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

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Abstract

Purpose

Vitamin 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.

Methods

To 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.

Results

In 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).

Conclusions

In patients with AF, indirect comparisons suggest that apixaban reduces all-cause death by approximately one third compared with an imputed placebo.

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Acknowledgements

The ARISTOTLE trial was funded by Bristol-Myers Squibb, Princeton, NJ, USA, and Pfizer Inc., New York, NY, USA, and coordinated by the Duke Clinical Research Institute (DCRI), USA, and Uppsala Clinical Research Center (UCR), Sweden.

JJVM and RDL had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. RDL, POG, and JJVM drafted the manuscript. All authors made substantial contributions to the design of the work and the acquisition, analysis, or interpretation of data; reviewed and revised the work; gave final approval of the version to be submitted; and agreed to be accountable for all aspects of the work. The authors certify that the manuscript represents valid work and that neither this one nor one with substantially similar content under their authorship has been published or is being considered for publication elsewhere.

Editorial assistance was provided by Elizabeth Cook of the Duke Clinical Research Institute. We would like to thank Li Wang who conducted these analyses under the guidance of co-authors, and Weihua Tang provided validation of the results.

Funding

This work and the ARISTOTLE trial were supported by Bristol-Myers Squibb and Pfizer. The sponsor had no role in the interpretation of the results or decision to submit the article for publication.

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Correspondence to Renato D. Lopes.

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Potential Conflicts of Interest

POG, DMW, AHA-R: none. RDL: Institutional research grants from Bristol-Myers Squibb and GlaxoSmithKline and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, and Portola. SJC: Consulting fees from Bristol-Myers Squibb and Pfizer. GCF: Consulting fees from Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Janssen Pharmaceuticals, and Sanofi Aventis. JW: Employee of Merck Serono. MH: Employee of Bristol-Myers Squibb. CBG: Institutional research grants from Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, US Food and Drug Administration, GlaxoSmithKline, Janssen Pharmaceuticals, The Medicines Company, Medtronic Foundation, Novartis, Pfizer, Sanofi Aventis, and Takeda and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Daiichi Sankyo, Gilead, GlaxoSmithKline, Hoffmann-LaRoche, Janssen Pharmaceuticals, The Medicines Company, Medtronic, National Institutes of Health, Novartis, Pfizer, Sanofi Aventis, and Takeda. LW: Institutional research grants from Bristol-Myers Squibb/Pfizer, AstraZeneca, Merck, Boehringer Ingelheim, and GlaxoSmithKline and consulting fees from GlaxoSmithKline, Bristol-Myers Squibb/Pfizer, Abbott, AstraZeneca, and Boehringer Ingelheim. KRL: Fees and expenses from Boehringer Ingelheim, EVER Neuro Pharma, Nestle, and Novartis but no external support in connection with this manuscript. JHA: Institutional research grants from Bristol-Myers Squibb, Boehringer Ingelheim, CSL Behring, National Institutes of Health, Sanofi, and Tenax Therapeutics and consulting fees from Bristol-Myers Squibb, CSL Behring, Duke Private Diagnostic Clinic, Pfizer, Portola, and VA Cooperative Studies Program. JJVM: Institutional consulting fees from Novartis, Cardiorentis, Amgen, Oxford University/Bayer, GlaxoSmithKline, Theracos, Abbvie, DalCor, Pfizer, and Merck.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

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Guimarães, P.O., Lopes, R.D., Wojdyla, D.M. et al. Effect of Apixaban on All-Cause Death in Patients with Atrial Fibrillation: a Meta-Analysis Based on Imputed Placebo Effect. Cardiovasc Drugs Ther 31, 295–301 (2017). https://doi.org/10.1007/s10557-017-6728-z

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  • DOI: https://doi.org/10.1007/s10557-017-6728-z

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