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) co-therapy could affect risk of upper gastrointestinal bleeding, a frequent and potentially serious complication of oral anticoagulant treatment. Objective: Compare upper gastrointestinal bleeding hospitalization incidence for individual anticoagulants without and with PPI co-therapy and determine variation according to underlying gastrointestinal bleeding risk. Design, Setting, and Participants: Retrospective cohort study in Medicare patients between 1 January 2011 and 30 September 2015. Exposures: Apixaban, dabigatran, rivaroxaban or warfarin treatment; PPI co-therapy; and gastrointestinal bleeding risk score encompassing patient characteristics, medication use, and comorbidity. Main Outcomes and Measures: Upper gastrointestinal bleeding hospitalizations: adjusted incidence and risk difference (RD) per 10,000 person-years of anticoagulant treatment, incidence-rate-ratios (IRR). Results: There were 1,643,123 patients with 1,713,183 new episodes of oral anticoagulant treatment (mean age 76.4 [std, 2.4] years, 56.1% female, 74.9% atrial fibrillation). During 754,389 treatment person-years without PPI co-therapy, the adjusted incidence of upper gastrointestinal bleeding hospitalizations (N=7,119) was 115 (95% confidence interval, 112–118) per 10,000 person-years. The incidence for rivaroxaban (1,278 hospitalizations/114,168 person-years) was 144 (136–152) per 10,000 person-years, significantly greater than that for apixaban (279/43,970, IRR=1.97 [1.73–2.25], RD=71 [59 to 83]), dabigatran (629/79,739, IRR=1.19 [1.08–1.32], RD=23 [11 to 36]) and warfarin (4,933/516,512, IRR=1.27 [1.19–1.35], RD=30 [20 to 41]). The incidence for apixaban was significantly lower than that for dabigatran (IRR=0.61 [0.52–0.70], RD=−48 [−61 to −34]) and warfarin (IRR=0.64 [0.57–0.73], RD=−40 [−50 to −31]). When anticoagulant treatment with PPI co-therapy (264,447 person-years) was compared to that without PPI co-therapy, risk of upper gastrointestinal bleeding hospitalizations (N=2,245) was lower for each anticoagulant: apixaban—IRR=0.66 (0.52–0.85), RD=−24 (−38 to −11); dabigatran--IRR=0.49 (0.41–0.59), RD=−61 (−75 to −47); rivaroxaban:--IR=0.75 (0.68–0.84), RD=−36 (−49 to −22); warfarin—IRR=0.65 (0.62–0.69), RD=−39 (−44 to −34). Absolute differences between anticoagulants and treatment without/with PPI co-therapy were greater for patients with higher gastrointestinal bleeding risk scores. For patients in the upper quartile, the incidence for rivaroxaban without PPI was 327 (302–355) per 10,000 versus 120 (93–153) per 10,000 for apixaban with PPI (RD=208 [169 to 247]). Conclusions and Relevance: Among Medicare patients initiating oral anticoagulant treatment, incidence of upper gastrointestinal bleeding hospitalization was highest for rivaroxaban and lowest for apixaban and for each anticoagulant, was lower among patients prescribed PPI co-therapy. These findings may inform assessment of risks and benefits when choosing anticoagulant agents.

Sustained resolution of anticoagulation related iron deficiency anemia with the use of apixaban

“…3 The increase in upper GIT bleeding risk with rivaroxaban and dabigatran compared with apixaban was also recently demonstrated in a large population based study of US Medicare beneficiaries. 14 The topical anticoagulant effect of NOACs is proposed to be the mechanism of increased GIT bleeding risk compared with warfarin. The direct thrombin inhibitor dabigatran is associated with lower GIT bleeding, a finding attributed to incomplete absorption and increasing concentrations in the lower GIT tract, in addition to the direct caustic effect of its tartaric acid content on the upper GIT mucosa.…”

“…Conversely, apixaban had similar GIT bleeding risk to warfarin . The increase in upper GIT bleeding risk with rivaroxaban and dabigatran compared with apixaban was also recently demonstrated in a large population based study of US Medicare beneficiaries . The topical anticoagulant effect of NOACs is proposed to be the mechanism of increased GIT bleeding risk compared with warfarin.…”

Proton pump inhibitors co‐prescribed with warfarin reduce warfarin control as measured by time in therapeutic range

“…Warfarin control is affected by numerous factors including drug interactions . PPIs have been reported to interact with warfarin resulting in increased INR and bleed risk, however the clinical significance of this interaction remains unclear because of conflicting reports particularly regarding bleeds . This study aimed to determine the impact on warfarin control with concurrent administration of PPIs as measured by warfarin TTR and bleed events.…”

“…Similarly, Henriksen et al reported no evidence that PPIs affected INR values in the few weeks after PPI initiation, whilst Shirayama et al reported no change in warfarin dose or INR for more than 6 weeks after addition of PPIs. In terms of bleeds, Nagata et al reported no increased risk of bleeding with PPIs, whilst two studies by Ray et al reported a reduced risk of gastrointestinal bleeds in patients taking PPIs with warfarin. Thus, there remain conflicting data in regard to the interaction with warfarin and PPIs when bleeds and/or INR are reported as endpoints.…”

Optimization of Pharmacotherapy with Direct Oral Anticoagulants: the Need to Choose the Right Dosage Regimen

“…В сравнении с пациентами без мультиморбидности больные в группе с высоким ее уровнем были старше (средний возраст, соответственно, 69 и 74 лет), принимали в два раза большее количество препаратов (5 против 10) и имели больший балл по шкале CHA 2 DS 2 -VASc (2,7 против 4,9) (р<0,001 во всех случаях). Скорректированная распространенность на 100 пациенто-лет сочетания инсульта/системных тром-боэмболических осложнений, смертности и массивных кровотечений возрастала по мере увеличения мультиморбидности (группа без мультиморбидности рассматривалась в качестве референсной; ОР в группе умеренной мультимопбидности = 1, 42 [19,20]. Его первичной целью явился сравнительный анализ по критерию «не хуже» терапии апиксабаном и антагонистом витамина К (целевой уровень МНО 2,0-3,0) в отношении составной конечной точки из массивных и клинически незначимых кровотечений у больных с ФП в сочетании с острым коронарным синдромом и/или с наличием необходимости проведения чрескожного коронарного вмешательства, которым планировалось назначение ингибиторов P2Y 12 рецепторов тромбоцитов по меньшей мере на 6 мес.…”