Effect of Apixaban on All-Cause Death in Patients with Atrial Fibrillation: a Meta-Analysis Based on Imputed Placebo Effect

PurposeVitamin K antagonists (VKAs) are the standard of care for stroke prevention in patients with atrial fibrillation (AF); therefore, there is not equipoise when comparing newer oral anticoagulants with placebo in this setting.MethodsTo explore the effect of apixaban on mortality in patients with AF, we performed a meta-analysis of apixaban versus placebo using a putative placebo analysis based on randomized controlled clinical trials that compared warfarin, aspirin, and no antithrombotic control. We used data from two prospective randomized controlled trials for our comparison of apixaban versus warfarin (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) and apixaban versus aspirin (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment). Using meta-analysis approaches, we indirectly compared apixaban with an imputed placebo with respect to the risk of death in patients with AF. We used results from meta-analyses of randomized trials as our reference for the comparison between warfarin and placebo/no treatment, and aspirin and placebo/no treatment.ResultsIn these meta-analyses, a lower rate of death was seen both with warfarin (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.57–0.97) and aspirin (OR 0.86, 95% CI 0.69–1.07) versus placebo/no treatment. Using data from ARISTOTLE and AVERROES, apixaban reduced the risk of death by 34% (95% CI 12–50%; p = 0.004) and 33% (95% CI 6–52%; p = 0.02), respectively, when compared with an imputed placebo. The pooled reduction in all-cause death with apixaban compared with an imputed placebo was 34% (95% CI 18–47%; p = 0.0002).ConclusionsIn patients with AF, indirect comparisons suggest that apixaban reduces all-cause death by approximately one third compared with an imputed placebo.

[1]  S D Walter,et al.  The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. , 1997, Journal of clinical epidemiology.

[2]  D. Levy,et al.  Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. , 1998, Circulation.

[3]  L. Fisher,et al.  Active-control trials: how would a new agent compare with placebo? A method illustrated with clopidogrel, aspirin, and placebo. , 2001, American heart journal.

[4]  Yi Tsong,et al.  Utility and pitfalls of some statistical methods in active controlled clinical trials. , 2002, Controlled clinical trials.

[5]  A. Mattioli,et al.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients , 2002, BMJ : British Medical Journal.

[6]  Catherine Sudlow,et al.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients , 2002, BMJ : British Medical Journal.

[7]  S. Durrleman,et al.  The use of putative placebo in active control trials: two applications in a regulatory setting , 2003, Statistics in medicine.

[8]  K. Murray,et al.  Analysis of Cause-Specific Mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study , 2004, Circulation.

[9]  M. Aguilar,et al.  Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation , 2007, Annals of Internal Medicine.

[10]  Leon Poller,et al.  Dabigatran versus warfarin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[11]  G. Lip,et al.  Atrial fibrillation and mortality: the impact of antithrombotic therapy. , 2010, European heart journal.

[12]  C. Albert,et al.  Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation. , 2011, JAMA.

[13]  Donald R. Lynch Apixaban in patients with atrial fibrillation. , 2011, The New England journal of medicine.

[14]  Á. Chamorro,et al.  Oral anticoagulant-associated intracerebral hemorrhage , 2012, Journal of Neurology.

[15]  G. Breithardt,et al.  Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. , 2011, The New England journal of medicine.

[16]  S. Yusuf,et al.  Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With Warfarin or Dabigatran: The RE-LY Trial , 2012, Stroke.

[17]  Apixaban versus Warfarin in Patients with Atrial Fibrillation , 2012 .

[18]  J. Le Heuzey,et al.  Causes of Death and Influencing Factors in Patients With Atrial Fibrillation: A Competing-Risk Analysis From the Randomized Evaluation of Long-Term Anticoagulant Therapy Study , 2013, Circulation.

[19]  E. Antman,et al.  Edoxaban versus warfarin in patients with atrial fibrillation. , 2013, The New England journal of medicine.

[20]  G. Breithardt,et al.  Intracranial Hemorrhage Among Patients With Atrial Fibrillation Anticoagulated With Warfarin or Rivaroxaban: The Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation , 2014, Stroke.

[21]  Alexander Parkhomenko,et al.  Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials , 2014, The Lancet.

[22]  G. Breithardt,et al.  Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). , 2014, Journal of the American College of Cardiology.

[23]  E. Benjamin,et al.  Clinical course of atrial fibrillation in older adults: the importance of cardiovascular events beyond stroke. , 2014, European heart journal.

[24]  Akshay S. Desai,et al.  A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure , 2014, European heart journal.

[25]  G. Breithardt,et al.  Cause of Death and Predictors of All‐Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF , 2016, Journal of the American Heart Association.

[26]  C. Held,et al.  Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy. , 2017, Blood.