Although non-vitamin K antagonists oral anticoagulants (NOACs) are effective in stroke prevention, the risk of major gastrointestinal (GI) bleeding could affect the safety of patients in treatment.

A recent study compared the risk of stroke and systemic embolism (SE) and major bleeding among patients with nonvalvular atrial fibrillation (NVAF) and high risk of GI bleeding who received NOACs compared to patients who received warfarin.

Investigators, led by Gregory Y.H. Lip, MD, Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, found NOACs had an association with lower rates of both stroke and SE, but NOACs had risk of major bleeding in comparison with warfarin.

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Investigators performed the study among patients with NVAF and high risk of GI bleeding newly treated with apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin, as a subgroup analysis of the ARISTOPHANES study.

The ARISTOPHANES study was a retrospective cohort that collected data from the Centers for Medicare & Medicaid Services (CMS) database and 4 US commercial claim databases between January 2012 - September 2015.

Data show patients at high risk of GI bleed were ≥75 years old, with impaired kidney function (chronic kidney disease, stage III - V), a score of ≥3 on the HAS-BLED, or the concomitant use of NSAIDs, antiplatelet agents, or corticosteroids, or GI conditions, including ulcers or bleeds.

The primary effectiveness outcomes included stroke or SE, with stratification by ischemic stroke, hemorrhagic stroke, and SE, while the primary safety outcome included MD, stratified by GI bleeding, intracranial hemorrhage, and MB.

Primary outcomes were identified from inpatient claims with stroke, SE, or MB listed as principal diagnosis.

Investigators used propensity score matching (PSM) to compare NOAC versus warfarin (apixaban versus warfarin, dabigatran versus warfarin, and rivaroxaban versus warfarin), and NOAC versus NOAC (apixaban versus dabigatran, apixaban versus rivaroxaban, and dabigatran versus rivaroxaban).


Investigators identified a total of 381,054 patients with NVAF and high risk of GI bleed, representing nearly 82% of the total ARISTOPHANES population.

Of this population, 23.4% (n = 89,296) were prescribed apixaban, followed by 38.1% prescribed warfarin (n = 145,063), 31.1% (n = 118,378) prescribed rivaroxaban, and 7.4% (n = 28,317) were prescribed dabigatran.

Data show among the high-risk patients, 74.7% (n = 284,527) had a HAS-BLED score of ≥3, with 66.4% (n = 252,835) aged ≥75 years and 28.3% (n = 107,675) were using corticosteroid, antiplatelet, or NSAID therapy.

In addition, data show 19.6% (n = 74,818) had a prior GI bleeding condition and 14.9% (n = 56,892) had stage III to V CKD. A total of 355,673 patients had ≤3 risk factors concurrently at baseline.

Investigators observed all NOACs had a lower risk of stroke or SE compared to warfarin, including apixaban (hazard ratio 0.60; 95% CI, 0.52 - 0.68), dabigatran (HR 0.75; 95% CI, 0.64 - 0.88), and rivaroxaban (HR 0.79; 95% CI, 0.73 - 0.86).

Further, in comparison with warfarin, both apixaban and dabigatran were associated with a lower risk of MB (apixaban: HR, 0.59; 95% CI, 0.56 - 0.63; dabigatran: HR, 0.78; 95% CI, 0.70 - 0.86).

However, they also observed that rivaroxaban had associations with a higher risk of MB (HR 1.11; 95% CI, 1.05 - 1.16).

Moreover, investigators found patients taking apixaban had a lower risk of stroke or SE in comparison with dabigatran (HR 0.75; 95% CI, 0.62 - 0.91) and rivaroxaban (HR 0.74; 95% CI, 0.67 - 0.83). Apixaban had associations with lower risk of GI bleeding, while rivaroxaban was associated with a higher risk of GI bleeding compared to warfarin.


The team concluded NOACs had associations with lower risk of stroke or SE in comparison with warfarin in patients with NVAF and high risk for GI bleeding.

“This is one of the first real-world studies to compare NOACs in the patients with NVAF and high risk of GI bleed; the results may help inform decision-making regarding OACs in this high-risk patient population,” investigators wrote.

The study, “Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With High Risk of Gastrointestinal Bleeding,” was published in JAMA Network Open.

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