Comparison of two DOACs in AF patients

Association of rivaroxaban vs apixaban with major ischemic or hemorrhagic events in patients with atrial fibrillation

Literature - Ray WA, Chung CP, Stein CM, et al. - JAMA. 2021 Dec 21;326(23):2395-2404. Doi: 10.1001/jama.2021.21222

Introduction and methods


Patients with AF are preferably treated with a DOAC, such as apixaban and rivaroxaban, to prevent ischemic stroke [1]. Apixaban and rivaroxaban are both reversible inhibitors of activated factor X and have similar half-lives [2]. Because apixaban is taken twice daily, while a single dose is sufficient for rivaroxaban, the concentration of rivaroxaban varies considerably more throughout the day [2,3]. This raises the question of how the effectiveness and safety of both anticoagulants compare.

Aim of the study

The aim of this study to compare the effectiveness and safety of apixaban and rivaroxaban in patients with AF.


The researchers conducted a retrospective cohort study based on data from the U.S. health insurance company Medicare. Patients aged 65 years or older who had been diagnosed with AF or atrial flutter in the past 90 days and initiated treatment with apixaban (2.5 or 5 mg twice daily; n=353,879) or rivaroxaban (15 or 20 mg once daily; n=227,572) during the period January 1, 2013-November 30, 2018, were included. Patients with terminal illness, mitral valve stenosis, severe chronic kidney disease, mechanical heart valve, or a condition causing a reversible AF were excluded from participation. Also, long-term care residents and patients who had been treated with a DOAC in the past year or who had been hospitalized for stroke or bleeding in the past 30 days were excluded. The follow-up period was 4 years, beginning the day after filling the initial DOAC prescription.


The primary outcome was a composite of major ischemic events (ischemic stroke, systemic embolism) and major hemorrhagic events (intracerebral hemorrhage, other intracranial hemorrhage, fatal extracranial hemorrhage). Secondary outcomes were nonfatal extracranial bleeding and total mortality (death from an ischemic or hemorrhagic event, death from any other cause). Data on the outcome measures were collected from hospital principal discharge codes.

The analysis adjusted for covariates with stabilized inverse probability of treatment weights calculated from the propensity score. The propensity score was estimated with logistic regression that was stratified by anticoagulant dose.

Main results

Primary outcome

  • The incidence of major ischemic or hemorrhagic events was higher in the rivaroxaban group than in the apixaban group (16.1 vs. 13.4 per 1000 person-years; HR: 1.18; 95%CI: 1.12-1.24).
  • Both major ischemic events (8.6 vs. 7.6 per 1000 person-years; HR: 1.12; 95%CI: 1.04-1.20) and major hemorrhagic events (7.5 vs. 5.9 per 1000 person-years; HR: 1.26; 95%CI: 1.16-1.36) occurred more frequently in patients treated with rivaroxaban, compared with apixaban.
  • Patients treated with rivaroxaban had more frequent ischemic stroke (8.3 vs. 7.2 per 1000 person-years; HR: 1.12; 95%CI: 1.05-1.21), hemorrhagic stroke (2.5 vs. 1.7 per 1000 person-years; HR: 1.48; 95%CI: 1.30-1.70) and fatal extracranial hemorrhage (1.4 vs. 1.0 per 1000 person-years; HR: 1.41; 95%CI: 1.18-1.70) than patients treated with apixaban.
  • Risk of the primary outcome was increased in patients treated with rivaroxaban in both those receiving the reduced dose and the standard dose, when compared to apixaban groups.

Secondary outcomes

  • The incidence of nonfatal extracranial bleeding was higher in the rivaroxaban group than in the apixaban group (39.7 vs. 18.5 per 1000 person-years; HR: 2.07; 95%CI: 1.99-2.15).
  • Rate of total mortality was also higher in the rivaroxaban group than in the apixaban group (44.2 vs. 41.0 per 1000 person-years; HR: 1.06; 95%CI: 1.02-1.09).


In patients aged 65 years or older with AF, treatment with rivaroxaban more often resulted in major ischemic or hemorrhagic events, compared with apixaban.


1. January CT,Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons. Circulation. 2019;140(2):e125-e151. doi: 10.1161/CIR.0000000000000665.

2. Gong IY, Kim RB. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol. 2013;29(7)(suppl):S24-S33. doi:10. 1016/j.cjca.2013.04.002.

3. Frost C, Song Y, Barrett YC, et al. A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban. Clin Pharmacol. 2014;6:179-187. doi:10.2147/CPAA.

Find this article online at JAMA.

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