Risk for Bleeding-Related Hospitalizations During Use of Amiodarone With Apixaban or Rivaroxaban in Patients With Atrial Fibrillation : A Retrospective Cohort Study

Ann Intern Med. 2023 Jun;176(6):769-778. doi: 10.7326/M22-3238. Epub 2023 May 23.

Abstract

Background: Amiodarone, the most effective antiarrhythmic drug in atrial fibrillation, inhibits apixaban and rivaroxaban elimination, thus possibly increasing anticoagulant-related risk for bleeding.

Objective: For patients receiving apixaban or rivaroxaban, to compare risk for bleeding-related hospitalizations during treatment with amiodarone versus flecainide or sotalol, antiarrhythmic drugs that do not inhibit these anticoagulants' elimination.

Design: Retrospective cohort study.

Setting: U.S. Medicare beneficiaries aged 65 years or older.

Patients: Patients with atrial fibrillation began anticoagulant use between 1 January 2012 and 30 November 2018 and subsequently initiated treatment with study antiarrhythmic drugs.

Measurements: Time to event for bleeding-related hospitalizations (primary outcome) and ischemic stroke, systemic embolism, and death with or without recent (past 30 days) evidence of bleeding (secondary outcomes), adjusted with propensity score overlap weighting.

Results: There were 91 590 patients (mean age, 76.3 years; 52.5% female) initiating use of study anticoagulants and antiarrhythmic drugs, 54 977 with amiodarone and 36 613 with flecainide or sotalol. Risk for bleeding-related hospitalizations increased with amiodarone use (rate difference [RD], 17.5 events [95% CI, 12.0 to 23.0 events] per 1000 person-years; hazard ratio [HR], 1.44 [CI, 1.27 to 1.63]). Incidence of ischemic stroke or systemic embolism did not increase (RD, -2.1 events [CI, -4.7 to 0.4 events] per 1000 person-years; HR, 0.80 [CI, 0.62 to 1.03]). The risk for death with recent evidence of bleeding (RD, 9.1 events [CI, 5.8 to 12.3 events] per 1000 person-years; HR, 1.66 [CI, 1.35 to 2.03]) was greater than that for other deaths (RD, 5.6 events [CI, 0.5 to 10.6 events] per 1000 person-years; HR, 1.15 [CI, 1.00 to 1.31]) (HR comparison: P = 0.003). The increased incidence of bleeding-related hospitalizations for rivaroxaban (RD, 28.0 events [CI, 18.4 to 37.6 events] per 1000 person-years) was greater than that for apixaban (RD, 9.1 events [CI, 2.8 to 15.3 events] per 1000 person-years) (P = 0.001).

Limitation: Possible residual confounding.

Conclusion: In this retrospective cohort study, patients aged 65 years or older with atrial fibrillation treated with amiodarone during apixaban or rivaroxaban use had greater risk for bleeding-related hospitalizations than those treated with flecainide or sotalol.

Primary funding source: National Heart, Lung, and Blood Institute.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Amiodarone* / adverse effects
  • Anti-Arrhythmia Agents / adverse effects
  • Anticoagulants / adverse effects
  • Atrial Fibrillation* / complications
  • Atrial Fibrillation* / drug therapy
  • Dabigatran / adverse effects
  • Embolism* / epidemiology
  • Embolism* / prevention & control
  • Female
  • Flecainide / therapeutic use
  • Hemorrhage / chemically induced
  • Hospitalization
  • Humans
  • Ischemic Stroke* / drug therapy
  • Male
  • Medicare
  • Retrospective Studies
  • Rivaroxaban / adverse effects
  • Sotalol / therapeutic use
  • Stroke* / epidemiology
  • Stroke* / prevention & control
  • United States / epidemiology

Substances

  • Rivaroxaban
  • apixaban
  • Amiodarone
  • Flecainide
  • Sotalol
  • Anti-Arrhythmia Agents
  • Anticoagulants
  • Dabigatran