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Aspirin without Indication Added to DOAC Therapy Ups Risk for Bleeding


Study authors warn that ASA added to a medication regimen may be unintentional and call on clinicians to assess patients on DOACs for concomitant ASA and deprescribe.

©Sherry Yates Young/Shutterstock.com

©Sherry Yates Young/Shutterstock.com

Among patients taking a direct oral anticoagulant (DOAC) for atrial fibrillation (AF) and/or venous thromboembolism (VTE), one-third also were receiving aspirin (ASA) without a clear indication for the antiplatelet agent, according to an observational study in JAMA Internal Medicine.

Investigators, led by Jordan K. Schaefer, MD, assistant professor of internal medicine and a hematologist at Michigan Medicine, also reported that concomitant use of a DOAC and ASA compared with DOAC monotherapy was associated with increased rates of bleeding and hospitalization, although thrombosis rates were similar.

The registry-based cohort study took place at 4 anticoagulation clinics in Michigan from January 2015 to December 2019. Eligible participants were adults undergoing treatment with a DOAC for AF or VTE, without history of myocardial infarction (MI) or of heart valve replacement, and who had at least 3 months of follow-up.

Primary outcomes were rates of bleeding (any, nonmajor, major), rates of thrombosis (stroke, VTE, MI), emergency department visits, hospitalizations, and death.

The study cohort comprised 3280 patients (mean age, 58.2 years; 51% men). All had initiated therapy with a DOAC (ie, apixaban, dabigatran, edoxaban, or rivaroxaban) between 2015 and 2019. Approximately one-third (33.8%) of participants who did not have a clear indication for ASA were receiving a DOAC plus ASA.

Investigators analyzed 2 propensity score–matched cohorts, each with 1047 patients, one on concomitant aspirin/DOAC therapy, the other on DOAC montherapy. Median follow up was 12 months.


  • All bleeding: Patients taking DOAC and ASA experienced more bleeding events compared with DOAC monotherapy (26.0 vs 31.6 bleeds per 100 patient years [PY], P = .01).
  • Nonmajor bleeding: Dual therapy had significantly higher rates of nonmajor bleeding (26.1 vs 21.7 bleeds per 100 PY, P = .02).
  • Major bleeding rates and bleeding subtypes were similar between the 2 cohorts.
  • Thrombotic events: Thrombotic events were also similar (2.5 vs 2.3 events per 100 PY, P = .80).
  • Hospitalization: Patients taking ASA plus DOAC also were hospitalized more often than those on DOACs alone (9.1 vs 6.5 admissions per 100 PY, P = .02).
  • Mortality: Rates were similar between ASA/DOAC treatment and DOAC monotherapy (3.8 vs 3.4 per 100 PY, P = 0.76)

Combination therapy also was associated with an increase in minor gastrointestinal bleeds (4.6 vs 3.0 bleeds per 100 PY).

“There remains limited evidence on how to optimally combine DOACs with ASA outside the setting of an ACS and/or PCI procedure,” wrote investigators, commenting on the outcomes.

“Efforts should be made to help clinicians identify and deprescribe ASA for patients taking a DOAC without an indication for ASA.”

"The combination of an anticoagulant and an antiplatelet may be appropriate for people who have had a recent heart attack, recent coronary stent placement or bypass surgery, prior mechanical valve surgery or have known peripheral artery disease, among other conditions," said study coauthor Geoffrey Barnes, MD, MSc, assistant professor of internal medicine and a vascular cardiologist at the Michigan Medicine Frankel Cardiovascular Center, in a Michigan Medicine press release.

For the others, “combination therapy may not be happening intentionally; rather, the addition of aspirin might get overlooked because it’s not in any one specialist or general care provider’s territory,” said Barnes.

The authors called for additional research to help determine whether there are subgroups of high-risk patients that might derive a net benefit from this type of combination therapy. “Efforts should be made to help clinicians identify and deprescribe ASA for patients taking a DOAC without an indication for ASA.”

Schaefer, Barnes, and colleagues had also shown excess bleeding when aspirin was combined with warfarin, also in the absence of any clear indication for the former. The study was published in 2019, also in JAMA Internal Medicine.

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