Prof. Gregory Y. H. Lip
Anticoagulation therapy is superior to antiplatelet therapy in preventing strokes in AF. Combining aspirin with anticoagulation therapy (combination therapy) in AF will increase the bleeding risk. The only situation where combination therapy might be needed is in the setting of AF plus percutaneous coronary intervention and/or stents and/or acute coronary syndrome.
This brief overview will address anticoagulant therapy, antiplatelet therapy and where combination therapy may or may not have a role for the prevention of stroke and thromboembolism in patients with atrial fibrillation (AF).
The provision of thromboprophylaxis for AF has many clinical trials to inform an appropriate management strategy. Generally, anticoagulation therapy reduces strokes by two-thirds compared to control, whilst aspirin reduces stroke by one-fifth . Also, the superiority of anticoagulation therapy (with a 40% risk reduction) over aspirin as thromboprophylaxis in patients with nonvalvular AF is clear . Mortality is not significantly decreased by the use of aspirin compared to placebo in patients with AF.
Aspirin has been used as an alternative to prescribing warfarin, despite the evidence that aspirin is poorly effective for stroke reduction in ‘high risk’ AF patients. The overall benefit for aspirin in stroke reduction is 22% with fairly wide confidence intervals, almost including unity, indicating no benefit . Of note, aspirin was not beneficial in reducing recurrent strokes or severe strokes.
In the recently presented Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA), anticoagulation with warfarin was superior to aspirin for primary stroke prevention amongst elderly patients (age>75 years) with AF, in the primary care setting . The BAFTA trial showed that warfarin was very effective thromboprophylaxis in the elderly, with no significant increased bleeding risk with age. Thus, there is a very strong argument to use warfarin more often in elderly patients.
What is less well known is that the perceived overall stroke reduction benefit of aspirin (by approximately one-fifth) in AF is largely driven by one clinical trial—the first Stroke Prevention in Atrial Fibrillation (SPAF-I) Trial which had a degree of internal inconsistency in the aspirin effect within the study itself . As AF commonly coexists with vascular disease, the effect of antiplatelet therapy [or aspirin alone] in AF is probably the effect on vascular disease, rather than on the stroke associated with AF per se – indeed, antiplatelet therapy compared to control in ‘high risk’ vascular disease patients also reduces stroke by 22% .
The relative inefficacy of aspirin (and antiplatelet therapy) in high risk patients with AF is also clearly evident from other studies [7,8]. One recent clinical trial, the ACTIVE-W trial  of moderate to high risk patients with AF randomized patients to warfarin or combination antiplatelet therapy of aspirin/clopidogrel. This trial was stopped early due to the inferiority of aspirin/clopidogrel combination therapy vs anticoagulant therapy for the composite endpoint of stroke, embolism, or vascular death, with no significant difference in bleeding rates .
Even in ‘low risk’ patients with AF, the evidence for aspirin use is pretty weak. In the Japanese AF Stroke Trial , which was performed in low risk patients with AF, there was no significant difference in primary endpoint rate between aspirin or placebo.
The data combining aspirin with anticoagulant therapy also shows little evidence for additive benefit for stroke prevention but a substantial increase in bleeding rate by using such combination therapy . In a more recent analysis , there was again no significant additive effect of aspirin to anticoagulant therapy in stroke prevention or the reduction in vascular events (including death or myocardial infarction) but instead, combining aspirin with anticoagulants resulted in a substantial increase in bleeding risk.
Perhaps the one situation where we might need combination therapy with anticoagulant plus antiplatelet therapy is in the setting of AF plus percutaneous coronary intervention and/or stents and/or acute coronary syndrome . Here cardiologists have to balance the risk of stroke in AF versus the prevention of recurrent cardiac ischemic events in the acute coronary syndrome setting, against the bleeding risks associated with combination ‘triple antithrombotic therapies’.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Lip GY, Boos CJ. Antithrombotic treatment in atrial fibrillation. Heart. 2006;92(2):155-61. 2. Lip GYH, Edwards SJ. Stroke prevention with aspirin, warfarin and xilmelagatran in patients with non-valvular atrial fibrillation: a systematic review and meta-analysis. Thromb Res 2006;118(3):321-33 3. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131: 492–501 4. Mant J, Hobbs R, Fitzmaurice D, et al for the BAFTA trialists. BAFTA: A randomised controlled trial of warfarin versus aspirin for stroke prevention in atrial fibrillation in a primary care population aged over 75. 16th European Stroke Conference; May 29-June 1, 2007: Glasgow, Scotland. Abstract 2. 5. Stroke prevention in Atrial Fibrillation (SPAF) Investigators. A differential effect of aspirin in prevention of stroke on atrial fibrillation. J Stroke Cerebrovasc Dis 1993; 3: 181–8. 6. Antithrombotic trialist’s collaboration. Collaborative analysis of randomised trials of anti platelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324; 71-86 7. Singer DE, Hughes RA, Gress DR, Sheehan MA, Oertel LB, Maraventano SW, Blewett DR, Rosner B, Kistler JP. The effect of aspirin on the risk of stroke in patients with nonrheumatic atrial fibrillation: The BAATAF Study. Am Heart J. 1992 Dec;124(6):1567-73. 8. The ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W): A randomised controlled trial. Lancet 2006;367:1903-1912 9. Sato H, Ishikawa K, Kitabatake A, Ogawa S, Maruyama Y, Yokota Y, Fukuyama T, Doi Y, Mochizuki S, Izumi T, Takekoshi N, Yoshida K, Hiramori K, Origasa H, Uchiyama S, Matsumoto M, Yamaguchi T, Hori M; Japan Atrial Fibrillation Stroke Trial Group. Low-dose aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan Atrial Fibrillation Stroke Trial. Stroke. 2006;37:447-51. 10. Lechat P, Lardoux H, Mallet A, Sanchez P, Derumeaux G, Lecompte T, Maillard L, Mas JL, Mentre F, Pousset F, Lacomblez L, Pisica G, Solbes-Latourette S, Raynaud P, Chaumet-Riffaud P; FFAACS (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane) Investigators. Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation. A randomized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane; FFAACS). Cerebrovasc Dis. 2001;12:245-52. 11. Flaker GC, Gruber M, Connolly SJ, Goldman S, Chaparro S, Vahanian A, Halinen MO, BHorrow J, Halperin JL; SPORTIF Investigators. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J. 2006 Nov;152(5):967-73. 12. Lip GY, Karpha M. Anticoagulant and antiplatelet therapy use in patients with atrial fibrillation undergoing percutaneous coronary intervention: the need for consensus and a management guideline. Chest. 2006;130(6):1823-7.
Prof. Gregory YH Lip MD FRCP FACC FESC
Haemostasis Thrombosis and Vascular Biology Unit University Department of Medicine, City Hospital, Birmingham B18 7QH. United Kingdom
Correspondence to: Professor GYH Lip Tel: +44(0)121 507 5080; Fax: +44(0)121 554 4803; email@example.com
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