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Comparative effectiveness and safety of direct acting oral anticoagulants in nonvalvular atrial fibrillation for stroke prevention: a systematic review and meta-analysis

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Abstract

Purpose:To systematically review available evidence of indirect comparisons from RCTs and direct comparisons from observational studies regarding the comparative effectiveness and safety of DOACs in patients with AF. Methods: Electronic databases including EMBASE, MEDLINE, and PUBMED were searched up to June 5th, 2020. Primary endpoints included effectiveness (stroke or systemic embolism [SE]) and safety (major bleeding) outcomes. Bucher methods and random-effects models were conducted for indirect and direct comparisons among DOACs, respectively. Ranking probability analyses and the number needed to treat for net effect (NNTnet) were applied. Results: A total of 36 studies, involving 7 RCTs (n = 60,292 patients) and 29 observational studies (n = 1,164,821 patients), were included for analyses. Regarding the risk of stroke/SE, no significant differences were found from indirect comparisons of RCTs among the DOACs. For major bleeding, apixaban tended to be safer than rivaroxaban and dabigatran based on both direct and indirect comparisons (all p < 0.05; evidence quality: very low to moderate). Ranking probability analysis showed that apixaban had a high probability of being the best treatment in decreased risk of stroke/SE and major bleeding (80.30% and 91.30%, respectively). Likewise, apixaban was found to have the highest net clinical benefit (0.02, 95% CI: 0.014–0.029) and smallest NNTnet (48, 95% CI: 35–74). Conclusions: Apixaban appeared to have a favorable effectiveness-safety profile compared with the other DOACs in AF for stroke prevention, based on evidence from both direct and indirect comparisons. However, additional high-quality evidence is needed to support firm recommendations on clinical decision-making.

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Abbreviations

DOACs:

Direct acting oral anticoagulants

AF:

Atrial fibrillation

VKAs:

Vitamin K antagonists

RCTs:

Randomized controlled trials

SE:

Systemic embolism

SCURA:

Surface under the cumulative ranking

NNTnet:

Number needed to treat for net effect

ICH:

Intracranial hemorrhage

GI:

Gastrointestinal

ROB:

Risk of bias

ROBINS-I:

Bias In Non-randomized Studies of Interventions

HRs:

Hazard ratios

CIs:

Confidence intervals

ARR:

Absolute risk reduction

ARI:

Absolute risk increase

GRADE:

Grading of recommendations, assessment, development, and evaluation

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Acknowledgement

We acknowledge Professor Gordon H Guyatt for his help with data analyses and discussions.

Funding

This study was funded by Science Foundation of Guangdong Second Provincial General Hospital (Grant recipient: Dr. Guowei Li; Grant no. :YY2018–002), Doctoral Workstation Foundation of Guangdong Second Provincial General Hospital (Grant recipient: Dr. Junguo Zhang; Grant no. :2021BSGZ007) and Medical Scientific Research Foundation of Guangdong Province of China (Grant recipient: Dr. Guowei Li; Grant no. :A2020453).

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Authors and Affiliations

  1. Center for Clinical Epidemiology and Methodology (CCEM), Guangdong Second Provincial General Hospital, Guangzhou, 510317, China

    Junguo Zhang & Guowei Li

  2. Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, China

    Xiaojie Wang

  3. Department of Neurology, Guangdong Second Provincial General Hospital, Guangzhou, China

    Xintong Liu

  4. Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark

    Torben B. Larsen

  5. Department of Pharmacotherapy, University of Utah, Salt Lake City, USA

    Daniel M. Witt

  6. Department of Cardiology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China

    Zebing Ye

  7. Department of Health Research Methods, Evidence, and Impact (HEI), McMaster University, 1280 Main St West, Hamilton, ON, L8S 4L8, Canada

    Lehana Thabane & Guowei Li

  8. Liverpool Centre for Cardiovascular Science, University of Liverpool, 6 West Derby St, Liverpool, L7 8TX, UK

    Gregory Y. H. Lip

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  7. Lehana Thabane
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  8. Guowei Li
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  9. Gregory Y. H. Lip
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Contributions

JZ, GL, XL and GYL designed research and generated study plan; JZ, XW and GL conducted the meta-analysis and drafted the manuscript; JZ, XW, TBL, DMW, and GL analyzed the data; JZ, XW, TBL, DMW, ZY, LT, GL and GYL revised the manuscript. GL and GYL had primary responsibility for final content. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Guowei Li or Gregory Y. H. Lip.

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Supplementary Information

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Supplementary file1 (TIFF 703 kb)

10654_2021_751_MOESM2_ESM.tiff

Supplementary Figure 2 Risk of bias graph - Methodological quality summary: review authors' judgments about each methodological quality item for each included RCTs (TIFF 678 kb)

Supplementary Figure 3 Risk of bias in non-randomized studies of interventions for observational studies (TIF 4563 kb)

Supplementary Figure 4 Direct comparative effect on death amongst DOACs in patients with AF (TIF 1063 kb)

Supplementary file5 (DOCX 1300 kb)

Supplementary file6 (DOCX 75 kb)

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Zhang, J., Wang, X., Liu, X. et al. Comparative effectiveness and safety of direct acting oral anticoagulants in nonvalvular atrial fibrillation for stroke prevention: a systematic review and meta-analysis. Eur J Epidemiol 36, 793–812 (2021). https://doi.org/10.1007/s10654-021-00751-7

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  • DOI: https://doi.org/10.1007/s10654-021-00751-7

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