Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding

Abstract

Importance: Anticoagulant choice and proton pump inhibitor (PPI) cotherapy could affect the risk of upper gastrointestinal tract bleeding, a frequent and potentially serious complication of oral anticoagulant treatment.

Objectives: To compare the incidence of hospitalization for upper gastrointestinal tract bleeding in patients using individual anticoagulants with and without PPI cotherapy, and to determine variation according to underlying gastrointestinal bleeding risk.

Design, setting, and participants: Retrospective cohort study in Medicare beneficiaries between January 1, 2011, and September 30, 2015.

Exposures: Apixaban, dabigatran, rivaroxaban, or warfarin with or without PPI cotherapy.

Main outcomes and measures: Hospitalizations for upper gastrointestinal tract bleeding: adjusted incidence and risk difference (RD) per 10 000 person-years of anticoagulant treatment, incidence rate ratios (IRRs).

Results: There were 1 643 123 patients with 1 713 183 new episodes of oral anticoagulant treatment included in the cohort (mean [SD] age, 76.4 [2.4] years, 651 427 person-years of follow-up [56.1%] were for women, and the indication was atrial fibrillation for 870 330 person-years [74.9%]). During 754 389 treatment person-years without PPI cotherapy, the adjusted incidence of hospitalization for upper gastrointestinal tract bleeding (n = 7119) was 115 per 10 000 person-years (95% CI, 112-118). The incidence for rivaroxaban (n = 1278) was 144 per 10 000 person-years (95% CI, 136-152), which was significantly greater than the incidence of hospitalizations for apixaban (n = 279; 73 per 10 000 person-years; IRR, 1.97 [95% CI, 1.73-2.25]; RD, 70.9 [95% CI, 59.1-82.7]), dabigatran (n = 629; 120 per 10 000 person-years; IRR, 1.19 [95% CI, 1.08-1.32]; RD, 23.4 [95% CI, 10.6-36.2]), and warfarin (n = 4933; 113 per 10 000 person-years; IRR, 1.27 [95% CI, 1.19-1.35]; RD, 30.4 [95% CI, 20.3-40.6]). The incidence for apixaban was significantly lower than that for dabigatran (IRR, 0.61 [95% CI, 0.52-0.70]; RD, -47.5 [95% CI,-60.6 to -34.3]) and warfarin (IRR, 0.64 [95% CI, 0.57-0.73]; RD, -40.5 [95% CI, -50.0 to -31.0]). When anticoagulant treatment with PPI cotherapy (264 447 person-years; 76 per 10 000 person-years) was compared with treatment without PPI cotherapy, risk of upper gastrointestinal tract bleeding hospitalizations (n = 2245) was lower overall (IRR, 0.66 [95% CI, 0.62-0.69]) and for apixaban (IRR, 0.66 [95% CI, 0.52-0.85]; RD, -24 [95% CI, -38 to -11]), dabigatran (IRR, 0.49 [95% CI, 0.41-0.59]; RD, -61.1 [95% CI, -74.8 to -47.4]), rivaroxaban (IRR, 0.75 [95% CI, 0.68-0.84]; RD, -35.5 [95% CI, -48.6 to -22.4]), and warfarin (IRR, 0.65 [95% CI, 0.62-0.69]; RD, -39.3 [95% CI, -44.5 to -34.2]).

Conclusions and relevance: Among patients initiating oral anticoagulant treatment, incidence of hospitalization for upper gastrointestinal tract bleeding was the highest in patients prescribed rivaroxaban, and the lowest for patients prescribed apixaban. For each anticoagulant, the incidence of hospitalization for upper gastrointestinal tract bleeding was lower among patients who were receiving PPI cotherapy. These findings may inform assessment of risks and benefits when choosing anticoagulant agents.

Figure 1.

Adjusted incidence of hospitalizations for upper gastrointestinal bleeding according to individual oral anticoagulants and proton-pump inhibitor (PPI) co-therapy. Adjusted for all of the variables in eTable 3. Intervals represent 95% confidence intervals. GI = gastrointestinal, PY = person-years, N = number of bleeding hospitalizations, Rate = unadjusted incidence per 10,000 person-years, IRR = incidence rate-ratio, RD = risk difference per 10,000 person-years.

Figure 2.

Unadjusted incidence of hospitalizations for upper gastrointestinal bleeding with and without proton-pump inhibitor (PPI) co-therapy, according to decile of the gastrointestinal bleeding risk score. The gastrointestinal bleeding risk score is the expected incidence of upper gastrointestinal bleeding hospitalization given the study covariates, expressed as a quantile between 0 and 19. A score of 0 represents patients with expected incidence less than the 5^th percentile for the cohort, a score of 10 the 50-th to 54^th percentile, and a score of 19 at or above the 95^th percentile. The decile-specific incidence is not adjusted for covariates because residual confounding is limited within each decile. Intervals represent 95% confidence intervals. GI = gastrointestinal, IRR = incidence rate-ratio, RD = risk difference.

Figure 3.

Adjusted incidence of hospitalizations for upper gastrointestinal bleeding according to quartiles of gastrointestinal bleeding risk score, individual oral anticoagulant and proton-pump inhibitor (PPI) co-therapy. Quartiles 1 and 2 were combined because the absolute differences in incidence between these quartiles were much lower than those for the other quartiles. The gastrointestinal bleeding risk score is the expected incidence of upper gastrointestinal bleeding hospitalization given the study covariates, expressed as a quantile between 0 and 19. A score of 0 represents patients with expected incidence less than the 5^th percentile for the cohort, a score of 10 the 50-th to 54^th percentile, and a score of 19 at or above the 95^th percentile. Incidence within each group is adjusted for all variables in eTable 3 to reduce residual confounding within the quartiles of the gastrointestinal bleeding risk score. Intervals represent 95% confidence intervals. GI = gastrointestinal, IRR = incidence rate-ratio, RD = risk difference.