Proton pump inhibitors and gastroprotection in patients treated with antithrombotic drugs: A cardiologic point of view

Table 2 Oral anticoagulant drugs and gastrointestinal bleeding in the real world

Ref.	Setting	Main results
Abraham et al[70], 2015	Retrospective study; the risk of GIB was assessed in a cohort of 92816 patients taking anticoagulants (9.2% patients on dabigatran, 17.5% on rivaroxaban, and 73.2% on warfarin)	Using a propensity score matched model, the risk of GIB with DOACs was similar to that with warfarin in AF patients (dabigatran vs warfarin: HR: 0.79; 95%CI: 0.61-1.03; rivaroxaban vs warfarin: HR: 0.93; 95%CI: 0.69-1.25) and in non-AF patients (dabigatran vs warfarin: HR: 1.14; 95%CI: 0.54 to 2.39; rivaroxaban vs warfarin: HR: 0.89; 95%CI: 0.60-1.32). The risk of bleeding increased with age, so that in patients aged ≥ 76 yr, the risk exceeded that with warfarin among AF patients taking dabigatran (HR: 2.49; 95%CI: 1.61-3.83) and in patients with and without AF taking rivaroxaban (HR: 2.91; 95%CI: 1.65-4.81; and HR: 4.58; 95%CI: 2.40-8.72; respectively)
Brodie et al[71], 2018	Retrospective evaluation of electronic medical records of patients with GIB (n = 8496) from 2010-2016 identified 61 patients with GIB episodes while treated with DOACs (rivaroxaban, dabigatran, or apixaban) and 123 patients with GIB while taking warfarin. The DOAC and warfarin groups were similar in terms of age and underlying comorbidity	After adjusting for differences in baseline variables, the DOAC group had fewer hospitalizations and required fewer transfusions than the warfarin group. The DOAC and control groups were not statistically different for all outcomes despite significantly greater concomitant aspirin use in the DOAC group compared with warfarin users
Ray et al[35], 2018	Retrospective cohort study in Medicare patients, during 754389 treatment person-years without PPI co-therapy	The adjusted incidence of upper GIB hospitalizations was 115 (95%CI: 112-118) per 10000 person-years. The incidence for rivaroxaban (1278 hospitalizations/114168 person-years) was 144 (136-152) per 10000 person-years, significantly greater than that for apixaban (279/43970, RR: 1.97, 1.73-2.25), dabigatran (629/79739, RR: 1.19, 1.08-1.32), and warfarin (4933/516512, RR: 1.27, 1.19-1.35). The incidence for apixaban was significantly lower than that for dabigatran (RR: 0.61, 0.52-0.70) and warfarin (RR: 0.64, 0.57-0.73)
Yanagisawa et al[72], 2018	Data from 218 patients receiving oral anticoagulants (73 DOAC users, 145 warfarin users) and 218 patients not receiving any antithrombotics (age- and sex-matched controls) who underwent polypectomy	Bleeding rate was significantly higher in warfarin users and DOAC users compared with controls (13.7% and 13.7% vs 0.9%, P < 0.001), but was not significantly different between rivaroxaban (13.2%), dabigatran (11.1%), and apixaban (13.3%) users
Tang et al[32], 2021	Retrospective review of medical records of 626 patients taking warfarin for at least 2 wk	Variables that increase the likelihood of bleeding in warfarin users included aspirin, PPI, history of previous GIB, CRF, and elevated prothrombin time/international normalized ratio values. Concomitant antiplatelet use showed a slight increase in GIB but this was not statistically significant (P = 0.082). Patients who are on PPI and warfarin simultaneously are more likely to be on aspirin or have a history of GIB or CRF, all of which are associated with increased incidences of GIB. Although concomitant use of warfarin and PPI appears to be associated with an increased incidence of GIB, these patients are more likely to have other risk factors that also increase the risk of a GIB outcome
Scibelli et al[73], 2021	Retrospective study using the HCA Healthcare Enterprise Data Warehouse to analyse 13440 patients aged > 18 yr that were admitted with an upper GIB from 2017 to 2019. The patients were categorized based on oral anticoagulant (i.e., rivaroxaban, apixaban, dabigatran, and warfarin). The control group was patients admitted with an upper GIB not on oral anticoagulation	Patients on a DOAC without home PPI have a mortality (OR: 3.066, 95%CI: 1.48-6.26, P < 0.05) compared to patients on a DOAC and home PPI. Patients on warfarin and no home PPI have a mortality (OR: 5.55, 95%CI: 1.02-30.35, P < 0.05) compared to those on warfarin with home PPI use. In the no anticoagulation group, those not on PPI have an OR of 3.28 (95%CI: 2.54-4.24, P < 0.05) of death compared to home PPI users. Overall, patients taking the DOACs or warfarin had no statistically significant increase in RBC transfusions, length of stay, shock, acute renal failure, or mortality rate compared to patients who were not on oral anticoagulation. Home PPI use was shown to lower odds of mortality in patients on anticoagulation who presented with upper GIB
Lee et al[74], 2021	In the Korean National Health Insurance Service claims database, covering the entire Korean population, among patients initiating oral anticoagulants (warfarin and DOACs, during 2013-2017, those concomitantly prescribed PPIs were identified (n = 19851)	Overall, DOACs were associated with lower upper GIB risk after adjustment for age, sex, comorbidities, and concomitant medications (aHR: 0.78, 95%CI: 0.65-0.94), compared to warfarin. There was no significant difference in upper gastrointestinal bleeding risk among the individual DOACs
Kwon et al[75], 2021	In the Korean claims database on 42048 patients with prior GIB, DOAC users were compared with warfarin users by balancing covariates	Lower risks of ischemic stroke, major bleeding, and the composite outcome were associated with DOAC use than with warfarin use (weighted HR: 0.608; 95%CI: 0.543-0.680)
Lip et al[76], 2021	Retrospective cohort study including patients with NVAF who were 75 yr and older; had stage III to V CKD; had an HAS-BLED score of 3 or greater; used corticosteroids, antiplatelets, or NSAIDs; or had GI conditions. Data were collected from the Centers for Medicare & Medicaid Services and 4 commercial insurance databases between January 1, 2012 and September 30, 2015	All NOACs were associated with a lower risk of stroke and/or systemic embolism vs warfarin (apixaban: HR: 0.60; 95%CI: 0.52-0.68; dabigatran: HR: 0.75; 95%CI: 0.64-0.88; rivaroxaban: HR: 0.79; 95%CI: 0.73-0.86). Compared with warfarin, apixaban and dabigatran were associated with a lower risk of major GIB (apixaban: HR: 0.59; 95%CI: 0.56-0.63; dabigatran: HR: 0.78; 95%CI: 0.70-0.86), while rivaroxaban was associated with a higher risk (HR: 1.11; 95%CI: 1.05-1.16)
Moudallel et al[77], 2023	Pharmacovigilance data based on spontaneous reports of GIB with DOACs reported to EudraVigilance	Dabigatran is more frequently involved in GIB events than the other DOACs
Ingason et al[78], 2021	Data on all patients in Iceland who received a prescription for oral anticoagulation from 2014 to 2019 were collected and their personal identification numbers linked to the electronic medical record system of the National University Hospital and the 4 regional hospitals	Warfarin was associated with higher rates of upper GIB (1.7 events per 100 person-years vs 0.8 events per 100 person-years; HR: 2.12; 95%CI: 1.26-3.59) but similar rates of lower GIB compared with DOACs. Specifically, warfarin was associated with higher rates of upper GIB compared with apixaban (HR: 2.63; 95%CI: 1.35-5.13), dabigatran (HR: 5.47; 95%CI: 1.87-16.05), and rivaroxaban (HR: 1.74; 95%CI: 1.00-3.05)

AF: Atrial fibrillation; aHR: Adjusted hazard ratio; CI: Confidence interval; CRF: Chronic renal failure; DOAC: Direct oral anticoagulants; GIB: Gastrointestinal bleeding; HR: Hazard ratio; OR: Odds ratio; PPI: Proton pump inhibitor; RR: Relative risk.