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©The Author(s) 2023.
World J Cardiol. Aug 26, 2023; 15(8): 375-394
Published online Aug 26, 2023. doi: 10.4330/wjc.v15.i8.375
Published online Aug 26, 2023. doi: 10.4330/wjc.v15.i8.375
Table 1 Antiplatelet drugs and gastrointestinal bleeding in the real world
| Ref. | Setting | Main results |
| Casado Arroyo et al[49], 2012 | Spanish observational register with 1219 patients undergoing PTA, 96.7% of whom were in DAPT with LDA and clopidogrel, and 76.6% on PPI therapy | Eight patients developed GIB during hospitalization, and 27 during follow-up (1.52 bleeds per patient/year). Most GIB cases (81.4%) occurred during the first year. Overall, 84.6% of patients were on long-term PPI at the time of the bleed; lower GIB occurred more frequently than upper GIB (74% vs 26%) |
| Tsai et al[50], 2012 | Observational study aiming to investigate the characteristics of endoscopic findings in clopidogrel or aspirin users undergoing endoscopy for upper gastrointestinal symptoms | Gastroduodenal haemorrhagic spots were more common in clopidogrel users than in aspirin users (10.1% vs 25.5%, P = 0.004). Gastroduodenal erosions were more common in aspirin users than clopidogrel users (53.2% vs 38.7%; P = 0.04), whilst gastroduodenal peptic ulcers were more common in clopidogrel users than in aspirin users (38.7% vs 23.9%; P = 0.027) |
| de Abajo et al[51], 2013 | Case-control study involving 669115 patients assessed the incidence of GIB, evaluating the age of the patients and use of different treatments | The incidence of bleeding observed was 76 per 100000 people/year, with a prevalence higher in men than in women (109 vs 49 per 100000 people/year; OR: 2.23; 95%CI: 1.99-2.50), and with a progressive increase of incidence with age. The risk was significantly higher in patients with a previous episode of GIB (RR: 11.27, 95%CI: 8.35-15.20), in those using aspirin (medium-high doses: RR: 3.29; 95%CI: 1.42-7.62; low doses: RR: 1.74; 95%CI: 1.37-2.21), and other antiplatelet agents (RR: 1.73; 95%CI: 1.27-2.36) |
| Lanas et al[26], 2015 | Case-control study | Non-aspirin antiplatelet agents (mostly clopidogrel) were associated with an increased risk of upper GIB that was similar to that observed with aspirin |
| Alexopoulos et al[52], 2016 | Prospective, observational multicentre cohort trial (GRAPE), performed in patients with ACS undergoing PTA-48% of whom treated with clopidogrel, 18% with prasugrel, and 35% with ticagrelor in dual therapy with LDA | The rate of MACEs was lower in prasugrel treated patients (4.4%) than in clopidogrel treated patients (10.1%) (HR: 0.53; 95%CI: 0.30-0.91), although not significantly different between ticagrelor (6.8%) and clopidogrel groups (HR: 0.78; 95%CI: 0.54-1.12). Any type of bleeding was more frequent in prasugrel-treated patients (51.2%) than in clopidogrel-treated patients (37.6%) (HR: 1.61; 95%CI: 1.33-1.95), and more frequent in ticagrelor-treated patients (56.9%) than in clopidogrel-treated patients (HR: 1.81; 95%CI: 1.55-2.10), but there was no significant difference for fatal events |
| Sahlén et al[53], 2016 | Swedish register SWEDEHEART, where 45073 patients with ACS were enrolled | At 24 mo, the risk of ischemic events, death, and MI was lower with ticagrelor than with clopidogrel (11.7% vs 22.3%, aHR 0.85, 95%CI: 0.78-0.93; 5.8% vs 12.9%, aHR 0.83, 95%CI:0.75-0.92; 6.1% vs 10.8%, Ahr aHR 0.89, 95%CI: 0.78-1.01; respectively). However, re-admission with bleeding was lower in patients taking ticagrelor as compared to those taking clopidogrel: 5.5% vs 5.2%; aHR: 1.20; 95%CI: 1.04-1.40. Furthermore, in a subset of patients undergoing PCI, the PCI-related in-hospital bleeding was higher in patients on ticagrelor compared to those on clopidogrel (7.0% vs 2.7%, aOR: 1.57, 95%CI: 1.30-1.90) |
| Sehested et al[54], 2019 | Danish registry on 46301 patients hospitalized with a MI (35% of whom were at high risk of GIB) treated with clopidogrel (76.2%), ticagrelor (20.3%), or prasugrel (3.5%) | At 12 mo, an episode of digestive bleeding occurred in 1.0% (95%CI: 0.9-1.1) of patients with low risk of bleeding, and in 1.7% (95%CI: 1.5-2.0) of those at high risk. In patients receiving PPIs, the absolute risk of bleeding was overall reduced by 0.44% (95%CI: 0.39-0.48), and by 0.47% (95%CI: 0.43%-0.51%) in those at high risk |
| Nishtala et al[55], 2019 | Study performed in New Zealand on 66500 patients aged ≥ 65 yr | No significant change in the incidence of GIB in patients using aspirin (Arr: 0.84; 95%CI: 0.79-0.89), or clopidogrel (Arr: 0.97; 95%CI: 0.87-1.08) in monotherapy, while DAPT resulted in an increased rate of bleeding (aRR: 1.34, 95%CI: 1.14-1.57). In addition, the incidence of bleeding was increased when an anticoagulant therapy was associated with aspirin (aRR: 1.79; 95%CI: 1.30-2.46), clopidogrel (aRR: 6.36; 95%CI: 2.24-18.03), or DAPT (aRR: 4.85; 95%CI: 1:51 to 15:57) |
| Vidyanti et al[56], 2019 | Retrospective study on 1119 ischemic stroke patients | The HR for GIB was significantly in favour of clopidogrel (HR: 2.60; 95%CI: 2.82-3.70) |
| Zheng et al[57], 2019 | Meta-analysis of 13 trials-with a median age of trial participants of 62 yr (range, 53-74) | Aspirin use was associated with an increased risk of bleeding events compared with no aspirin (23.1 per 10000 participant-years with aspirin and 16.4 per 10000 participant-years with no aspirin-HR: 1.43; absolute risk increases 0.47%) |
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) |
Table 3 Main guideline and consensus documents on gastroprotection in patients under antithrombotic treatment
| Guideline/consensus documents | Year | Main recommendations |
| The joint United States guidelines of the American College of Cardiology Foundation, the American College of Gastroenterology, and the American Heart Association[139] | 2008 | Recommended the use of PPIs only in patients taking warfarin in combination with antiplatelet therapy and/or NSAIDs. It did not recommend the substitution of clopidogrel for LDA in high-risk patients to reduce the risk of recurrence ulcer bleeding |
| Focused update of the joint United States guidelines of the American College of Cardiology Foundation, the American College of Gastroenterology, and the American Heart Association[141] | 2010 | Recommended use of PPIs in patients taking DAPT and in those who have multiple risk factors for GIB |
| Position paper issued by Italian Society of Pharmacology, the Italian Association of Hospital Gastroenterologists, and the Italian Federation of General Practitioners[33] | 2016 | Recommended the use of standard doses of PPIs for those taking antiplatelet agents (individually or in association) only if at least one risk factor is present (age > 65 yr, concomitant use of steroids or anticoagulants, previous history of peptic ulcer). In addition, the use of pantoprazole or rabeprazole was suggested if clopidogrel was used, while there were no restrictions on the choice of PPIs with prasugrel and ticagrelor |
| The ESC guidelines on DAPT[145] | 2017 | Recommended gastroprotection with PPIs in all patients |
| Maastricht/Florence Consensus report on management of Helicobacter pylori infection[146] | 2017 | Search for H. pylori should be performed in patients with a history of peptic disease who take NSAIDs or aspirin. However, there were no specific recommendations on LDA since the evidence was considered controversial; no recommendations were provided for non-aspirin antiplatelet agents and/or oral anticoagulants |
| Consensus of the American College of Gastroenterology on treatment of Helicobacter pylori infection[140] | 2017 | Suggested searching for the infection in patients starting aspirin therapy, even if it was emphasized that the basis for this recommendation was weak. No specific recommendations regarding non-aspirin antiplatelet agents and/or oral anticoagulants |
| ESC guidelines on non-ST-segment elevation acute coronary syndrome[144] | 2020 | Recommended (class I, level of evidence A), for pharmacological long-term management, concomitant use of PPIs in patients receiving aspirin monotherapy, DAPT, DAT, TAT, or OAC monotherapy who are at high risk of GIB. They suggested as a strategy to reduce bleeding risk related to percutaneous coronary intervention the use of PPIs in patients on DAPT at higher-than-average risk of gastrointestinal bleeds (i.e., history of gastrointestinal ulcer/haemorrhage, anticoagulant therapy, chronic NSAIDS/corticosteroid use, or two or more of: Age ≥ 65 yr; dyspepsia; gastro-oesophageal reflux disease; H. pylori infection; chronic alcohol use) |
| 2020 ESC guidelines on the management of AF[147] | 2020 | Apixaban or dabigatran 110 mg bid is not associated with an excess of gastrointestinal bleeding compared with warfarin. It suggests the use of apixaban in patients with AF at high risk of bleeding from the GI tract |
| The Korean guidelines for the Clinical Guidelines for Drug-related Peptic Ulcer, revised under the Korean College of Helicobacter and Upper Gastrointestinal Research in 2020[143] | 2020 | Treatment for Helicobacter pylori infections is recommended in patients with a history of peptic ulcers and receiving long-term LDA therapy to prevent peptic ulcers and complications. The maintenance of anti-ulcer drugs, such as PPIs, is also recommended after H. pylori eradication if patients require other antiplatelet agents or anticoagulants. Regardless of H. pylori eradication, when patients with a history of peptic ulcer take long-term LDA, the concomitant use of a PPI according to the severity of the peptic ulcer is recommended |
| Gastroprotection in patients on antiplatelet and/or anticoagulant therapy: A position paper of the National Association of Hospital Cardiologists and the Italian Association of Hospital Gastroenterologists and Endoscopists[148] | 2021 | PPIs are recommended: In single antiplatelet therapy in presence of risk factors; in DAPT; in dual and triple antithrombotic therapy; in single anticoagulant therapy in presence of risk factors |
Table 4 Summary statements
| No. | PPIs are recommended |
| 1 | In single antiplatelet therapy in presence of risk factors (history of peptic disease; concomitant treatment with non-steroidal anti-inflammatory drugs or steroids; two of the following: Age > 65 yr, dyspeptic symptoms, and gastrointestinal reflux symptoms) |
| 2 | In double antiplatelet therapy |
| 3 | In dual and triple antithrombotic therapy |
| 4 | In single anticoagulant therapy in presence of risk factors (at least one of the following: Age > 75 yr; history of peptic disease; concomitant use of non-steroidal anti-inflammatory drugs) |
| Searching for Helicobacter pylori infection could be useful in patients starting aspirin therapy | |
- Citation: Abrignani MG, Lombardo A, Braschi A, Renda N, Abrignani V. Proton pump inhibitors and gastroprotection in patients treated with antithrombotic drugs: A cardiologic point of view. World J Cardiol 2023; 15(8): 375-394
- URL: https://www.wjgnet.com/1949-8462/full/v15/i8/375.htm
- DOI: https://dx.doi.org/10.4330/wjc.v15.i8.375