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. 2018 Dec 4;169(11):774-787.
doi: 10.7326/M18-1523. Epub 2018 Oct 30.

Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review

Angela Lowenstern  1 , Sana M Al-Khatib  1 , Lauren Sharan  1 , Ranee Chatterjee  1 , Nancy M Allen LaPointe  2 , Bimal Shah  3 , Ethan D Borre  1 , Giselle Raitz  1 , Adam Goode  1 , Roshini Yapa  4 , J Kelly Davis  5 , Kathryn Lallinger  1 , Robyn Schmidt  1 , Andrzej S Kosinski  1 , Gillian D Sanders  6
Affiliations

Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review

Angela Lowenstern et al. Ann Intern Med. .

Abstract

Background: The comparative safety and effectiveness of treatments to prevent thromboembolic complications in atrial fibrillation (AF) remain uncertain.

Purpose: To compare the effectiveness of medical and procedural therapies in preventing thromboembolic events and bleeding complications in adults with nonvalvular AF.

Data sources: English-language studies in several databases from 1 January 2000 to 14 February 2018.

Study selection: Two reviewers independently screened citations to identify comparative studies of treatments to prevent stroke in adults with nonvalvular AF who reported thromboembolic or bleeding complications.

Data extraction: Two reviewers independently abstracted data, assessed study quality and applicability, and rated strength of evidence.

Data synthesis: Data from 220 articles were included. Dabigatran and apixaban were superior and rivaroxaban and edoxaban were similar to warfarin in preventing stroke or systemic embolism. Apixaban and edoxaban were superior and rivaroxaban and dabigatran were similar to warfarin in reducing the risk for major bleeding. Treatment effects with dabigatran were similar in patients with renal dysfunction (interaction P > 0.05), and patients younger than 75 years had lower bleeding rates with dabigatran (interaction P < 0.001). The benefit of treatment with apixaban was consistent in many subgroups, including those with renal impairment, diabetes, and prior stroke (interaction P > 0.05 for all). The greatest bleeding risk reduction was observed in patients with a glomerular filtration rate less than 50 mL/min/1.73 m2 (P = 0.003). Similar treatment effects were observed for rivaroxaban and edoxaban in patients with prior stroke, diabetes, or heart failure (interaction P > 0.05 for all).

Limitation: Heterogeneous study populations, interventions, and outcomes.

Conclusion: The available direct-acting oral anticoagulants (DOACs) are at least as effective and safe as warfarin for patients with nonvalvular AF. The DOACs had similar benefits across several patient subgroups and seemed safe and efficacious for a wide range of patients with nonvalvular AF.

Primary funding source: Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42017069999).

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Figures

Appendix Figure 1.
Appendix Figure 1.. Analytic framework
AF=atrial fibrillation; DVT=deep vein thrombosis; KQ=Key Question; ICH=intracranial hemorrhage; PE=pulmonary embolism
Appendix Figure 2.
Appendix Figure 2.. Forest plots for comparison of warfarin versus dabigatran (observational studies)
A. Ischemic or Hemorrhagic Stroke; B. Stroke or Systemic Embolism; C. Ischemic or Uncertain Stroke; D. Hemorrhagic Stroke; E. Major Bleeding; F. Intracranial Bleeding; G. Gastrointestinal Bleeding; H. All-Cause Mortality; I. Myocardial Infarction CI=confidence interval
Appendix Figure 2.
Appendix Figure 2.. Forest plots for comparison of warfarin versus dabigatran (observational studies)
A. Ischemic or Hemorrhagic Stroke; B. Stroke or Systemic Embolism; C. Ischemic or Uncertain Stroke; D. Hemorrhagic Stroke; E. Major Bleeding; F. Intracranial Bleeding; G. Gastrointestinal Bleeding; H. All-Cause Mortality; I. Myocardial Infarction CI=confidence interval
Appendix Figure 2.
Appendix Figure 2.. Forest plots for comparison of warfarin versus dabigatran (observational studies)
A. Ischemic or Hemorrhagic Stroke; B. Stroke or Systemic Embolism; C. Ischemic or Uncertain Stroke; D. Hemorrhagic Stroke; E. Major Bleeding; F. Intracranial Bleeding; G. Gastrointestinal Bleeding; H. All-Cause Mortality; I. Myocardial Infarction CI=confidence interval
Appendix Figure 2.
Appendix Figure 2.. Forest plots for comparison of warfarin versus dabigatran (observational studies)
A. Ischemic or Hemorrhagic Stroke; B. Stroke or Systemic Embolism; C. Ischemic or Uncertain Stroke; D. Hemorrhagic Stroke; E. Major Bleeding; F. Intracranial Bleeding; G. Gastrointestinal Bleeding; H. All-Cause Mortality; I. Myocardial Infarction CI=confidence interval
Appendix Figure 2.
Appendix Figure 2.. Forest plots for comparison of warfarin versus dabigatran (observational studies)
A. Ischemic or Hemorrhagic Stroke; B. Stroke or Systemic Embolism; C. Ischemic or Uncertain Stroke; D. Hemorrhagic Stroke; E. Major Bleeding; F. Intracranial Bleeding; G. Gastrointestinal Bleeding; H. All-Cause Mortality; I. Myocardial Infarction CI=confidence interval
Appendix Figure 3.
Appendix Figure 3.. Forest plots for comparisons of factor Xa inhibitors versus warfarin (observational studies)
A. Stroke or Systemic Embolism; B. Ischemic or Uncertain Stroke; C. Hemorrhagic Stroke; D. Major Bleeding; E. Intracranial Bleeding; F. Gastrointestinal Bleeding; G. All-Cause Mortality CI=confidence interval
Appendix Figure 3.
Appendix Figure 3.. Forest plots for comparisons of factor Xa inhibitors versus warfarin (observational studies)
A. Stroke or Systemic Embolism; B. Ischemic or Uncertain Stroke; C. Hemorrhagic Stroke; D. Major Bleeding; E. Intracranial Bleeding; F. Gastrointestinal Bleeding; G. All-Cause Mortality CI=confidence interval
Appendix Figure 3.
Appendix Figure 3.. Forest plots for comparisons of factor Xa inhibitors versus warfarin (observational studies)
A. Stroke or Systemic Embolism; B. Ischemic or Uncertain Stroke; C. Hemorrhagic Stroke; D. Major Bleeding; E. Intracranial Bleeding; F. Gastrointestinal Bleeding; G. All-Cause Mortality CI=confidence interval
Appendix Figure 3.
Appendix Figure 3.. Forest plots for comparisons of factor Xa inhibitors versus warfarin (observational studies)
A. Stroke or Systemic Embolism; B. Ischemic or Uncertain Stroke; C. Hemorrhagic Stroke; D. Major Bleeding; E. Intracranial Bleeding; F. Gastrointestinal Bleeding; G. All-Cause Mortality CI=confidence interval
Appendix Figure 3.
Appendix Figure 3.. Forest plots for comparisons of factor Xa inhibitors versus warfarin (observational studies)
A. Stroke or Systemic Embolism; B. Ischemic or Uncertain Stroke; C. Hemorrhagic Stroke; D. Major Bleeding; E. Intracranial Bleeding; F. Gastrointestinal Bleeding; G. All-Cause Mortality CI=confidence interval
Appendix Figure 3.
Appendix Figure 3.. Forest plots for comparisons of factor Xa inhibitors versus warfarin (observational studies)
A. Stroke or Systemic Embolism; B. Ischemic or Uncertain Stroke; C. Hemorrhagic Stroke; D. Major Bleeding; E. Intracranial Bleeding; F. Gastrointestinal Bleeding; G. All-Cause Mortality CI=confidence interval
Figure 1.
Figure 1.. Literature flow diagram
KQ=Key Question; SR=systematic review
Figure 2.
Figure 2.. Treatment comparisons
Obs=observational; RCT=randomized controlled trials; LAA= Left Atrial Appendage; VKA=vitamin K antagonist
Figure 3.
Figure 3.. Forest plots for comparison of Xa inhibitors versus warfarin (RCTs)
A. Stroke or Systemic Embolism; B. Ischemic or Uncertain Stroke; C. Hemorrhagic Stroke; D. Major bleeding; E. Intracranial Bleeding; F. All-Cause Mortality’ G. Death from Cardiovascular Causes; H. Myocardial Infarction CI=confidence interval; RCTs=randomized controlled trials
Figure 3.
Figure 3.. Forest plots for comparison of Xa inhibitors versus warfarin (RCTs)
A. Stroke or Systemic Embolism; B. Ischemic or Uncertain Stroke; C. Hemorrhagic Stroke; D. Major bleeding; E. Intracranial Bleeding; F. All-Cause Mortality’ G. Death from Cardiovascular Causes; H. Myocardial Infarction CI=confidence interval; RCTs=randomized controlled trials
Figure 3.
Figure 3.. Forest plots for comparison of Xa inhibitors versus warfarin (RCTs)
A. Stroke or Systemic Embolism; B. Ischemic or Uncertain Stroke; C. Hemorrhagic Stroke; D. Major bleeding; E. Intracranial Bleeding; F. All-Cause Mortality’ G. Death from Cardiovascular Causes; H. Myocardial Infarction CI=confidence interval; RCTs=randomized controlled trials
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