Stroke and recurrent haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study. Br Med J 2015; 351: h5876.
    PubMedGoogle Scholar
  • 35 Witt DM, Clark NP, Martinez K. et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for intracranial hemorrhage. Thromb Res 2015; 136: 1040-1044.
    CrossrefPubMedGoogle Scholar
  • 36 Molina CA, Selim MH. The dilemma of resuming anticoagulation after intracranial hemorrhage: little evidence facing big fears. Stroke 2011; 42: 3665-3666.
    CrossrefPubMedGoogle Scholar
  • 37 Paciaroni M, Agnelli G. Should oral anticoagulants be restarted after warfarin-associated cerebral haemorrhage in patients with atrial fibrillation?. Thromb Haemost 2014; 111: 14-18.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Nielsen PB, Larsen TB, Skjoth F. et al. Restarting Anticoagulant Treatment After Intracranial Hemorrhage in Patients With Atrial Fibrillation and the Impact on Recurrent Stroke, Mortality, and Bleeding: A Nationwide Cohort Study. Circulation 2015; 132: 517-525.
    CrossrefPubMedGoogle Scholar
  • 39 Proietti M, Nobili A, Raparelli V. et al. Adherence to antithrombotic therapy guidelines improves mortality among elderly patients with atrial fibrillation: insights from the REPOSI study. Clin Res Cardiol 2016 ; Epub ahead of print.
    PubMedGoogle Scholar
  • 40 Nieuwlaat R, Olsson SB, Lip GY. et al. Guideline-adherent antithrombotic treatment is associated with improved outcomes compared with undertreatment in high-risk patients with atrial fibrillation. The Euro Heart Survey on Atrial Fibrillation. Am Heart J 2007; 153: 1006-1012.
    CrossrefPubMedGoogle Scholar
  • 41 Gorin L, Fauchier L, Nonin E. et al. Prognosis and guideline-adherent antithrombotic treatment in patients with atrial fibrillation and atrial flutter: implications of undertreatment and overtreatment in real-life clinical practice; the Loire Valley Atrial Fibrillation Project. Chest 2011; 140: 911-917.
    CrossrefPubMedGoogle Scholar