GI bleeding less common in U.S. veterans on NOACs than those on warfarin

Significant bleeding occurred in 2.5% of the patients on warfarin and 0.6% of the patients on non-vitamin K antagonist oral anticoagulants (NOACs).


GI bleeding was more common among patients taking warfarin than among those taking NOACs, according to a recent study of U.S. veterans.

Researchers used a Veterans Affairs pharmacy database to identify 6,263 patients taking warfarin between January 2011 and June 2015 and 803 patients taking dabigatran, rivaroxaban, or apixaban in the same period. The primary outcome was clinically significant GI bleeding, defined as documented GI blood loss with a hemoglobin drop of 2 g/dL or more, hemodynamic instability, or need for endoscopic evaluation, angiography, or surgery. Results were published by the American Journal of Gastroenterology on Feb. 28.

Significant bleeding occurred in 2.5% of the patients on warfarin and 0.6% of the patients on NOACs (odds ratio, 4.13; 95% CI, 1.69 to 10.09). Among the patients with bleeds, blood transfusions for GI bleeding were more often required in the patients on warfarin than in those on NOACs (64.6% vs. 20%; P=0.04). In the 90 days after hospitalization for a GI bleed, 12 patients on warfarin died, while none of the NOAC patients did. The warfarin group also had longer mean length of stay (7.7 days vs. 3.8 days; P=0.068).

The study's results suggest that the risk of GI bleeding and complications is considerably lower for patients on NOACs than for those on warfarin, the authors concluded. This should “allay the concerns of early reports suggesting that the risk of GI [bleeding] is higher with NOACs than that with warfarin,” they wrote. Possible explanations for the difference between this study's findings and previous research include that warfarin is monitored more closely in clinical trials than in real-world settings and that the choice of NOAC and dose can affect bleeding risk.

The study was limited by an almost exclusively male population, only 20% of whom were on dabigatran, the drug that has been most associated with GI bleeding in previous reports. The warfarin patients also had a higher burden of comorbid disease and higher rate of concomitant anticoagulant or antiplatelet use than those on NOACs, although these differences were not statistically significant. The study authors called for future studies comparing bleeding risk among the NOACs.

On the same topic, a recent cohort study summarized in ACP Hospitalist Weekly found differences in treatment and outcomes of major bleeding between patients taking warfarin and those taking direct oral anticoagulants (DOACs).

Patients had atrial fibrillation or flutter, were 66 years of age or older, and presented to one of five tertiary care hospitals in Ontario, Canada, with oral anticoagulant-related major bleeding (exposure to dabigatran, rivaroxaban, apixaban, or warfarin within three days of presentation). The primary outcome was treatment strategy during the course of the hospital encounter, and secondary outcomes were in-hospital and 30-day mortality. Researchers included 2,002 cases (460 DOAC and 1,542 warfarin) involving 1,799 patients in their analysis. Results were published online in February by Chest.

Among DOAC cases, 245 (53.3%) involved dabigatran, 155 (33.7%) involved rivaroxaban, and 60 (13.0%) involved apixaban. Patients were 81.2 years old on average, had a mean CHA2DS2-VASc score of 4.4, and had a median HAS-BLED score of 3.

Intracranial hemorrhages, especially subdural hematomas, comprised a higher proportion of major bleeding in patients taking warfarin compared to those taking DOACs (29.8% vs. 21.9%, P<0.001 for all intracranial bleeds).A higher proportion of gastrointestinal bleeding, especially in the lower gastrointestinal tract, was seen in the DOAC cohort (61.7% vs. 42.5%, P<0.001, for all gastrointestinal bleeds). Fewer DOAC patients required transfusion of blood products than those on warfarin (278 [60.4%] vs. 1,014 [65.8%]; adjusted risk ratio [RR], 0.92, 95% CI, 0.85 to 1.00). Reflecting the gastrointestinal-predominant bleeding pattern, packed red blood cells were most frequently used in DOAC-related events, whereas prothrombin complex concentrate, vitamin K, and fresh frozen plasma were used more in cases involving warfarin.

Overall, 9.8% of patients in the DOAC cohort and 15.2% of those in the warfarin cohort died in the hospital (P<0.0001). The adjusted RR for inpatient mortality was 0.66 (95% CI, 0.49 to 0.89) for DOAC-related major bleeds compared to warfarin. There were no significant differences in all-cause 30-day mortality between groups (12.6% for DOAC bleeds vs. 16.3% for warfarin bleeds; adjusted RR, 0.79; 95% CI, 0.61 to 1.03).

The study authors noted limitations, such as how the outcomes may not apply to settings other than regional referral centers and that the observational design is prone to immortal time bias and confounding by indication (patients on warfarin who died prior to the study start date were excluded). In addition, the study population was limited to patients undergoing thromboprophylaxis for atrial fibrillation.

The lower in-hospital mortality rate seen with DOACs compared to warfarin (despite high rates of warfarin reversal) is consistent with previous clinical trial findings, the authors noted. “This … suggests patients on these novel agents do not suffer excess harm compared to warfarin in the real-world context, even with the lack of specific antidotes,” they wrote. “Our findings will serve as useful baseline data for comparison of effectiveness and cost-effectiveness of drug-specific reversal agents to guide their optimal use.”