Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation

Summary

Bleeding risk (often perceived, rather than actual) is a common reason for cessation of oral anticoagulation with Vitamin K antagonists (VKA). We investigate clinical outcomes in a consecutive population of VKA naïve atrial fibrillation (AF) patients, who initiated VKA therapy in our clinic. We included consecutive VKA-naíve patients with non valvular AF, initiated on VKA therapy in our anticoagulation outpatient clinic in 2009. During follow-up, adverse events [thrombotic/vascular events (stroke, acute coronary syndrome, acute heart failure and cardiac death), major bleeding and death], and VKA cessation were recorded. At the end of the follow-up, we determined time within therapeutic range (TTR), using a linear approximation (Rosendaal method). We studied 529 patients (49% male, median age 76), median follow-up 835 days (IQR 719−954). During this period 114 patients stopped VKA treatment. 63 patients suffered a thrombotic/cardiovascular event (5.17%/year, 27 thrombotic/ischaemic strokes), 51 major bleeding (4.19%/year) and 48 died (3.94%/year). Median TTR was 54% (34a57). On multivariate analysis (adjusted by CHA₂DS₂-VASc score), VKA cessation was associated with death [Hazard Ratio (HR) 3.43; p<0.001], stroke [4.21; p=0.001] and thrombotic/cardiovascular events [2.72; p<0.001]. Independent risk factors for major bleeding were age [1.08; p<0.001], previous stroke [1.85; p=0.049], and TTR [0.97; p=0.001], but not VKA cessation. In conclusion, in AF patients AF, VKA cessation is independently associated with mortality stroke and cardiovascular events. Specifically, VKA cessation independently increased the risk of stroke, even after adjusting for CHA₂DS₂-VASc score. TTR was an independent risk factor for major bleeding following initiation of VKA therapy.

Note: The editorial process for this paper was fully handled by Prof Christian Weber, Editor in Chief.

Keywords

Atrial fibrillation - oral anticoagulants - mortality - thrombosis

• References

• 1 Lip GYH. Stroke in atrial fibrillation: epidemiology and thromboprophylaxis. J Thromb Haemost 2011; 9 (Suppl. 01) 344-351.
• 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.
• 3 Poli D, Antonucci E, Marcucci R. et al. Risk of bleeding in very old atrial fibrillation patients on warfarin: relationship with ageing and CHADS2 score. Thromb Res 2007; 121: 347-352.
• 4 Hylek EM, Evans-Molina C, Shea C. et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007; 115: 2689-2696.
• 5 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.
• 6 Waldo AL, Becker RC, Tapson VF. et al. NABOR Steering Committee. 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.
• 7 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.
• 8 Task Force Members. Camm AJ, Lip GY, De Caterina R. et al. 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 J 2012; 33: 2719-2747.
• 9 Skanes AC, Healey JS, Cairns JA. et al. Canadian Cardiovascular Society Atrial Fibrillation Guidelines Committee. 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.
• 10 Pisters R, Lane DA, Nieuwlaat R. et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest 2010; 138: 1093-1100.
• 11 Lip GY, Andreotti F, Fauchier L. et al. European Heart Rhythm Association. Bleeding risk assessment and management in atrial fibrillation patients. Executive Summary of a Position Document from the European Heart Rhythm Association [EHRA], endorsed by the European Society of Cardiology [ESC] Working Group on Thrombosis. Thromb Haemost 2011; 106: 997-1011.
• 12 Garcia DA, Lopes RD, Hylek EM. New-onset atrial fibrillation and warfarin initiation: high risk periods and implications for new antithrombotic drugs. Thromb Haemost 2010; 104: 1099-1105.
• 13 Palareti G, Leali N, Coccheri S. et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996; 348: 423-428.
• 14 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-694.
• 15 Rosendaal FR, Cannegieter SC, van der Meer FJM. et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239.
• 16 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.
• 17 Douketis JD, Foster GA, Crowther MA. et al. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 2000; 160: 3431-3436.
• 18 Fihn SD, McDonell M, Martin D. et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin optimized outpatient follow-up study group. Ann Intern Med 1993; 118: 511-520.
• 19 Olesen JB, Lip GY, Lindhardsen J. et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a 'real world' nationwide cohort study. Thromb Haemost 2011; 106: 739-749.
• 20 Friberg L, Rosenqvist M, Lip GY. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation 2012; 125: 2298-2307.
• 21 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.
• 22 Donze J, Clair C, Hug B. et al. Risk of falls and major bleeds in patients on oral anticoagulation therapy. Am J Med 2012; 125: 773-778.
• 23 Man-Son-Hing M, Nichol G, Lau A. et al. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med 1999; 159: 677-685.
• 24 Wyse DG, Waldo AL, DiMarco JP. et al. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347: 1825-1833.
• 25 Steinberg BA, Holmes DN, Ezekowitz MD. et al. Rate versus rhythm control for management of atrial fibrillation in clinical practice: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Am Heart J 2013; 165: 622-629.
• 26 Saksena S, Slee A, Waldo AL. et al. Cardiovascular outcomes in the AFFIRM Trial (Atrial Fibrillation Follow-Up Investigation of Rhythm Management): an assessment of individual antiarrhythmic drug therapies compared with rate control with propensity score-matched. J Am Coll Cardiol 2011; 58: 1975-1985.
• 27 Healey JS, Connolly SJ, Gold MR. et al. Subclinical atrial fibrillation and the risk of stroke. N Eng J Med 2012; 366: 120-129.
• 28 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.
• 29 Poller L, Keown M, Ibrahim S. et al. An international multicenter randomized study of computer-assisted oral anticoagulant dosage vs. medical staff dosage. J Thromb Haemost 2008; 6: 935-943.
• 30 Wallentin L, Yusuf S, Ezekowitz MD. et al. RE-LY investigators. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010; 376: 975-983.