[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Views 4,409
Citations 0
Original Investigation
March 4, 2019

Association of Adding Aspirin to Warfarin Therapy Without an Apparent Indication With Bleeding and Other Adverse Events

Author Affiliations
  • 1Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor
  • 2Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor
  • 3Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor
  • 4College Student, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor
  • 5Department of Internal Medicine, Beaumont Health, Oakland University School of Medicine, Royal Oak, Michigan
  • 6Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan
  • 7Department of Cardiovascular Medicine, Huron Valley Sinai Hospital, Commerce Township, Michigan
JAMA Intern Med. 2019;179(4):533-541. doi:10.1001/jamainternmed.2018.7816
Key Points

Question  Among patients receiving warfarin sodium for management of atrial fibrillation or venous thromboembolism, how often are patients receiving aspirin (acetylsalicylic acid) without a clear therapeutic indication, and what is the clinical impact?

Findings  In a registry-based cohort study of 3688 propensity score–matched patients followed up prospectively at anticoagulation clinics, without a heart valve replacement or recent acute coronary syndrome, 37.5% received aspirin. These patients had a statistically higher rate of bleeding, emergency department visits, and hospitalizations for bleeding; there was no observed difference in thrombosis rates.

Meaning  Some patients receiving anticoagulation treatment with warfarin may be receiving concomitant aspirin therapy that may increase bleeding risk with unclear therapeutic benefit.


Importance  It is not clear how often patients receive aspirin (acetylsalicylic acid) while receiving oral anticoagulation with warfarin sodium without a clear therapeutic indication for aspirin, such as a mechanical heart valve replacement, recent percutaneous coronary intervention, or acute coronary syndrome. The clinical outcomes of such patients treated with warfarin and aspirin therapy compared with warfarin monotherapy are not well defined to date.

Objective  To evaluate the frequency and outcomes of adding aspirin to warfarin for patients without a clear therapeutic indication for combination therapy.

Design, Setting, and Participants  A registry-based cohort study of adults enrolled at 6 anticoagulation clinics in Michigan (January 1, 2010, to December 31, 2017) who were receiving warfarin therapy for atrial fibrillation or venous thromboembolism without documentation of a recent myocardial infarction or history of valve replacement.

Exposure  Aspirin use without therapeutic indication.

Main Outcomes and Measures  Rates of any bleeding, major bleeding events, emergency department visits, hospitalizations, and thrombotic events at 1, 2, and 3 years.

Results  Of the study cohort of 6539 patients (3326 men [50.9%]; mean [SD] age, 66.1 [15.5] years), 2453 patients (37.5%) without a clear therapeutic indication for aspirin were receiving combination warfarin and aspirin therapy. Data from 2 propensity score–matched cohorts of 1844 patients were analyzed (warfarin and aspirin vs warfarin only). At 1 year, patients receiving combination warfarin and aspirin compared with those receiving warfarin only had higher rates of overall bleeding (cumulative incidence, 26.0%; 95% CI, 23.8%-28.3% vs 20.3%; 95% CI, 18.3%-22.3%; P < .001), major bleeding (5.7%; 95% CI, 4.6%-7.1% vs 3.3%; 95% CI, 2.4%-4.3%; P < .001), emergency department visits for bleeding (13.3%; 95% CI, 11.6%-15.1% vs 9.8%; 95% CI, 8.4%-11.4%; P = .001), and hospitalizations for bleeding (8.1%; 6.8%-9.6% vs 5.2%; 4.1%-6.4%; P = .001). Rates of thrombosis were similar, with a 1-year cumulative incidence of 2.3% (95% CI, 1.6%-3.1%) for those receiving combination warfarin and aspirin therapy compared with 2.7% (95% CI, 2.0%-3.6%) for those receiving warfarin alone (P = .40). Similar findings persisted during 3 years of follow-up as well as in sensitivity analyses.

Conclusions and Relevance  Compared with warfarin monotherapy, receipt of combination warfarin and aspirin therapy was associated with increased bleeding and similar observed rates of thrombosis. Further research is needed to better stratify which patients may benefit from aspirin while anticoagulated with warfarin for atrial fibrillation or venous thromboembolism; clinicians should be judicious in selecting patients for combination therapy.

Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    Inappropriate medications: an invitation to adverse events.
    Rajeev Gupta, MBBS;MD;DM (Cardiology) | Mediclinic Al Jowhara Hospital, Al Ain, United Arab Emirates (UAE)

    I read the article with interest; 37.5% of patients using warfarin were put on aspirin concomitantly without an evidence-based or guideline-based need. This is alarming. Inappropriately administered drugs cause more complications than appropriately administered drugs. (1)
    If concomitant administration of OAC with an antiplatelet agent is deemed imperative, a recently completed study with real-world data and retrospective analysis, showed that a DOAC-antiplatelet combination was safer than a VKA-antiplatelet combination, with a lower risk of major bleeding including intracranial hemorrhage. (2)

    1. Hamilton H, Gallagher P, Ryan C, et al. Potentially inappropriate medications defined by STOPP criteria
    and the risk of adverse drug events in older hospitalized patients. Ann Intern Med. 2011;171:1013-1019.

    2. Douros A, Renoux C, Yin H, et al. Concomitant use of direct oral anticoagulants with antiplatelet agents and the risk of major bleeding in patients with nonvalvular atrial fibrillation: Am J Med. 2019; 132:2, 191-199 e12. doi:10.1016/j.amjmed.2018.10.08