Drug Safety

, Volume 42, Issue 11, pp 1355–1363 | Cite as

Non-Vitamin K Antagonist Oral Anticoagulants and Angioedema: A Cohort and Case-Crossover Study

  • John G. ConnollyEmail author
  • Sebastian Schneeweiss
  • Robert J. Glynn
  • Joshua J. Gagne
Original Research Article



Patients taking non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, and apixaban have reported experiencing angioedema in randomized trials and routine care.


The aim of this study was to quantify the association between NOACs and angioedema relative to warfarin among routinely treated patients with atrial fibrillation in a cohort study. We also compared warfarin users with non-users in a case-crossover study.


We utilized a cohort design that drew eligible patients from the Truven Health MarketScan Commercial database, the Optum© Clinformatics® Data Mart, and Medicare. Within each database, we compared the 6-month relative rate of angioedema among new users of NOACs (dabigatran, rivaroxaban, apixaban) and new users of warfarin. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for confounders using propensity score stratification, and meta-analyzed the database-specific HRs using a random-effects model. We also estimated an odds ratio (OR) for the association between warfarin and angioedema using a case-crossover design, a self-controlled design that controls for time-invariant confounders.


In the cohort study, we observed 249 incident angioedema events among 267,681 NOAC initiators and 281,143 warfarin initiators across all databases. The meta-analyzed HR for angioedema comparing any NOAC versus warfarin was 0.98 (95% CI 0.76–1.27). In the case-crossover design, the OR for the association between warfarin and angioedema was 0.91 (95% CI 0.68–1.21) based on 431 cases.


Our estimates were inconsistent with substantial short-term relative increases in the rate of angioedema associated with oral anticoagulant therapy.



John G. Connolly received a training grant from the Pharmacoepidemiology Program at the Harvard T.H. Chan School of Public Health, which is partially supported by training grants from Pfizer, Takeda, Bayer, and Asisa. This project was internally funded by the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital.

Compliance with Ethical Standards

Conflicts of Interest

John G. Connolly has no conflicts of interest to declare. Sebastian Schneeweiss is a consultant to WHISCON LLC and Aetion Inc., a software manufacturer in which he also owns equity. He is principal investigator of investigator-initiated grants to the Brigham and Women’s Hospital from Genentech, Bayer, Boehringer Ingelheim, US FDA, and the Patient-Centered Outcomes Research Institute, not directly related to the topic of this submitted work. Robert J. Glynn reports grants from Pfizer, Novartis, and Kowa outside the submitted work. Joshua J. Gagne has received salary support from grants from Novartis Pharmaceutical Corporation and Eli Lilly and Company to Brigham and Women’s Hospital, and is a consultant to Aetion, Inc. and Optum Inc., all for unrelated work.


This work was funded internally by the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital.

Supplementary material

40264_2019_852_MOESM1_ESM.docx (559 kb)
Supplementary material 1 (DOCX 559 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Pharmacoepidemiology and Pharmacoeconomics, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA

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