LESS IS MORE Risk of Bleeding With Single , Dual , or Triple Therapy With Warfarin , Aspirin , and Clopidogrel in Patients With Atrial Fibrillation

Results: A total of 82 854 of 118 606 patients (69.9%) surviving AF hospitalization had at least 1 prescription filled for warfarin, aspirin, or clopidogrel after discharge. During mean (SD) follow-up of 3.3 (2.6) years, 13 573 patients (11.4%) experienced a nonfatal or fatal bleeding. The crude incidence rate for bleeding was highest for dual clopidogrel and warfarin therapy (13.9% per patient-year) and triple therapy (15.7% per patientyear). Using warfarin monotherapy as a reference, the hazard ratio (95% confidence interval) for the combined end point was 0.93 (0.88-0.98) for aspirin, 1.06 (0.87-1.29) for clopidogrel, 1.66 (1.34-2.04) for aspirinclopidogrel, 1.83 (1.72-1.96) for warfarin-aspirin, 3.08 (2.32-3.91) for warfarin-clopidogrel, and 3.70 (2.894.76) for warfarin-aspirin-clopidogrel.

[1]  Donald Martin,et al.  Risk Factors for Complications of Chronic Anticoagulation: A Multicenter Study , 1993, Annals of Internal Medicine.

[2]  Anders Odén,et al.  Optimal INR for prevention of stroke and death in atrial fibrillation: a critical appraisal. , 2006, Thrombosis research.

[3]  G. Elta,et al.  Gastroduodenal mucosal damage with salsalate versus aspirin: results of experimental models and endoscopic studies in humans. , 1990, Seminars in arthritis and rheumatism.

[4]  W. J. Hamilton,et al.  Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial , 1996, The Lancet.

[5]  Salim Yusuf,et al.  Effect of clopidogrel added to aspirin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[6]  J. Douketis,et al.  Meta-analysis: Anticoagulant Prophylaxis to Prevent Symptomatic Venous Thromboembolism in Hospitalized Medical Patients , 2007, Annals of Internal Medicine.

[7]  Palle Petersen,et al.  PLACEBO-CONTROLLED, RANDOMISED TRIAL OF WARFARIN AND ASPIRIN FOR PREVENTION OF THROMBOEMBOLIC COMPLICATIONS IN CHRONIC ATRIAL FIBRILLATION The Copenhagen AFASAK Study , 1989, The Lancet.

[8]  J. Tolstrup,et al.  Alcohol Consumption and Risk of Atrial Fibrillation in Men and Women: The Copenhagen City Heart Study , 2005, Circulation.

[9]  S. Connolly,et al.  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. , 2006, American heart journal.

[10]  M Gent,et al.  Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. , 1991, Journal of the American College of Cardiology.

[11]  P. Vestergaard,et al.  Trends in Risk of Stroke in Patients with a Hospital Diagnosis of Nonvalvular Atrial Fibrillation: National Cohort Study in Denmark, 1980–2002 , 2006, Neuroepidemiology.

[12]  L. Køber,et al.  Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data , 2009, The Lancet.

[13]  A. Zwisler,et al.  Hospital Variation in Mortality After First Acute Myocardial Infarction in Denmark From 1995 to 2002: Lower Short-Term and 1-Year Mortality in High-Volume and Specialized Hospitals , 2005, Medical care.

[14]  G. Lip,et al.  Increased major bleeding complications related to triple antithrombotic therapy usage in patients with atrial fibrillation undergoing percutaneous coronary artery stenting. , 2008, Chest.

[15]  J. Hallas,et al.  Use of sumatriptan in Denmark in 1994-5: an epidemiological analysis of nationwide prescription data. , 1997, British journal of clinical pharmacology.

[16]  L. Køber,et al.  Atrial fibrillation pharmacotherapy after hospital discharge between 1995 and 2004: a shift towards beta-blockers. , 2008, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[17]  Carl van Walraven,et al.  Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. , 2002, JAMA.

[18]  L. Køber,et al.  Long-term compliance with beta-blockers, angiotensin-converting enzyme inhibitors, and statins after acute myocardial infarction. , 2006, European heart journal.

[19]  A. Kastrati,et al.  Aspirin and clopidogrel with or without phenprocoumon after drug eluting coronary stent placement in patients on chronic oral anticoagulation , 2008, Journal of internal medicine.

[20]  E. Hylek,et al.  Risk Factors for Intracranial Hemorrhage in Outpatients Taking Warfarin , 1994, Annals of Internal Medicine.

[21]  M. Pfeffer,et al.  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 , 2006, The Lancet.

[22]  Susan Regan,et al.  Major Hemorrhage and Tolerability of Warfarin in the First Year of Therapy Among Elderly Patients With Atrial Fibrillation , 2007, Circulation.

[23]  A. Budaj,et al.  Combining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events: is it safe and effective to use just one antiplatelet agent? , 2007, European heart journal.

[24]  Samuel G. Johnson,et al.  Outcomes associated with combined antiplatelet and anticoagulant therapy. , 2008, Chest.

[25]  David Schultz,et al.  A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) , 1996, The Lancet.

[26]  G. Lip,et al.  Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial , 2007, The Lancet.

[27]  G. Lip,et al.  Antithrombotic therapy in patients treated with oral anticoagulation undergoing coronary artery stenting. An expert consensus document with focus on atrial fibrillation , 2008, Annals of medicine.

[28]  L. Køber,et al.  The pattern of use of non‐steroidal anti‐inflammatory drugs (NSAIDs) from 1997 to 2005: a nationwide study on 4.6 million people , 2008, Pharmacoepidemiology and drug safety.

[29]  E. Romagnoli,et al.  Dual antiplatelet therapy after percutaneous coronary intervention with stent implantation in patients taking chronic oral anticoagulation. , 2008, JACC. Cardiovascular interventions.

[30]  M. Parikh,et al.  Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding. , 2006, The Journal of invasive cardiology.

[31]  A. Greenspon,et al.  Risk of Major Bleeding with Concomitant Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients Receiving Long‐Term Warfarin Therapy , 2007, Pharmacotherapy.

[32]  Bernard Rosner,et al.  The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. , 1990, The New England journal of medicine.

[33]  G. Boysen,et al.  Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. , 1998, Archives of internal medicine.

[34]  L. Poller,et al.  Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. , 1993, The New England journal of medicine.

[35]  H. Sørensen,et al.  The Danish prescription registries. , 1997, Danish medical bulletin.