Concurrent use of DOAC and aspirin without indication associated with increased bleeding in AF and VTE

Adverse Events Associated With the Addition of Aspirin to Direct Oral Anticoagulant Therapy Without a Clear Indication

Literature - Schaefer JK, Errickson J, Li Y et al. - JAMA Intern Med. 2021 Apr 19. doi: 10.1001/jamainternmed.2021.1197

Introduction and methods

Aspirin, or Acetylsalicylic acid (ASA), in combination with oral anticoagulation therapy is indicated for patients with non-valvular AF or VTE who experience ACS or undergo PCI, as well as for patients with certain assist devices [1,2]. Aside from conditions were combination of ASA and oral anticoagulation is indicated, combination therapy may increase bleeding without reducing thrombotic outcomes [3-7]. The 2019 ACC/AHA Guidelines on the primary prevention of CVD do not recommend use of prophylactic ASA in combination with anticoagulants in patients with an increased bleeding risk [7]. However, it remains unclear what proportion of patients who are on DOACs also receive ASA without a well-defined therapeutic indication and how concomitant ASA and DOAC therapy affects clinical outcomes in patients with AF and/or VTE.

This registry-based cohort study included 3280 patients (1673 men [51%], mean age 68.2 [SD:13.3] years) who received DOAC therapy and who had no clear indication for ASA . Patients who started a DOAC for AF or VTE at 4 anticoagulation clinics in the state of Michigan, USA were included in the registry. Patients who had<3 months follow-up data available, who experienced a MI <6 months prior to DOAC initiation, or had a history of heart valve replacement were excluded. Patients not using ASA were included in the DOAC monotherapy group (2173 of 3280, 66.3%) and patients using any dose of ASA were included in the DOAC combination therapy group (1107 of 3280, 33.8%). Propensity scoring resulted in two propensity score-matched cohorts of each 1047 patients. The primary outcome was rate of any patients-reported bleeding events, regardless of severity. Secondary bleeding outcomes included major bleeding, nonmajor bleeding, emergency visits for bleeding, and hospitalizations related to bleeding. Secondary thrombotic outcomes included ischemic strokes, TIA, VTE, ACS/MI, emergency visits for thrombosis, and hospitalizations for thrombosis. Median follow up was 12 (IQR 6-30) months.

Main results

  • Patients on combinational therapy experienced significantly more bleeding events compared to patients on DOAC monotherapy (any new bleed: 31.60 per 100 patient-years, 95%CI 30.54-32.75 vs. 26.00 per 100 patient-years, 95%CI 25.05-27.06, P=0.009). This was predominantly driven by increased rates of nonmajor bleeding in those on combination therapy compared to those on DOAC monotherapy (26.10 per 100 patient-years, 95%CI 25.14-27.15 vs. 21.70 per 100 patient-years, 95%CI 20.77-22.60, P=0.02). There was no significant difference in major bleedings between groups.
  • Emergency visits for bleeding were similar between groups. However, rates of hospitalizations for bleeding were higher in patients on combination therapy compared to DOAC monotherapy (8.20 per 100 patients-years, 95%CI 7.62-8.75 vs. 5.30 per 100 patient-years, 95%CI 4.87-5.78, P=0.006).
  • Rates of major gastrointestinal (GI) bleeding were similar between groups. However, minor GI bleeds occurred more often with combination therapy compared with DOAC monotherapy (4.57 per 100 patient years, 95%CI 4.16-5.01 vs. 3.04 per 100 patient years, 95%CI 2.71-3.40, P=0.03).
  • Thrombotic event rates were low and similar between groups. There was no difference in emergency visits for clotting or hospitalization for clotting between groups. There was also no difference in mortality between the two treatment groups.


This registry-based cohort study of patients with AF and/or VTE showed that 1 in 3 patients were taking ASA without clear therapeutic indication in addition to DOAC. Patients on ASA plus DOAC experienced significantly more bleeding events than patients on DOAC monotherapy. This difference was driven by a difference in minor bleeding. Patients on ASA plus DOAC were also more often hospitalized for bleeding events compared to those on DOAC alone. There was no significant difference in major bleedings rates nor in thrombotic event rates between groups.


1. O'Gara PT, Kushner FG, Ascheim DD, et al., 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv. 2013 Jul 1;82(1):E1-27.doi: 10.1002/ccd.24776.

2. You JJ, Singer DE, Howard PA, et al., Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e531S-e575S. doi: 10.1378/chest.11-2304.

3. Schaefer JK, Li Y, Gu X et al., Association of Adding Aspirin to Warfarin Therapy Without an Apparent Indication With Bleeding and Other Adverse Events. JAMA Intern Med. 2019 Apr 1;179(4):533-541. doi: 10.1001/jamainternmed.2018.7816.

4. Steinberg BA, Kim S, Piccini JP et al., Use and associated risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation: insights from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation. 2013 Aug 13;128(7):721-8. doi: 10.1161/CIRCULATIONAHA.113.002927.

5. Johnson SG, Rogers K, Delate T et al., Outcomes associated with combined antiplatelet and anticoagulant therapy. Chest. 2008 Apr;133(4):948-54. doi: 10.1378/chest.07-2627. Epub 2008 Jan 15.

6. So CH, Eckman MH, Combined aspirin and anticoagulant therapy in patients with atrial fibrillation. J Thromb Thrombolysis. 2017 Jan;43(1):7-17. doi: 10.1007/s11239-016-1425-5.

7. Arnett DK, Blumenthal RS, Albert MA et al., 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019 Sep 10;74(10):e177-e232. doi: 10.1016/j.jacc.2019.03.010. Epub 2019 Mar 17.

Find this article online at JAMA Intern Med.

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