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Gastroprotection in patients on antiplatelet and/or anticoagulant therapy: a position paper of National Association of Hospital Cardiologists (ANMCO) and the Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO)

Published:December 02, 2020DOI:https://doi.org/10.1016/j.ejim.2020.11.014

      Abstract

      Aspirin and P2Y12 receptor antagonists are widely used across the spectrum of cardiovascular and cerebrovascular diseases. Gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed. However, potential increased risk of cardiovascular events has been suggested for PPIs, and, in recent years, it has been discussed whether these drugs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Indeed, pharmacodynamic and pharmacokinetic studies suggested an interaction through hepatic CYP2C19 between PPIs and clopidogrel, which could translate into clinical inefficacy, leading to higher rates of cardiovascular events. The FDA and the EMA sent a warning in 2010 discouraging the concomitant use of clopidogrel with omeprazole or esomeprazole. In addition, whether the use of PPIs may affect the clinical efficacy of the new P2Y12 receptor antagonists, ticagrelor and prasugrel, remains less known. According to current guidelines, PPIs in combination with antiplatelet treatment are recommended in patients with risk factors for gastrointestinal bleeding, including advanced age, concurrent use of anticoagulants, steroids or non-steroidal anti-inflammatory drugs, and Helicobacter pylori infection. Like vitamin K antagonists (VKAs), DOACs can determine gastrointestinal bleeding. Results from both randomized clinical trials and observational studies suggest that high-dose dabigatran (150 mg bid), rivaroxaban and high-dose edoxaban (60 mg daily) are associated with a higher risk of GI bleeding as compared with apixaban and warfarin. In patients taking oral anticoagulant with GI risk factor, PPI could be recommended, even if usefulness of PPIs in these patients deserves further data. Helicobacter pylori should always be searched, and treated, in patients with history of peptic ulcer disease (with or without complication). Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition or anticoagulant effect potentially carries a considerable clinical impact. The present joint statement by ANMCO and AIGO summarizes the current knowledge regarding the widespread use of platelet inhibitors, anticoagulants, and PPIs in combination. Moreover, it outlines evidence supporting or opposing drug interactions between these drugs and discusses consequent clinical implications.

      Keywords

      Abbreviation

      ACS
      acute coronary syndromes
      AF
      atrial fibrillation
      AMI
      acute miocardial infarction
      ARR
      absolute risk reduction
      ASA
      aspirin
      BMI
      body mass index
      CI
      confidence interval
      COX
      cyclooxygenase
      DAT
      dual antithrombotic therapy
      DAPT
      dual antiplatelet therapy
      DOACs
      direct oral anticoagulants
      FDA
      Food and Drug Administration
      EMA
      European Medicines Agency
      GI
      gastrointestinal
      GIB
      gastrointestinal bleeding
      H2RA
      histamine-2 receptor antagonists
      H. pylori
      Helicobacter pylori
      HR
      hazard ratio
      LDA
      low-dose aspirin
      LGIB
      lower GI bleeding
      MACE
      Major adverse cardiovascular events
      MI
      myocardial infarction
      NSAIDs
      non-steroidal anti-inflammatory drug
      NNT
      number needed to treat
      OR
      odds ratio
      PCABs
      potassium-competitive acid blockers
      PCI
      percutaneous coronary intervention
      PPI
      proton pump inhibitors
      PTA
      percutaneous angioplasty
      PUB
      peptic ulcer bleeding
      PUD
      peptic ulcer disease
      RR
      relative risk
      RCT
      randomized controlled trial
      TAT
      Triple antithrombotic therapy
      UGIB
      upper GI bleeding
      VKAs
      vitamin K antagonists

      1. Introduction

      Antiplatelet therapy is a cornerstone for the treatment of cardiovascular diseases. However, it raises the risk of bleeding in the upper gastrointestinal tract (UGIB). The risk significantly increases if two antiplatelet agents are used, and it becomes even greater if an anticoagulant is also prescribed. Therefore, in order to reduce the risk of UGIB, there is a consensus in using proton pump inhibitor (PPI) in patients taking antiplatelet agents and/or anticoagulant and who have risk factors. In 2009, following several reassessments of pharmacokinetic and pharmacodynamic data, there was a worldwide alert on the possibility that PPIs might have caused a decrease of the therapeutic efficacy of clopidogrel on the basis of the results of platelet aggregation tests used as surrogate endpoint. However, there is no reliable evidence that the changes in these surrogate endpoints can have a relevant clinical consequence. Despite the observation that the interaction between PPIs and clopidogrel was not a class effect, this alert yielded a reduction in the use of PPIs with clopidogrel - whether or not associated with ASA – with an increase of UGIB episodes. Recently, the possibility of interactions between PPIs and ASA has also been suggested. The decision to use PPIs when a patient takes thienopyridine should be based on risk-benefit ratio assessing both cardiological and gastroenterological risks. In patients with acute cardiovascular diseases such as ACS, mechanical or surgical revascularizations, ischemic strokes and transient ischemic attacks, PPIs are often prescribed, regardless of the risk of bleeding. Instead, the prescription of these drugs at the time of discharge should be based on the presence of stents, the need for dual antiplatelet therapy (DAT), and assessing risk factors, such as previous UGIB, age >65 years, concomitant therapy with anticoagulants (oral or subcutaneous heparins), and/or NSAIDs, and H. pylori infection. On the other hand, UGIB in patients on oral anticoagulants - vitamin K antagonist (VKAs) and direct oral anticoagulants (DOACs) - is also a clinically relevant issue. The recent introduction of new antiplatelet agents (such as prasugrel and ticagrelor), the increasingly frequent indication for concomitant anticoagulant therapy, the need for long-term DAT in selected cases, the marketing of the new DOACs as well as the extension of the indications for these medications, make the appropriate prescription of PPIs even more important in order to reduce the UGIB. Taking into account all the above considerations, the National Association of Hospital Cardiologists (ANMCO) and the Italian Association of Hospital Gastroenterologists and Endoscopist (AIGO) summarizes the current knowledge regarding the widespread use of platelet inhibitors, anticoagulants, and PPIs in combination. Moreover, it outlines evidence supporting or opposing drug interactions between these drugs and discusses consequent clinical implications.

      2. Risk factors for GI bleeding

      Therapy with antiplatelet and anticoagulant medications is burdened by a significant incidence of GI bleeding. The risk is increased 1.8-times (95% CI: 1.5-2.1) during low-dose aspirin (LDA) therapy, and up to 7.4-times (95% CI: 3.5-15) with DAT [
      • Hallas J
      • Dall M
      • Andries A
      • Andersen BS
      • Aalykke C
      • Hansen JM
      • et al.
      Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: Population based case-control study.
      ]. Therapy with classic anticoagulant is also associated with a higher risk of bleeding compared to antiplatelet agents [
      • Lanas A
      • Carrera-Lasfuentes P
      • Arguedas Y
      • García S
      • Bujanda L
      • Calvet X
      • et al.
      Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants.
      ]. Moreover, the combined intake of anticoagulants and antiplatelet agents rises the risk of UGIB by 60% and of lower GI bleeding (LGIB) by 30%. Therefore, knowledge of risk factors predisposing to GI bleeding is important for the management of patients taking these treatments.

      2.1 Risk factors associated with bleeding in antiplatelet users

      The main risk factors for UGIB while taking ASA are: concomitant therapy with another antiplatelet agent (OR 7.4; 95% CI: 3.5-15)[1], previous peptic ulcer disease (OR 6.5; 95% CI: 2-21.2), concomitant therapy with NSAIDs (OR 2.9, 95% CI: 1.7-4.8), and H. pylori infection (OR 4.7; 95% CI: 2-10.9) [
      • Luo PJ
      • Lin XH
      • Lin CC
      • Luo JC
      • Hu HY
      • Ting PH
      • et al.
      Risk factors for upper gastrointestinal bleeding among aspirin users: An old issue with new findings from a population-based cohort study.
      ,
      • Lanas A
      • Gargallo CJ.
      Management of low-dose aspirin and clopidogrel in clinical practice: A gastrointestinal perspective.
      ]. The risk of UGIB in patients with H. pylori infection is also doubled during therapy with non-aspirin antiplatelet agents when compared to ASA [
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      ]. As regards age, a recent meta-analysis of 13 trials – with a median age of trial participants of 62 years (range, 53-74) - showed that aspirin use was associated with an increased risk of bleeding events compared with no aspirin (23.1 per 10,000 participant-years with aspirin and 16.4 per 10,000 participant-years) with no aspirin - HR 1.43; absolute risk increase 0.47%) [
      • Zheng SL
      • Roddick AJ.
      Association of Aspirin Use for Primary Prevention with Cardiovascular Events and Bleeding Events: A Systematic Review and Meta-analysis.
      ]. The presence of systemic comorbidities, alcohol use, smoking, and a high BMI are still controversial risk factors [
      • Lanas A
      • Gargallo CJ.
      Management of low-dose aspirin and clopidogrel in clinical practice: A gastrointestinal perspective.
      ]. Finally, in a study of patients aged >70 years, ASA was reported to increase the incidence of bleeding from colonic diverticula, both when it was given as monotherapy (OR 1.7; 95% CI: 1.2-2.3) and, specifically, when it was used in combination with other antiplatelet agents (OR 2.7; 95% CI: 1.8-4.1) [
      • Hashash JG
      • Shamseddeen W
      • Skoury A
      • Aoun N
      • Barada K
      Gross lower gastrointestinal bleeding in patients on anticoagulant and/or antiplatelet therapy: Endoscopic findings, management, and clinical outcomes.
      ].

      2.2 Risk factors associated with bleeding in VKAs users

      The risk factors associated with GI bleeding in VKAs anticoagulant users are: 1) age> 65 years (RR 2.5; 95% CI: 1.2-5.5); 2) a previous GI bleeding (RR 5.1; 95% CI: 1.9-13.5); 3) liver cirrhosis (RR 6.9; 95% CI: 2-24.5); and 4) presence of diverticulosis of the colon for the lower digestive tract [
      • Lanas A
      • Gargallo CJ.
      Management of low-dose aspirin and clopidogrel in clinical practice: A gastrointestinal perspective.
      ,
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      ]. The risk of UGIB is also increased by the concomitant use of lipid-lowering agents (RR 1.8; 95% CI: 1.4-2.4), NSAIDs (RR 8.7; 95% CI: 7.3-10.4), ASA (RR 6.9; 95% CI: 5.9-8.28), and COX-2 inhibitors (RR 5; 95% CI 1.2-8.9) [
      • Lanas-Gimeno A
      • Lanas A.
      Risk of gastrointestinal bleeding during anticoagulant treatment.
      ].

      2.3 Risk factors associated with bleeding in DOAC users

      Oral anticoagulant with direct antagonist action offers several advantages, including stable dosages, rapidity of action, and a short half-life compared to classic anticoagulants. However, recent studies have shown that the risk of GI bleeding was similar between DOACs and VKAs [
      • Abraham NS
      • Noseworthy PA
      • Yao X
      • Sangaralingham LR
      • Shah ND
      Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study.
      ,
      • Miller CS
      • Dorreen A
      • Martel M
      • Huynh T
      • Barkun AN
      Risk of Gastrointestinal Bleeding in Patients Taking Non–Vitamin K Antagonist Oral Anticoagulants: A Systematic Review and Meta-analysis.
      ]. The main risk factors associated with GI bleeding are: 1) age> 75 years (OR 2.5; 95% CI: 1.1-3.2 - > 70 years for dabigatran); 2) the presence of systemic comorbidities; 3) kidney failure; 4) a history of peptic ulcer complicated by bleeding (OR 2.5; 95% CI: 1.3-4.7); 5) concomitant use of ASA or NSAIDs (OR 1.8; 95% CI: 1.01-8.9) [
      • Abraham NS
      • Noseworthy PA
      • Yao X
      • Sangaralingham LR
      • Shah ND
      Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study.
      ,
      • Miller CS
      • Dorreen A
      • Martel M
      • Huynh T
      • Barkun AN
      Risk of Gastrointestinal Bleeding in Patients Taking Non–Vitamin K Antagonist Oral Anticoagulants: A Systematic Review and Meta-analysis.
      ,
      • Hernandez I
      • Baik SH
      • Piñera A
      • Zhang Y
      Risk of bleeding with dabigatran in atrial fibrillation.
      ]; and 6) drug interactions with medications that share cytochrome P450 metabolism, such as amiodarone, rifampicin, barbiturates and fluconazole [
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding.
      ]. The bleeding risk was also dependent by the type of DOAC used, with higher values ​​for rivaroxaban and lower values ​​for apixaban [
      • Hernandez I
      • Baik SH
      • Piñera A
      • Zhang Y
      Risk of bleeding with dabigatran in atrial fibrillation.
      ]. Table 1 summarizes the main gastrointestinal bleeding risk factors for the different classes of drugs [
      • Hallas J
      • Dall M
      • Andries A
      • Andersen BS
      • Aalykke C
      • Hansen JM
      • et al.
      Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: Population based case-control study.
      ,
      • Lanas A
      • Carrera-Lasfuentes P
      • Arguedas Y
      • García S
      • Bujanda L
      • Calvet X
      • et al.
      Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants.
      ,
      • Luo PJ
      • Lin XH
      • Lin CC
      • Luo JC
      • Hu HY
      • Ting PH
      • et al.
      Risk factors for upper gastrointestinal bleeding among aspirin users: An old issue with new findings from a population-based cohort study.
      ,
      • Lanas A
      • Gargallo CJ.
      Management of low-dose aspirin and clopidogrel in clinical practice: A gastrointestinal perspective.
      ,
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      ,
      • Zheng SL
      • Roddick AJ.
      Association of Aspirin Use for Primary Prevention with Cardiovascular Events and Bleeding Events: A Systematic Review and Meta-analysis.
      ,
      • Hashash JG
      • Shamseddeen W
      • Skoury A
      • Aoun N
      • Barada K
      Gross lower gastrointestinal bleeding in patients on anticoagulant and/or antiplatelet therapy: Endoscopic findings, management, and clinical outcomes.
      ,
      • Lanas-Gimeno A
      • Lanas A.
      Risk of gastrointestinal bleeding during anticoagulant treatment.
      ,
      • Abraham NS
      • Noseworthy PA
      • Yao X
      • Sangaralingham LR
      • Shah ND
      Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study.
      ,
      • Miller CS
      • Dorreen A
      • Martel M
      • Huynh T
      • Barkun AN
      Risk of Gastrointestinal Bleeding in Patients Taking Non–Vitamin K Antagonist Oral Anticoagulants: A Systematic Review and Meta-analysis.
      ,
      • Hernandez I
      • Baik SH
      • Piñera A
      • Zhang Y
      Risk of bleeding with dabigatran in atrial fibrillation.
      ,
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding.
      ].
      Table 1Main risk factors for gastrointestinal bleeding during antiplatelet or anticoagulant therapy
      • Hallas J
      • Dall M
      • Andries A
      • Andersen BS
      • Aalykke C
      • Hansen JM
      • et al.
      Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: Population based case-control study.
      ,
      • Lanas A
      • Carrera-Lasfuentes P
      • Arguedas Y
      • García S
      • Bujanda L
      • Calvet X
      • et al.
      Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants.
      ,
      • Luo PJ
      • Lin XH
      • Lin CC
      • Luo JC
      • Hu HY
      • Ting PH
      • et al.
      Risk factors for upper gastrointestinal bleeding among aspirin users: An old issue with new findings from a population-based cohort study.
      ,
      • Lanas A
      • Gargallo CJ.
      Management of low-dose aspirin and clopidogrel in clinical practice: A gastrointestinal perspective.
      ,
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      ,
      • Zheng SL
      • Roddick AJ.
      Association of Aspirin Use for Primary Prevention with Cardiovascular Events and Bleeding Events: A Systematic Review and Meta-analysis.
      ,
      • Hashash JG
      • Shamseddeen W
      • Skoury A
      • Aoun N
      • Barada K
      Gross lower gastrointestinal bleeding in patients on anticoagulant and/or antiplatelet therapy: Endoscopic findings, management, and clinical outcomes.
      ,
      • Lanas-Gimeno A
      • Lanas A.
      Risk of gastrointestinal bleeding during anticoagulant treatment.
      ,
      • Abraham NS
      • Noseworthy PA
      • Yao X
      • Sangaralingham LR
      • Shah ND
      Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study.
      ,
      • Miller CS
      • Dorreen A
      • Martel M
      • Huynh T
      • Barkun AN
      Risk of Gastrointestinal Bleeding in Patients Taking Non–Vitamin K Antagonist Oral Anticoagulants: A Systematic Review and Meta-analysis.
      ,
      • Hernandez I
      • Baik SH
      • Piñera A
      • Zhang Y
      Risk of bleeding with dabigatran in atrial fibrillation.
      ,
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding.
      Risk factorAntiplatelet agentWarfarinDOAC
      AgeContinuous parallel increaseContinuous parallel increaseContinuous parallel increase
      SexProbableProbableProbable
      Pervious peptic ulcer diseaseEstablishedEstablishedEstablished
      H. pylori infectionUnclearNot establishedNot established
      Hepatic cirrhosisEstablishedEstablishedProbable
      Kidney failureEstablishedUnclearNot established
      Diverticulosis/angiodysplasiaEstablishedEstablishedNot established
      Two antiplateletsEstablishedEstablishedEstablished
      Antiplatelets and anticoagulant/steroidsEstablished
      Antiplatelets and NSAID/COX-2 inhibitorEstablishedEstablishedEstablished
      Antiplatelets and lipid-lowering agentsEstablished

      3. Risk of GI bleeding with different antiplatelet agents

      3.1 Data from clinical trials

      The risk/benefit ratio between prevention of ischemic events and increase of bleeding events due to aspirin therapy used as primary prevention is still controversial. The meta-analysis of the Antithrombotic Trialists' Collaboration published in 2009 - which included 95,000 patients - showed that aspirin allocation increased major (usually defined as a bleed requiring transfusion or resulting in death) gastrointestinal and extracranial bleeds (0.10% vs. 0.07% per year, p<0.0001; RR 1.54; 95% CI: 1.30-1.82) [
      • Antithrombotic Trialists C
      • Collins R
      • Peto R
      • Hennekens C
      • Doll R
      • Bubes V
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      ]. The incidence of major GI bleeding is even higher when LDA is used in association with clopidogrel in patients with previous GI bleeding or undergoing prolonged antiplatelet therapy [
      • Serebruany VL
      • Dinicolantonio JJ
      • Can MM
      • Pershukov IV
      • Kuliczkowski W
      Gastrointestinal adverse events after dual Antiplatelet therapy: Clopidogrel is safer than Ticagrelor, but Prasugrel data are lacking or inconclusive.
      ]. Finally, the risk of bleeding is often proportional to cardiovascular risk. Although it does not act on cyclo-oxygenase, the harmful action of clopidogrel on the gastric mucosa has been widely demonstrated.
      The CAPRIE study[15] showed that clopidogrel has a lower risk of gastric damage and GI bleeding than aspirin (not considering the use of PPI). Thus, clopidogrel, obviously with appropriate PPI association, appeared to be a safer antiplatelet monotherapy in patients with recent damage due to aspirin. Clopidogrel administration seems to be associated with both an impaired spontaneous healing process of gastric ulcers, and haemorrhagic diathesis due to the inherent antiplatelet effect [
      • Laine L
      • Maller ES
      • Yu C
      • Quan H
      • Simon T
      Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: A double-blind trial.
      ]. However, the use of clopidogrel in patients with previous history of peptic ulcer disease (with or without complication) seems to be questionable [
      CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      ,
      • Chan FKL
      • Ching JYL
      • Hung LCT
      • Wong VWS
      • Leung VKS
      • Kung NNS
      • et al.
      Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding.
      ]. In two well-performed RCTs, patients who took aspirin to prevent vascular diseases and presented with ulcer bleeding, after the ulcers had healed, and H. pylori infection was eradicated if present, were randomized to receive either clopidogrel or LDA plus 20 mg of esomeprazole twice daily for 12 months. The cumulative incidence of recurrent bleeding during the 12-month period was significantly higher among patients who received clopidogrel compared to those treated with aspirin plus esomeprazole in both trials (difference for clopidogrel from 3.4 to 20.9) [
      • Chan FKL
      • Ching JYL
      • Hung LCT
      • Wong VWS
      • Leung VKS
      • Kung NNS
      • et al.
      Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding.
      ,
      • Lai KC
      • Chu KM
      • Hui WM
      • Wong BC
      • Hung WK
      • Loo CK
      • et al.
      Esomeprazole with aspirin versus clopidogrel for prevention of recurrent gastrointestinal ulcer complications.
      ]. Hence, the ACCF/ACG/AHA 2008 Expert Consensus Document on the prevention of GI risk of antiplatelet therapy did not recommend the substitution of clopidogrel for LDA in high-risk patients to reduce the risk of recurrence ulcer bleeding [
      • Bhatt DL
      • Scheiman J
      • Abraham NS
      • Antman EM
      • Chan FK
      • Furberg CD
      • et al.
      ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.
      ]. Finally, a very low dosage of aspirin (75 mg) could be also considered after GI bleeding in patients previously treated with higher dose of aspirin [
      • Chan FKL
      • Ching JYL
      • Hung LCT
      • Wong VWS
      • Leung VKS
      • Kung NNS
      • et al.
      Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding.
      ].
      In the CURE trial, the risk of major bleeding, and in particular GI bleeding, was clearly higher in patients undergoing DAPT with aspirin and clopidogrel compared to those treated with aspirin alone (1.3% vs. 0.7%) [
      • Yusuf S
      • Zhao F
      • Mehta SR
      • Chrolavicius S
      • Tognoni G
      • Fox KK
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      ]. When compared with ticagrelor, clopidogrel seems to be safer with regard to GI-related risks, including fewer overall GI/anal bleeding events and spontaneous GI haemorrhagic episodes, less nausea, vomiting, dyspepsia and diarrhoea, and a lower rate of presence of H. pylori [
      • Serebruany VL
      • Dinicolantonio JJ
      • Can MM
      • Pershukov IV
      • Kuliczkowski W
      Gastrointestinal adverse events after dual Antiplatelet therapy: Clopidogrel is safer than Ticagrelor, but Prasugrel data are lacking or inconclusive.
      ,
      • Fahmy AI
      • Mekkawy MA
      • Abou-Ali A
      Evaluation of adverse events involving bleeding associated with oral P2Y12 inhibitors use in the Food and Drug Administration adverse event reporting system.
      ,
      • Wallentin L
      • Becker RC
      • Budaj A
      • Cannon CP
      • Emanuelsson H
      • Held C
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      ]. Prasugrel also causes a significant increase in digestive bleeding from 45 days after the start of therapy, but less data are available compared to ticagrelor and clopidogrel [
      • Serebruany VL
      • Dinicolantonio JJ
      • Can MM
      • Pershukov IV
      • Kuliczkowski W
      Gastrointestinal adverse events after dual Antiplatelet therapy: Clopidogrel is safer than Ticagrelor, but Prasugrel data are lacking or inconclusive.
      ,
      • Wiviott SD
      • Braunwald E
      • McCabe CH
      • Montalescot G
      • Ruzyllo W
      • Gottlieb S
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      ]. Furthermore, it should be considered that the prolongation of DAPT beyond 12 months in selected cases can be indicated. While this leads to a significant reduction in ischemic events, it might confer an increased risk of GI bleeding. Therefore, it is desirable to carry out a correct stratification of bleeding risk without disregarding gastrointestinal symptoms that could be the expression of an unknown underlying disease. A recent meta-analysis of RCTs aimed to compare the risk of gastrointestinal bleeding (GIB) among users of third generation P2Y12 inhibitors with clopidogrel [
      • Guo CG
      • Chen L
      • Chan EW
      • Cheung KS
      • Isshiki T
      • Wong ICK
      • et al.
      Systematic review with meta-analysis: the risk of gastrointestinal bleeding in patients taking third-generation P2Y12 inhibitors compared with clopidogrel.
      ]. The results showed that third generation P2Y12 inhibitors were associated with higher risk of upper GI bleeding (RR 1.32, 95% CI 1.05‐1.67) and unspecified GI bleeding (RR 1.25, 95% CI 1.01‐1.53), but not lower GI bleeding (RR 1.25, 95% CI 0.95‐1.65).

      3.2 Data from real word

      The guidelines recommend the early use of risk stratification in patients with ACS. This stratification should include both an ischaemic risk assessment (preferably on the basis of the DAPT score), and a bleeding risk evaluation (with the PRECISE-DAPT score) [
      • Valgimigli M
      • Bueno H
      • Byrne RA
      ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Gulizia MM
      • Colivicchi F
      • Abrignani MG
      • Ambrosetti M
      • Aspromonte N
      • Barile G
      • et al.
      Consensus Document ANMCO/ANCE/ARCA/GICR-IACPR/GISE/SICOA: Long-term Antiplatelet Therapy in Patients with Coronary Artery Disease.
      ]. However, patients enrolled in RCTs are often different from those seen in the real practice in term of clinical characteristics, risk factors, and comorbidities. For these reasons, it is important to assess evidence coming also from clinical practice. In a Danish registry, 46,301 patients hospitalized with an acute myocardial infarction (AMI) (35% of whom were at high risk of GI bleeding) were treated with clopidogrel (76.2%), ticagrelor (20.3%), or prasugrel (3.5%) [
      • Sehested TSG
      • Carlson N
      • Hansen PW
      • Gerds TA
      • Charlot MG
      • Torp-Pedersen C
      • et al.
      Reduced risk of gastrointestinal bleeding associated with proton pump inhibitor therapy in patients treated with dual antiplatelet therapy after myocardial infarction.
      ]. At 12 months, 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. In a Spanish observational register with 1,219 patients undergoing percutaneous angioplasty (PTA), 96.7% of whom were in DTA with LDA and clopidogrel, and the 76.6% on PPI therapy, 8 patients developed GI bleeding during hospitalization, and 27 during follow-up (1.52 bleeds per patient/year) [
      • Arroyo RC
      • Polo-Tomas M
      • Roncalés MP
      • Scheiman J
      • Á Lanas
      Lower GI bleeding is more common than upper among patients on dual antiplatelet therapy: Long-term follow-up of a cohort of patients commonly using PPI co-therapy.
      ]. Most GI bleeding (81.4%) occurred during the first year. Overall, 84.6% of patients were on long-term PPI at the time of the bleed, and indeed, lower GI bleeding occurred more frequently than upper GI bleeding (74% lower vs. 26% upper) [
      • Arroyo RC
      • Polo-Tomas M
      • Roncalés MP
      • Scheiman J
      • Á Lanas
      Lower GI bleeding is more common than upper among patients on dual antiplatelet therapy: Long-term follow-up of a cohort of patients commonly using PPI co-therapy.
      ]. A study performed in New Zealand on 66,500 patients aged ≥65 years showed no significant change in the incidence of GI bleeding in patients using ASA (ARR 0.84; 95% CI: 0.79-0.89), or with clopidogrel (ARR 0.97; 95% CI: 0.87-1.08) in monotherapy, while dual therapy resulted in an increased bleeding (ARR 1.34, 95% CI: 1.14-1.57) [
      • Nishtala PS
      • Jamieson HA
      • Hanger HC
      • Chyou TY
      • Hilmer SN
      Examining the Risks of Major Bleeding Events in Older People Using Antithrombotics.
      ]. In addition, the incidence of bleeding was increased when an anticoagulant therapy was associated with ASA (ARR 1.79; 95% CI: 1.30-2.46), clopidogrel (ARR 6.36; 95% CI: 2.24-18.03), or dual therapy (ARR 4.85; 95% CI: 1:51 to 15:57) [
      • Nishtala PS
      • Jamieson HA
      • Hanger HC
      • Chyou TY
      • Hilmer SN
      Examining the Risks of Major Bleeding Events in Older People Using Antithrombotics.
      ]. A case-control study involving 669,115 patients assessed the incidence of GI bleeding evaluating the age of the patients and use of different treatments [
      • De Abajo FJ
      • Gil MJ
      • Bryant V
      • Timoner J
      • Oliva B
      • García-Rodríguez LA
      Upper gastrointestinal bleeding associated with NSAIDs, other drugs and interactions: A nested case-control study in a new general practice database.
      ]. The incidence of bleeding observed was 76 per 100,000 people/year, with a prevalence higher in men than in women (109 vs. 49 per 100,000 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 GI bleeding (RR 11.27, 95% CI: 8.35-15.20), in those using ASA (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). On the contrary, risk was not significantly higher in those using steroids (RR 1.11; 95% CI: 0.66-1.86), or paracetamol (RR 1.00; 95% CI: 0.82-1.23) [
      • De Abajo FJ
      • Gil MJ
      • Bryant V
      • Timoner J
      • Oliva B
      • García-Rodríguez LA
      Upper gastrointestinal bleeding associated with NSAIDs, other drugs and interactions: A nested case-control study in a new general practice database.
      ]. Among the NSAIDs, aceclofenac (RR 1.02; 95% CI: 0.51-2.02), diclofenac (RR 1.32; 95% CI: 0.87-1.98), and ibuprofen (RR 1.33; 95% CI: 0.94-1.89) were the medications with the lower risk of bleeding if prescribed concomitantly with the antiplatelet agents compared to lornoxicam (RR 13.57; 95% CI: 4.61-29.93), piroxicam (RR 4.49; 95% CI: 2.36-8.54), and desketoprofen/ketoprofen (RR 3.79; 95% CI: 1.70-8.46). The results of a 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 - showed that the rate of MACE 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) [
      • Alexopoulos D
      • Xanthopoulou I
      • Deftereos S
      • Hamilos M
      • Sitafidis G
      • Kanakakis I
      • et al.
      Contemporary antiplatelet treatment in acute coronary syndrome patients undergoing percutaneous coronary intervention: 1-year outcomes from the GReek AntiPlatElet (GRAPE) Registry.
      ]. 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 [
      • Alexopoulos D
      • Xanthopoulou I
      • Deftereos S
      • Hamilos M
      • Sitafidis G
      • Kanakakis I
      • et al.
      Contemporary antiplatelet treatment in acute coronary syndrome patients undergoing percutaneous coronary intervention: 1-year outcomes from the GReek AntiPlatElet (GRAPE) Registry.
      ]. However, bleeding is often associated with a discontinuation of a DAT, with harmful consequences on ischemic events in the medium and long term [
      • Harding SA
      • Holley A
      • Wilkins B
      • Fairley S
      • Simmonds M
      • Larsen PD
      Contemporary antiplatelet therapy in acute coronary syndromes: are there differences in outcomes and discontinuation between clopidogrel and ticagrelor?.
      ]. Similar data emerged from the Swedish register SWEDEHEART, where 45,073 patients with ACS were enrolled [
      • Sahlén A
      • Varenhorst C
      • Lagerqvist B
      • Renlund H
      • Omerovic E
      • Erlinge D
      • et al.
      Outcomes in patients treated with ticagrelor or clopidogrel after acute myocardial infarction: Experiences from SWEDEHEART registry.
      ]. At 24 months, the risk of ischemic events, death, and MI was lower with ticagrelor than to clopidogrel (11.7% vs. 22.3%, adjusted HR 0.85, 95% CI: 0.78–0.93; 5.8% vs. 12.9%, adjusted HR 0.83, 95% CI:0.75–0.92; 6.1% vs. 10.8%, adjusted HR 0.89, 95% CI: 0.78–1.01; respectively) [
      • Sahlén A
      • Varenhorst C
      • Lagerqvist B
      • Renlund H
      • Omerovic E
      • Erlinge D
      • et al.
      Outcomes in patients treated with ticagrelor or clopidogrel after acute myocardial infarction: Experiences from SWEDEHEART registry.
      ]. However, re-admission with bleeding was lower in patients taking ticagrelor as compared to those taking clopidogrel: 5.5% vs. 5.2%; adjusted HR 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 in clopidogrel (7% vs.2.7%, adjusted OR 1.57, 95% CI: 1.30–1.90) [
      • Sahlén A
      • Varenhorst C
      • Lagerqvist B
      • Renlund H
      • Omerovic E
      • Erlinge D
      • et al.
      Outcomes in patients treated with ticagrelor or clopidogrel after acute myocardial infarction: Experiences from SWEDEHEART registry.
      ]. Furthermore, a sub-analysis of data in patients with a reduced renal function, showed a correlation between clearance creatinine and bleeding events [
      • Edfors R
      • Sahlén A
      • Szummer K
      • Renlund H
      • Evans M
      • Carrero JJ
      • et al.
      Outcomes in patients treated with ticagrelor versus clopidogrel after acute myocardial infarction stratified by renal function.
      ]. There are few studies in the literature comparing the prevalence of upper GI lesions between aspirin and clopidogrel users. In addition to the CAPRIE study [
      CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      ], in 2012, an observational study aimed to investigate the characteristics of endoscopic findings in clopidogrel or aspirin users undergoing endoscopy for upper gastrointestinal symptoms [
      • Tsai TJ
      • Lai KH
      • Hsu PI
      • Lin CK
      • Chan HH
      • Yu HC
      • et al.
      Upper gastrointestinal lesions in patients receiving clopidogrel anti-platelet therapy.
      ]. Authors found that gastroduodenal haemorrhagic spots were more common between clopidogrel users than aspirin users (10.1% vs. 25.5%, p= 0.004). Gastroduodenal erosions were barely more common between the aspirin users than clopidogrel users (53.2% vs. 38.7%; p=0.04), whilst gastroduodenal peptic ulcers were more common between the clopidogrel users than the aspirin users (38.7% vs. 23.9%; p= 0.027). Similarly, in 2015, a case-control study found that non-aspirin antiplatelet agents (mostly clopidogrel) were associated with an increased risk of UGIB that was similar to that observed with ASA [
      • Lanas A
      • Carrera-Lasfuentes P
      • Arguedas Y
      • García S
      • Bujanda L
      • Calvet X
      • et al.
      Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants.
      ]. Finally, in 2019, a retrospective study on 1119 ischemic stroke patients found that the HR for GIB was significantly in favour of clopidogrel (HR: 2.60; 95% CI: 2.82 - 3.70) [
      • Vidyanti AN
      • Chan L
      • Lin CL
      • Muo CH
      • Hsu CY
      • Chen YC
      • et al.
      Aspirin better than clopidogrel on major adverse cardiovascular events reduction after ischemic stroke: A retrospective nationwide cohort study.
      ].

      4. Oral anticoagulant agents and risk of GI bleeding

      4.1 Data from Clinical Trials

      GI bleeding represents an adverse event associated also with oral anticoagulant therapy. In two Meta-analyses of phase 3 registration studies, DOACs increased the risk of major GI bleeding by 23-25% compared to warfarin in patients with AF, even if this difference was barely significant [
      • Ruff CT
      • Giugliano RP
      • Braunwald E
      • Hoffman EB
      • Deenadayalu N
      • Ezekowitz MD
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials.
      ,
      • Loffredo L
      • Perri L
      • Violi F
      Impact of new oral anticoagulants on gastrointestinal bleeding in atrial fibrillation: A meta-analysis of interventional trials.
      ]. In the RE-LY trial, when patients with AF with a mean age of 71 years were evaluated, the use of dabigatran 150 mg bid was associated with a higher risk of GI bleeding than warfarin (RR 1.50; 95% CI: 1.19-1.89), while there was no significant difference between dabigatran 110 mg bid and warfarin (RR 1.10; 95% CI: 0.86-1.41) (Fig. 1) [
      • Connolly SJ
      • Ezekowitz MD
      • Yusuf S
      • Eikelboom J
      • Oldgren J
      • Parekh A
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ]. However, the increased risk of bleeding observed with the higher doses of dabigatran in this study, could be attributed to blind administration of dabigatran 150 mg also in very fragile patients [
      • Connolly SJ
      • Ezekowitz MD
      • Yusuf S
      • Eikelboom J
      • Oldgren J
      • Parekh A
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ]. The European (EU) label recommends the dose of 150 mg bid in patients with AF who are aged < 80 years without an increased risk for bleeding (e.g., HAS-BLED score <3), and not on concomitant verapamil, whilst in other patients, the dose of 110 mg bid is recommended. [
      • Lip GYH
      • Clemens A
      • Noack H
      • Ferreira J
      • Connolly SJ
      • Yusuf S
      Patient outcomes using the European label for dabigatran: A post-hoc analysis from the RE-LY database.
      ]. In a post-hoc simulation using the RE-LY dataset, it was therefore assessed how dabigatran, used according to the EU label, would compare to well-controlled warfarin treatment (INR 2–3; median time in therapeutic range 67.3%). The results of this simulation showed that was no difference between the two medications in term of major GI bleeding (HR 1.23; 95% CI: 0.96–1.59), although this was barely not significant [
      • Lip GYH
      • Clemens A
      • Noack H
      • Ferreira J
      • Connolly SJ
      • Yusuf S
      Patient outcomes using the European label for dabigatran: A post-hoc analysis from the RE-LY database.
      ]. In the ROCKET-AF trial, patients randomized to rivaroxaban had a significantly higher incidence of GI bleeding than warfarin (3.15% vs. 2.16%, p <0.001; Fig. 1), although the frequency of fatal bleeding was comparable between the two [
      • Patel MR
      • Mahaffey KW
      • Garg J
      • Pan G
      • Singer DE
      • Hacke W
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ]. In the ENGAGE AF-TIMI 48 study, there was an increased risk of major GI bleeding with the high dose of edoxaban (60 mg daily) compared to warfarin (HR 1.23; 95% CI: 1.02-1.5) although this was barely significant (Fig. 1) [
      • Giugliano RP
      • Ruff CT
      • Braunwald E
      • Murphy SA
      • Wiviott SD
      • Halperin JL
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      ]. However, in patients who received the low dose of edoxaban (30 mg daily), the rate of G bleeding was significantly lower compared to warfarin (HR: 0.67; 95% CI: 0.53 to 0.83) (Fig. 1).
      The only DOAC that does not appear to be associated with an increase in GI bleeding greater than warfarin is apixaban. Indeed, in the ARISTOTLE trial, there was a comparable incidence of major GI bleeding between apixaban 5 mg bid and warfarin (HR 0.89; 95% CI: 0.7-1.15) (Fig. 1) [
      • Granger CB
      • Alexander JH
      • McMurray JJV
      • Lopes RD
      • Hylek EM
      • Hanna M
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ]. Therefore, the Working Group of the European Society of Cardiology suggests the use of apixaban in patients with AF at high risk of bleeding from the GI tract [
      • Diener HC
      • Aisenberg J
      • Ansell J
      • Atar D
      • Breithardt G
      • Eikelboom J
      • et al.
      Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: Part 2.
      ]. However, there are no RCTs where the different DOACs are compared directly. It is also useful to highlight that GI bleeding site can vary between the different DOACs [
      • Cheung KS
      • Leung WK.
      Gastrointestinal bleeding in patients on novel oral anticoagulants: Risk, prevention and management.
      ,
      • Heidbuchel H
      • Verhamme P
      • Alings M
      • Antz M
      • Diener HC
      • Hacke W
      • et al.
      Updated European Heart Rhythm Association Practical Guide on the use of non-Vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation.
      ]. Bleeding events during dabigatran therapy affect the lower digestive tract in 53% of cases [
      • Eikelboom JW
      • Wallentin L
      • Connolly SJ
      • Ezekowitz M
      • Healey JS
      • Oldgren J
      • et al.
      Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.
      ]. This could be due to the incomplete absorption of dabigatran in the upper GI tract, and to the greater availability of the medication in the colon, where it would induce bleeding from pre-existing lesions, such as angiodysplasias and erosions [
      • Cheung KS
      • Leung WK.
      Gastrointestinal bleeding in patients on novel oral anticoagulants: Risk, prevention and management.
      ,
      • Heidbuchel H
      • Verhamme P
      • Alings M
      • Antz M
      • Diener HC
      • Hacke W
      • et al.
      Updated European Heart Rhythm Association Practical Guide on the use of non-Vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation.
      ]. On the contrary, with rivaroxaban, bleeding is more frequent in the upper tract (76% vs 24%), while with apixaban 10 mg/day there is no difference in the incidence between upper and lower bleeding [
      • Eikelboom JW
      • Wallentin L
      • Connolly SJ
      • Ezekowitz M
      • Healey JS
      • Oldgren J
      • et al.
      Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.
      ]. Single administration of rivaroxaban results in a higher peak of the drug than fractional administration of apixaban [
      • Granger CB
      • Alexander JH
      • McMurray JJV
      • Lopes RD
      • Hylek EM
      • Hanna M
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ,
      • Cheung KS
      • Leung WK.
      Gastrointestinal bleeding in patients on novel oral anticoagulants: Risk, prevention and management.
      ]. This may explain the higher incidence of rivaroxaban-induced bleeding compared to apixaban, although they have a similar bioavailability. The same mechanism has been proposed to elucidate the higher relative incidence of major GI bleeding observed with rivaroxaban, administered once daily, compared to dabigatran administered twice daily [
      • Lanas-Gimeno A
      • Lanas A.
      Risk of gastrointestinal bleeding during anticoagulant treatment.
      ,
      • Abraham NS
      • Noseworthy PA
      • Yao X
      • Sangaralingham LR
      • Shah ND
      Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study.
      ]. Finally, in a meta-analysis aimed to assess the risk of GIB and clinically relevant bleeding in patients taking DOACs, it was found a total of 1.5% of GIB, 89% of which represented by major events [
      • Holster IL
      • Valkhoff VE
      • Kuipers EJ
      • Tjwa ETTL
      New oral anticoagulants increase risk for gastrointestinal bleeding: A systematic review and meta-analysis.
      ]. The overall OR for GIB among patients taking DOACs, when compared to standard anticoagulant therapy, was 1.45 (95% CI:1.07 -1.97). Among the DOACs, only dabigatran (OR 1.58; 95% CI: 1.29-1.93) and rivaroxaban (OR 1.48; 95% CI: 1.21-1.82) were associated with a significantly increased risk of bleeding [
      • Holster IL
      • Valkhoff VE
      • Kuipers EJ
      • Tjwa ETTL
      New oral anticoagulants increase risk for gastrointestinal bleeding: A systematic review and meta-analysis.
      ].

      4.2 Data from real word

      The "real world" evidence show a higher incidence of GI bleeding with some DOACs compared to warfarin [
      • Desai JC
      • Chatterjee P
      • Friedman K
      • Aisenberg J
      Incidence and clinical presentation of gastrointestinal bleeding in atrial fibrillation patients taking direct oral anticoagulants.
      ]. In a retrospective study, the risk of GI bleeding was assessed in a cohort of 92,816 patients taking anticoagulants (9.2% patients on dabigatran, 17.5% on rivaroxaban, and 73.2% on warfarin) [
      • Abraham NS
      • Singh S
      • Caleb Alexander G
      • Heien H
      • Haas LR
      • Crown W
      • et al.
      Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: Population based cohort study.
      ]. The data allowed a head-to-head comparison between warfarin and each of the two DOACs for homogeneous subgroups of patients, with or without AF, and also by location of bleeding. Using a propensity score matched models, the risk of GI bleeding 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) [
      • Abraham NS
      • Singh S
      • Caleb Alexander G
      • Heien H
      • Haas LR
      • Crown W
      • et al.
      Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: Population based cohort study.
      ]. However, the risk of bleeding increased with age, so that in patients aged ≥76 years, 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) [
      • Abraham NS
      • Singh S
      • Caleb Alexander G
      • Heien H
      • Haas LR
      • Crown W
      • et al.
      Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: Population based cohort study.
      ]. Recently, a retrospective analysis was conducted on patients with non-valvular AF treated with dabigatran, rivaroxaban or apixaban. Data from three patient cohorts were compared, including 31,574 case treated with rivaroxaban vs. dabigatran, 13084 cases in apixaban vs. dabigatran, and 13,130 patients in apixaban vs. rivaroxaban [
      • Abraham NS
      • Noseworthy PA
      • Yao X
      • Sangaralingham LR
      • Shah ND
      Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study.
      ]. Gastrointestinal bleeding was more frequent, even if not statistically significant, in rivaroxaban patients compared to dabigatran (HR 1.20; 95% CI: 1.00-1.45), confirming the result of other observations. Apixaban, on the other hand, showed a lower risk than dabigatran (HR 0.39; 95% CI: 0.27-0.58; p <0.001) and rivaroxaban (HR 0.33; 95% CI: 0.22-0.49; p <0.001). In the three subgroups, the frequency of bleeding events increased in patients over 75 years of age [
      • Abraham NS
      • Noseworthy PA
      • Yao X
      • Sangaralingham LR
      • Shah ND
      Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study.
      ]. Interestingly, a retrospective cohort study found that the incidence of hospitalization for upper gastrointestinal tract bleeding, among users of NOACs or warfarin, was lower among patients who were receiving PPIs co-therapy compared to those not receiving PPIs [
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding.
      ]. Apixaban showed a lower risk of GI bleeding also in elderly subjects compared to dabigatran (HR 0.45; 95% CI: 0.29-0.71) or rivaroxaban (HR 0.39; 95% CI: 0.25-0.61) (Table 2) [
      • Luo PJ
      • Lin XH
      • Lin CC
      • Luo JC
      • Hu HY
      • Ting PH
      • et al.
      Risk factors for upper gastrointestinal bleeding among aspirin users: An old issue with new findings from a population-based cohort study.
      ,
      • Lanas A
      • Gargallo CJ.
      Management of low-dose aspirin and clopidogrel in clinical practice: A gastrointestinal perspective.
      ]. Other "real world" evidence raised from post-marketing pharmacovigilance data. A recent Italian study analysed data coming from the Adverse Reactions of Medicines Report System of the National Pharmacovigilance Network, between January and December 2017 for all DOACs [
      • Camporese G
      • Simioni P
      • Bernard E
      Primo anno di edoxaban in Italia: Dati di sicurezza dalla Rete Nazionale di Farmacovigilanza.
      ], and it also evaluated the locations of the reported bleeding adverse events (Fig. 2). The study showed that the percentage of overall bleeding events per site was substantially overlapped between the various DOACs, with a peak (12-15%) corresponding to the GI system, which was expected as a "class effect". Even if there was a slight increase in some of the minor locations considered, the lower rate of anaemia might suggest a low clinical relevance and an easy management of these bleedings.
      Table 2Gastrointestinal bleeding based on age: comparison between different direct oral anticoagulants [
      • Luo PJ
      • Lin XH
      • Lin CC
      • Luo JC
      • Hu HY
      • Ting PH
      • et al.
      Risk factors for upper gastrointestinal bleeding among aspirin users: An old issue with new findings from a population-based cohort study.
      ,
      • Lanas A
      • Gargallo CJ.
      Management of low-dose aspirin and clopidogrel in clinical practice: A gastrointestinal perspective.
      ].
      Age

      (years)
      Rivaroxaban vs. DabigatranApixaban vs. DabigatranApixaban vs. Dabigatran
      HR95% CIpHR95% CIpHR95% CIp
      18-642.031.06-3.90<0.050.380.08-1.84NS0.380.08 – 1.89NS
      65-741.441.00 – 2.06<0.050.250.10 – 0.65<0.0101.80.07 – 0.47<0.001
      ≥ 751.060.84 – 1.34NS0.450.29 – 0.71<0.0010.390.25 – 0.61<0.001

      5. Pharmacological and clinical interactions between proton pump inhibitors and antiplatelet agents

      PPIs are among the most prescribed medications in the world, and are often used in the long term to treat chronic conditions such as gastroesophageal reflux disease or the prophylaxis of gastroduodenal lesions from ASA or NSAIDs, particularly in elderly patients and those at high risk of digestive bleeding events [
      • Wolfe MM
      • Sachs G
      Acid suppression: Optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome.
      ,
      • Vigneri S
      • Termini R
      • Leandro G
      • Badalamenti S
      • Pantalena M
      • Savarino V
      • et al.
      A comparison of five maintenance therapies for reflux esophagitis.
      ,
      • Lanas A
      • García-Rodríguez LA
      • Arroyo MT
      • Bujanda L
      • Gomollón F
      • Forné M
      • et al.
      Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants.
      ]. In the last years, some reports have questioned the safety in the long-term use of PPIs due to potential negative effects including an increase in cardiovascular events [
      • Freedberg DE
      • Kim LS
      • Yang YX
      The Risks and Benefits of Long-term Use of Proton Pump Inhibitors: Expert Review and Best Practice Advice From the American Gastroenterological Association.
      ]. In a case-control study based on a regional prescriptive database, the risk of cardiovascular events was significant increased (OR 1.61; CI 95%: 1.55-1.68) in patients treated with PPIs, regardless of the administration of antithrombotic drugs, emphasizing the need to encourage an appropriate prescription for these class of medications [
      • Casula M
      • Scotti L
      • Galimberti F
      • Mozzanica F
      • Tragni E
      • Corrao G
      • et al.
      Use of proton pump inhibitors and risk of ischemic events in the general population.
      ]. However, in a large analysis of administrative claims from commercial and Medicare Supplemental plans from 2001 to 2014 in the United States, it was found no evidence that prescription of PPIs increased the risk of MI compared with prescription H2RA [
      • Landi SN
      • Sandler RS
      • Pate V
      • Lund JL
      No Increase in Risk of Acute Myocardial Infarction in Privately Insured Adults Prescribed Proton Pump Inhibitors vs Histamine-2 Receptor Antagonists (2002–2014).
      ]. In patients taking antiplatelet agents, both as monotherapy and DAT, PPIs were superior to H2RA in preventing GI bleeding [
      • Almufleh A
      • Ramirez FD
      • So D
      • Le May M
      • Chong AY
      • Torabi N
      • et al.
      H2 Receptor Antagonists versus Proton Pump Inhibitors in Patients on Dual Antiplatelet Therapy for Coronary Artery Disease: A Systematic Review.
      ]. However, an increased risk (OR 1.40, 95% CI: 1.10-1.77) of recurrent MI was reported in 2009 in patients taking clopidogrel and PPIs [
      • Juurlink DN
      • Gomes T
      • Ko DT
      • Szmitko PE
      • Austin PC
      • Tu JV
      • et al.
      A population-based study of the drug interaction between proton pump inhibitors and clopidogrel.
      ]. This risk was attributed to the inhibition of the cytochrome P450 2C19 (CYP2C19) by several PPIs as clopidogrel and prasugrel, but not ticagrelor, are biotransformed by CYP2C19 into active metabolites [
      • Scott SA
      • Owusu Obeng A
      • Hulot JS
      Antiplatelet drug interactions with proton pump inhibitors.
      ]. However, in the same study, it was found that the use of PPIs did result in a lower incidence of MI with prasugrel (HR 0.61; 95% CI: 0.42-0.88) compared to clopidogrel [
      • Nicolau JC
      • Bhatt DL
      • Roe MT
      • Lokhnygina Y
      • Neely B
      • Corbalán R
      • et al.
      Concomitant proton-pump inhibitor use, platelet activity, and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel and managed without revascularization: Insights from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial.
      ]. The increased cardiological risk observed in this study was therefore questioned as it was a surrogate endpoint. Indeed, the data of two meta-analyses were conflicting. The increased incidence (OR 1.39; 95% CI: 1.29-1.49) of MACE, stent thrombosis, and MI in patients taking clopidogrel and PPI was confirmed in the former [
      • Bundhun PK
      • Teeluck AR
      • Bhurtu A
      • Huang WQ
      Is the concomitant use of clopidogrel and Proton Pump Inhibitors still associated with increased adverse cardiovascular outcomes following coronary angioplasty?: A systematic review and meta-analysis of recently published studies (2012 - 2016).
      ], but not in the latter meta-analysis [
      • Cardoso RN
      • Benjo AM
      • DiNicolantonio JJ
      • Garcia DC
      • MacEdo FYB
      • El-Hayek G
      • et al.
      Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: An updated meta-analysis.
      ]. Furthermore, it was observed that the variability of action of PPIs on CYP2C19 is not class-specific [
      • Chen CH
      • Yang JC
      • Uang YS
      • Lin CJ
      Differential inhibitory effects of proton pump inhibitors on the metabolism and antiplatelet activities of clopidogrel and prasugrel.
      ]. The interaction is more marked for omeprazole and esomeprazole, while some studies have shown that pantoprazole has a lower inhibiting effect on CYP2C19, without reducing the antiplatelet efficacy of clopidogrel [
      • Choi YJ
      • Kim N
      • Jang IJ
      • Cho JY
      • Nam RH
      • Park JH
      • et al.
      Pantoprazole does not reduce the antiplatelet effect of clopidogrel: A randomized controlled trial in Korea.
      ]. The only prospective study (the COGENT trial) demonstrated that omeprazole significantly reduces the rate of composite GI events but did not show any increase in the composite CV events in patients at high CV risk [
      • Bhatt DL
      • Cryer BL
      • Contant CF
      • Cohen M
      • Lanas A
      • Schnitzer TJ
      • et al.
      Clopidogrel with or without omeprazole in coronary artery disease.
      ]. However, since the trial was terminated prematurely, the absence of interaction between clopidogrel and omeprazole could not be viewed as a definitive finding.
      Ticagrelor is a P2Y12 receptor inhibitor that does not require biotransformation, and for this reason there should be no drug interactions with PPIs. However, in the PLATO study, among patients treated with PPIs, MACE were higher both in those treated with clopidogrel (HR 1.2: 95% CI: 1.04-1.38), and in those treated with ticagrelor (HR 1.24; 95% CI: 1.07-1.45) [
      • Goodman SG
      • Clare R
      • Pieper KS
      • Nicolau JC
      • Storey RF
      • Cantor WJ
      • et al.
      Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: Insights from the platelet inhibition and patient outcomes trial.
      ]. A similar observation has also been found in patients treated with other gastroprotective agents, and therefore it was hypothesized that treatment with PPI may be a marker rather than a cause of MACE. In a Dutch monocentric observational registry on ACS patients, it was shown that PPI prescription at discharge significantly increased from 34.7% in 2010 to 88.7% in 2014 (p<0.001). PPI treatment was associated with reduction in cardiac death or MI (adjusted HR 0.27; 95% CI: 0.10-0.76) and cardiac death, MI or stroke (adjusted HR 0.33; 95% CI: 0.14-0.81), both at 30-days post-discharge. However, this association was not present in subgroup analyses of patients treated with clopidogrel or ticagrelor, and there was also no difference in GI bleeding between patients treated with or without PPI [
      • Hoedemaker NPG
      • Damman P
      • Ottervanger JP
      • Dambrink JHE
      • Gosselink ATM
      • Kedhi E
      • et al.
      Trends in cardiovascular and bleeding outcomes in acute coronary syndrome patients treated with or without proton-pump inhibitors during the introduction of novel P2Y12 inhibitors: A five-year experience from a single-centre observational registry.
      ]. It was therefore suggested that therapy with PPI may serve as a marker of improved therapies and outcome, rather than causing a reduction in cardiovascular events [
      • Hoedemaker NPG
      • Damman P
      • Ottervanger JP
      • Dambrink JHE
      • Gosselink ATM
      • Kedhi E
      • et al.
      Trends in cardiovascular and bleeding outcomes in acute coronary syndrome patients treated with or without proton-pump inhibitors during the introduction of novel P2Y12 inhibitors: A five-year experience from a single-centre observational registry.
      ]. It is clear that what is important is the net risk/benefit ratio, which must take into account both cardiovascular events and severe GI bleeding. In an international multicentre registry conducted from 2003 to 2014 on patients undergoing PCI after ACS, the impact of the concomitant administration of PPIs and clopidogrel or ticagrelor on a 1-year composite endpoint (total mortality, reinfarction and severe bleeding) was assessed [
      • Yan Y
      • Wang X
      • Fan JY
      Impact of concomitant use of proton pump inhibitors and clopidogrel or ticagrelor on clinical outcomes in patients with acute coronary syndrome.
      ]. Overall, 54.8% of patients a PPI at discharge was prescribed. Patients receiving a PPI were older, more often female, and were more likely to have comorbidities. No association was observed between PPIs use and the primary endpoint for patients receiving clopidogrel (adjusted HR: 1.036; 95% CI: 0.903–1.189) or ticagrelor (adjusted HR: 2.32; 95% CI: 0.875–6.151). Finally, it has recently been reported that PPIs can also mitigate the anti-aggregating effect of ASA [
      • Würtz M
      • Grove EL.
      Proton pump inhibitors in cardiovascular disease: Drug interactions with antiplatelet drugs.
      ].

      6. Pharmacological and clinical interactions between proton pump inhibitors and anticoagulant agents

      The role of therapy with PPIs in reducing the risk of GI bleeding in patients receiving oral anticoagulants still appears to be controversial.

      6.1 Proton pump inhibitors and VKAs

      In the absence of RCTs, a large retrospective observational study in patients taking warfarin showed that PPI co-therapy, among those concurrently using antiplatelet drugs or NSAIDs, significantly reduced the risk of hospitalization for UGIB (HR 0.55; 95% CI: 0.39- 0.77) compared to those not using PPI co-therapy, with a NNT of 78 [
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Proton Pump Inhibitors With Reduced Risk of Warfarin-Related Serious Upper Gastrointestinal Bleeding.
      ]. On the contrary, in the absence of a concurrently use of antiplatelet drugs or NSAIDs, PPI co-therapy in patients taking warfarin did not significantly reduce the risk of hospitalization for UGIB (HR 0.86, 95% CI 0.70-1.06) [
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Proton Pump Inhibitors With Reduced Risk of Warfarin-Related Serious Upper Gastrointestinal Bleeding.
      ]. A recent cohort study with 1,643,123 patients on anticoagulant therapy with an average age of 76.4 years - mainly for atrial fibrillation – compared the data of 754,389 person-years on anticoagulant treatment without PPIs (516,512 cases on warfarin) with those of 264,447 person-years in co-therapy with PPIs (183,929 on warfarin) [
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding.
      ]. The incidence of hospitalizations for GI bleeding was significantly reduced in patients receiving warfarin and PPIs (74 episodes per 10,000 person-years) compared to the group receiving warfarin but not treated with PPIs (113 episodes per 10,000 person-years), after adjustment for numerous covariates including also use of antiplatelet agents, steroids, and NSAIDs [
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding.
      ]. It should be noted that there is a pharmacological interaction between PPIs and warfarin due to their liver metabolism. Therefore, international normalized ratios should be monitored when initiating or discontinuing PPI therapy in patients taking VKAs [
      • Scarpignato C
      • Gatta L
      • Zullo A
      • Blandizzi C
      for the SIFA-FG, on behalf of the Italian Society of P, et al.
      ].

      6.2 Proton pump inhibitors and DOACs

      DOACs have a different pharmacokinetic from warfarin. Dabigatran also differs from other DOACs due to its low bioavailability and is administered as a prodrug (dabigratan etexilate). Since its absorption increases in an acidic environment, the capsules are intended for a release in the stomach and the drug is absorbed in the distal small intestine. The co-administration of PPIs involves a lowersolubility of dabigatran with a reduction of about 30% of its absorption, without however changing its clinical efficacy [
      • Connolly SJ
      • Ezekowitz MD
      • Yusuf S
      • Eikelboom J
      • Oldgren J
      • Parekh A
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ,
      • Heidbuchel H
      • Verhamme P
      • Alings M
      • Antz M
      • Diener HC
      • Hacke W
      • et al.
      Updated European Heart Rhythm Association Practical Guide on the use of non-Vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation.
      ,
      • Stöllberger C.
      Drug interactions with new oral anticoagulants in elderly patients.
      ]. Furthermore, it has been observed that dyspeptic symptoms arising in some patients taking dabigatran can be successfully treated with PPIs without clinically relevant interactions [
      • Agewall S
      • Cattaneo M
      • Collet JP
      • Andreotti F
      • Lip GYH
      • Verheugt FWA
      • et al.
      Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy.
      ]. Recently, a large retrospective study aimed to compare the incidence of hospitalization for UGIB in patients using individual anticoagulants (VKAs or DOACs) with and without PPI co-therapy, according to presence of GI risk factors [
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding.
      ]. In patients receiving anticoagulant treatment without PPI co-therapy, the adjusted incidence of hospitalization for UGIB for rivaroxaban was significantly greater than the incidence for apixaban (incidence rate ratio: 1.97; 95% CI: 1.73-2.25), dabigatran (incidence rate ratio: 1.19; 95% CI: 1.08-1.32), and warfarin (incidence rate ratio 1.27; 95% CI: 1.19-1.35]. For patients receiving anticoagulant treatment with PPI co-therapy, the adjusted incidence of hospitalization for UGIB was lower than the incidence in patients receiving treatment without PPI co-therapy (incidence rate ratio: 0.66; 95% CI: 0.62-0.69), and was significantly lower for each individual anticoagulant evaluated [
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding.
      ]. This raises the possibility that the use of PPIs might be able to reduce the risk of UGIB in all patients taking oral anticoagulants (VKAs or DOACs) regardless of the presence of risk factors. However, more studies are needed to make recommendations. The adjusted incidence of hospitalization for UGIB in patients with PPI co-therapy was most pronounced for dabigatran, probably explained by dabigatran-related upper gastrointestinal tract lesions that are potentially the result of direct mucosal injury by the drug's tartaric acid core [
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding.
      ].
      Concomitant treatment with gastroprotective agents - both PPI, which demonstrated a slightly better protective effect, and H2RA - was associated with a 50% reduction of risk of GI bleeding, with the maximum effect when the two drugs were used in association [
      • Chan EW
      • Lau WCY
      • Leung WK
      • Mok MTC
      • He Y
      • Tong TSM
      • et al.
      Prevention of Dabigatran-Related Gastrointestinal Bleeding with Gastroprotective Agents: A Population-Based Study.
      ]. This protective effect appears to be confined to the upper GI tract, and to patients with previous peptic disease or GI bleeding, being mediated by the reduction of bleeding from pre-existing ulcers [
      • Cheung KS
      • Leung WK.
      Gastrointestinal bleeding in patients on novel oral anticoagulants: Risk, prevention and management.
      ]. The impact of gastroprotective agents is also significant in patients treated with dabigatran, but modest with rivaroxaban [
      • He Y
      • Wong ICK
      • Li X
      • Anand S
      • Leung WK
      • Siu CW
      • et al.
      The association between non-vitamin K antagonist oral anticoagulants and gastrointestinal bleeding: a meta-analysis of observational studies.
      ]. The COMPASS study, recently published, evaluated 17,598 patients with stable cardiovascular disease and peripheral arterial disease who were randomized to receive pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone for 3 years [
      • Moayyedi P
      • Eikelboom JW
      • Bosch J
      • Connolly SJ
      • Dyal L
      • Shestakovska O
      • et al.
      Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial.
      ]. There were no significant differences in clinical events (overt bleeding of gastroduodenal origin confirmed by endoscopy or radiography, overt upper GI bleeding of unknown origin, bleeding of presumed occult upper GI tract origin with documented decrease in Hb ≥2 g/dL, GI pain with underlying multiple gastroduodenal erosions, symptomatic gastroduodenal ulcer, upper GI obstruction or perforation). However, as upper GI events as defined in the study protocol were uncommon in this trial, in a post-hoc analysis the definition was broadened. This analysis showed that pantoprazole therapy significantly reduced overt bleeding of gastroduodenal origin with no need for active bleeding at time of investigation (HR 0.45; 95% CI: 0.270.74), gastroduodenal ulcer without the need for symptoms prior to diagnosis (HR 0.46; 95% CI: 0.25-0.83), and multiple gastroduodenal erosions without the need for symptoms prior to diagnosis (HR 0.33; 95% CI: 0.13-0.84), particularly in patients treated with ASA) [
      • Moayyedi P
      • Eikelboom JW
      • Bosch J
      • Connolly SJ
      • Dyal L
      • Shestakovska O
      • et al.
      Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial.
      ]. On the other hand, the same study showed that there was a statistically significant difference between the pantoprazole and placebo groups for enteric infections (1.4% vs 1.0% in the placebo group; OR 1.33; 95% CI: 1.01–1.75). For all other safety outcomes (gastric atrophy, chronic kidney disease, dementia, pneumonia, fracture, chronic obstructive pulmonary disease, diabetes mellitus, cumulative incidence of combined and individual cardiovascular death, myocardial infarction, and stroke, hospitalization rates, and all-cause mortality) proportions were similar between groups except for C. difficile infection, which was approximately twice as common in the pantoprazole vs. the placebo group, although there were only 13 events, so this difference was not statistically significant [
      • Moayyedi P
      • Eikelboom JW
      • Bosch J
      • Connolly SJ
      • Dyal L
      • Shestakovska O
      • et al.
      Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin.
      ]. In cirrhotic patients, current guidelines recommend all oral anticoagulants (VKAs or DOACs) in patients with Child-Pugh class A, while contraindicate their use in patients with liver disease associated with coagulopathy and clinically relevant bleeding risk, including Child-Pugh C. DOACs are variably recommended in Child-Pugh class B cirrhosis [
      • Qamar A
      • Vaduganathan M
      • Greenberger NJ
      • Giugliano RP
      Oral Anticoagulation in Patients With Liver Disease.
      ,
      • Ballestri S
      • Capitelli M
      • Fontana MC
      • Arioli D
      • Romagnoli E
      • Graziosi C
      • et al.
      Direct Oral Anticoagulants in Patients with Liver Disease in the Era of Non-Alcoholic Fatty Liver Disease Global Epidemic: A Narrative Review.
      ]. In these patients, PPI should be recommended according to guidelines [
      • Qamar A
      • Vaduganathan M
      • Greenberger NJ
      • Giugliano RP
      Oral Anticoagulation in Patients With Liver Disease.
      ,
      • Ballestri S
      • Capitelli M
      • Fontana MC
      • Arioli D
      • Romagnoli E
      • Graziosi C
      • et al.
      Direct Oral Anticoagulants in Patients with Liver Disease in the Era of Non-Alcoholic Fatty Liver Disease Global Epidemic: A Narrative Review.
      ,
      • Steffel J
      • Verhamme P
      • Potpara TS
      • Albaladejo P
      • Antz M
      • Desteghe L
      • et al.
      The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
      ].

      H. pylori infection and risk of peptic ulcer bleeding in patients on antiplatelet and/or anticoagulants agents

      H. pylori infection and use of aspirin are two main risk factors in the pathogenesis of peptic ulcers and peptic ulcer complications. However, not all patients H. pylori positive or taking aspirin develop PUD, suggesting that individual susceptibility to the infection and drug toxicity are critical factors to the initiation of mucosal damage [
      • Lanas A
      • Chan FKL
      Peptic ulcer disease.
      ,
      • Sostres C
      • Carrera-Lasfuentes P
      • Benito R
      • Roncales P
      • Arruebo M
      • Arroyo MT
      • et al.
      Peptic Ulcer Bleeding Risk. The Role of Helicobacter pylori Infection in NSAID/Low-Dose Aspirin Users.
      ]. In 2010, a systematic review aimed to determine the influence of the infection on the risk of UGIB in patients taking ASA or LDA. However, the heterogeneity of the studies and the controversial results did not allow for strong conclusions [
      • Fletcher EH
      • Johnston DE
      • Fisher CR
      • Koerner RJ
      • Newton JL
      • Gray CS
      Systematic review: Helicobacter pylori and the risk of upper gastrointestinal bleeding risk in patients taking aspirin.
      ]. Afterwards, a case-control study showed that NSAIDs, LDA, and H. pylori infection were three independent risk factors for the development of PUB. An additive effect was also found between H. pylori infection and NSAID use, whilst no interaction was shown between LDA and the infection [
      • Sostres C
      • Carrera-Lasfuentes P
      • Benito R
      • Roncales P
      • Arruebo M
      • Arroyo MT
      • et al.
      Peptic Ulcer Bleeding Risk. The Role of Helicobacter pylori Infection in NSAID/Low-Dose Aspirin Users.
      ]. Analogous results were also reported in a recent German study [
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      ] (Table 3). As for the relationship between H. pylori and non-aspirin antiplatelet agents or oral anticoagulants, there are limited data in the literature. A recent cohort study found that, in H. pylori positive patients taking non-aspirin antiplatelet agents, there was an increased risk of haemorrhagic peptic disease (OR: 4.37; 95% CI: 1.28–14.99), while the risk was not increased in infected patients taking oral anticoagulants (OR: 0.95; 95% CI: 0.58-1.55) [
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      ]. The uncertainty of evidence is mirrored in the recommendations of two recent international guidelines. In the European Maastricht V/Florence Consensus, it is stated that testing for H. pylori should be performed in patients with a history of peptic disease taking NSAIDs or aspirin [
      • Malfertheiner P
      • Megraud F
      • O'Morain CA
      • Gisbert JP
      • Kuipers EJ
      • Axon AT
      • et al.
      Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.
      ]. But regarding LDA, as evidence was considered controversial, no specific recommendations were provided. Similarly, no specific advices were given for non-aspirin antiplatelet agents or oral anticoagulants [
      • Malfertheiner P
      • Megraud F
      • O'Morain CA
      • Gisbert JP
      • Kuipers EJ
      • Axon AT
      • et al.
      Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.
      ]. The American guideline recommend to search for H. pylori infection in patients starting NSAID or LDA therapy [
      • Chey WD
      • Leontiadis GI
      • Howden CW
      • Moss SF
      ACG Clinical Guideline: Treatment of Helicobacter pylori Infection.
      ]. However, it was highlighted that the basis for the LDA recommendation was weak in the absence of a prospective randomized study addressing H. pylori eradication in North American patients at increased risk for adverse cardiovascular outcomes. Furthermore, even in this consensus, there were no specific advices regarding non-aspirin antiplatelet agents or oral anticoagulants [
      • Chey WD
      • Leontiadis GI
      • Howden CW
      • Moss SF
      ACG Clinical Guideline: Treatment of Helicobacter pylori Infection.
      ]. After these guidelines have been issued, two meta-analyses were published [
      • Sarri GL
      • Grigg SE
      • Yeomans ND
      Helicobacter pylori and low-dose aspirin ulcer risk: A meta-analysis.
      ,
      • Ng JC
      • Yeomans ND.
      Helicobacter pylori infection and the risk of upper gastrointestinal bleeding in low dose aspirin users: systematic review and meta-analysis.
      ]. The former showed that H. pylori infection increased the risk of gastroduodenal ulcers during LDA therapy by approximately 70% (OR: 1.65; 95% CI: 1.29-2.08) [
      • Sarri GL
      • Grigg SE
      • Yeomans ND
      Helicobacter pylori and low-dose aspirin ulcer risk: A meta-analysis.
      ]. The latter found that the odds of UGIB in patients taking LDA was almost two-and-one-half times as frequent in H. pylori-positive (OR: 2.32; 95% CI: 1.25 - 4.33) [
      • Ng JC
      • Yeomans ND.
      Helicobacter pylori infection and the risk of upper gastrointestinal bleeding in low dose aspirin users: systematic review and meta-analysis.
      ]. Nevertheless, the Authors estimated that, with such an OR, the NNT to prevent one bleeding event annually was to be between 100 and more than 1,000 [
      • Ng JC
      • Yeomans ND.
      Helicobacter pylori infection and the risk of upper gastrointestinal bleeding in low dose aspirin users: systematic review and meta-analysis.
      ]. This raises doubts about the possible cost effectiveness of a test and treatment strategy for all subjects receiving LDA, also considering the increasing primary resistance to antimicrobial agents [
      • Gatta L
      • Scarpignato C
      • Fiorini G
      • Belsey J
      • Saracino IM
      • Ricci C
      • et al.
      Impact of primary antibiotic resistance on the effectiveness of sequential therapy for Helicobacter pylori infection: lessons from a 5-year study on a large number of strains.
      ]. In addition, eradication was never adequately evaluated as a first-line strategy to prevent PUD in patients taking LDA with an average risk of GI bleeding. One study showed that incidence rates of ulcer bleeding were not significantly different between H. pylori eradicated patients with previous PUB and the average-risk cohort (i.e. LDA-naïve patients without a history of ulcer and with unknown H. pylori status) [
      • Chan FK
      • Ching JY
      • Suen BY
      • Tse YK
      • Wu JC
      • Sung JJ
      Effects of Helicobacter pylori infection on long-term risk of peptic ulcer bleeding in low-dose aspirin users.
      ]. More clarifying data could be obtained from the Helicobacter Eradication Aspirin Trial which is ongoing [
      • Lanas A
      • Chan FKL
      Peptic ulcer disease.
      ]. A proposed strategy is to classify patients taking LDA into two groups, low and high risk of bleeding, eradicating H. pylori only in the latter [
      • Sostres C
      • Carrera-Lasfuentes P
      • Benito R
      • Roncales P
      • Arruebo M
      • Arroyo MT
      • et al.
      Peptic Ulcer Bleeding Risk. The Role of Helicobacter pylori Infection in NSAID/Low-Dose Aspirin Users.
      ]. In addition to a previous peptic disease - which represents an indication to eradicate always the infection [
      • Bhatt DL
      • Scheiman J
      • Abraham NS
      • Antman EM
      • Chan FK
      • Furberg CD
      • et al.
      ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.
      ,
      • Lanas A
      • Chan FKL
      Peptic ulcer disease.
      ] - other risk factors are older age and the concomitant use of NSAIDs, oral anticoagulants, non-aspirin antiplatelet agents, and corticosteroids [
      • Sostres C
      • Carrera-Lasfuentes P
      • Benito R
      • Roncales P
      • Arruebo M
      • Arroyo MT
      • et al.
      Peptic Ulcer Bleeding Risk. The Role of Helicobacter pylori Infection in NSAID/Low-Dose Aspirin Users.
      ]. Since nearly all of the available studies are case-control or cohort studies -more prone to bias - well-designed RCTs are demanded as well as pharmaco-economic evaluations assessing the benefits and risks of H. pylori eradication in LDA, non-aspirin antiplatelet agents and oral anticoagulants users.
      Table 3Relationship between LDA, non-aspirin antiplatelet agents, oral anticoagulant, risk of PUD, PUB, UGIB, and H. pylori infection.
      Risk factorType of StudyOutcomeOR/RR/HR95% CIReference
      LDA and H. pyloriMetanalysisPUDOR: 1.651.29-2.08
      • Antithrombotic Trialists C
      • Collins R
      • Peto R
      • Hennekens C
      • Doll R
      • Bubes V
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      LDA and H. pyloriMetanalysisUGIBOR: 2.321.25-4.33
      • Serebruany VL
      • Dinicolantonio JJ
      • Can MM
      • Pershukov IV
      • Kuliczkowski W
      Gastrointestinal adverse events after dual Antiplatelet therapy: Clopidogrel is safer than Ticagrelor, but Prasugrel data are lacking or inconclusive.
      LDA - no H. pyloriCase-control studyPUBRR: 2.21.2-4.2
      CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      H. pylori- no LDACase-control studyPUBRR: 2.82.0-3.8
      CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      LDA and H. pyloriCase-control studyPUBRR: 3.52.0-6.1
      CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      LDA and H. pyloriCohort studyPUBOR: 2.231.52-3.28
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      NA and H. pyloriCohort studyPUBOR: 4.371.28-14.99
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      OC and H. pyloriCohort studyPUBOR: 0.950.58-1.55
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      PUD, peptic ulcer disease; PUB, peptic ulcer bleeding; UGIB, upper gastrointestinal bleeding; NA, non-aspirin antiplatelet agents; OC, oral anticoagulant.

      Are there alternatives to proton pumps inhibitors?

      Data from two RCTs, published over 20 years ago, demonstrated the superiority of PPIs over ranitidine and misoprostol in the prevention of gastroduodenal erosions and/or ulcers induced by NSAIDs [
      • Yeomans ND
      • Tulassay Z
      • Juhász L
      • Rácz I
      • Howard JM
      • Van Rensburg CJ
      • et al.
      A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs.
      ,
      • Hawkey CJ
      • Karrasch JA
      • Szczepañski L
      • Walker DG
      • Barkun A
      • Swannell AJ
      • et al.
      Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs.
      ]. A recent Dutch study showed that therapy with PPIs is cost-effective in reducing GI bleeding in patients aged ≥ 60 years taking antiplatelet agents [
      • Chau SH
      • Sluiter RL
      • Kievit W
      • Wensing M
      • Teichert M
      • Hugtenburg JG
      Cost Effectiveness of Gastroprotection with Proton Pump Inhibitors in Older Low-Dose Acetylsalicylic Acid Users in the Netherlands.
      ]. As for ranitidine, it was observed that its protective action of gastroduodenal mucosa decreased significantly within 4 weeks starting treatment, and that, at 6 months, it was significantly less effective than PPIs [
      • Yeomans ND
      • Tulassay Z
      • Juhász L
      • Rácz I
      • Howard JM
      • Van Rensburg CJ
      • et al.
      A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs.
      ]. Likewise, this depends on the onset of tachyphylaxis, typical of H2RA, but not of PPIs. Indeed, a pharmacodynamic study clearly showed that, already on the third day of therapy, the efficacy of ranitidine in reducing gastric acid secretion was almost halved [
      • Merki HS
      • Wilder-Smith CH.
      Do continuous infusions of omeprazole and ranitidine retain their effect with prolonged dosing?.
      ]. This aspect cannot be disregarded when long-term treatment is necessary, such as antiplatelet therapy in patients at risk of PUD or UGIB [
      • Scarpignato C
      • Gatta L
      • Zullo A
      • Blandizzi C
      for the SIFA-FG, on behalf of the Italian Society of P, et al.
      ]. The interest in the use of ranitidine has renewed in recent years following the aforementioned report of a potential liver drug interaction with PPIs, especially between omeprazole and clopidogrel [
      • Bhatt DL
      • Cryer BL
      • Liu Y
      • Hsieh WH
      • Doros G
      • Cohen M
      • et al.
      Proton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy.
      ]. Although ranitidine, like pantoprazole, does not interfere with the antiplatelet power of clopidogrel in vitro [
      • de Mendonça Furtado RH
      • Giugliano RP
      • Strunz CMC
      • Cavalheiro Filho C
      • Ramires JAF
      • Kalil Filho R
      • et al.
      Drug interaction between clopidogrel and ranitidine or omeprazole in stable coronary artery disease: A double- blind, double dummy, randomized study.
      ], it significantly attenuates the antiplatelet activity of the LDA, probably reducing its intestinal absorption [
      • Lev EI
      • Ramabadran RS
      • Guthikonda S
      • Patel R
      • Kleiman A
      • Granada JF
      • et al.
      Effect of Ranitidine on the Antiplatelet Effects of Aspirin in Healthy Human Subjects.
      ]. This effect could be relevant in the gastroprotection of patients on DAT or in monotherapy with LDA. Compared to PPIs, gastroprotection with misoprostol is also significantly less effective in prolonged treatment, is more frequently burdened by adverse events (diarrhoea and abdominal pain), and is less effective in reducing NSAID-induced dyspepsia [
      • Chau SH
      • Sluiter RL
      • Kievit W
      • Wensing M
      • Teichert M
      • Hugtenburg JG
      Cost Effectiveness of Gastroprotection with Proton Pump Inhibitors in Older Low-Dose Acetylsalicylic Acid Users in the Netherlands.
      ]. In addition, it requires the administration of at least 1-2 tablets twice daily, with possible negative implications for patient's compliance and costs compared to the single-administration of PPIs. The commercialization in Western countries of a new class of drugs, the P-CABs, of which vonoprazan is first, capable of effectively reducing gastric acid secretion, is expected in the short term. Therefore, these drugs could be useful in preventing gastroduodenal mucosal lesions induced by antiplatelet agents. A randomized double-blind study showed that peptic ulcer recurrence rates were significantly lower with vonoprazan 10 mg (p=0.039) compared with lansoprazole 15 mg in patients with a history of PUD who required long-term LDA therapy for cardiovascular and cerebrovascular protection [
      • Kawai T
      • Oda K
      • Funao N
      • Nishimura A
      • Matsumoto Y
      • Mizokami Y
      • et al.
      Vonoprazan prevents low-dose aspirin-associated ulcer recurrence: Randomised phase 3 study.
      ]. Furthermore, the absence of any effect of vonoprazan on the platelet-aggregating inhibitory activity of aspirin was shown in vitro, as well as the lack of pharmacodynamic interaction between the two drugs in vivo [
      • Sakurai Y
      • Shiino M
      • Horii S
      • Okamoto H
      • Nakamura K
      • Nishimura A
      • et al.
      Pharmacokinetic Drug–Drug Interactions Between Vonoprazan and Low-Dose Aspirin or Nonsteroidal Anti-inflammatory Drugs: A Phase 2, Open-Label, Study in Healthy Japanese Men.
      ]. However, data on the potential drug interaction of vonoprazan with clopidogrel, other antiplatelet agents, and oral anticoagulants are not yet available. Several other molecules are being evaluated in experimental models, such as potential NSAID gastroprotectors, including allantoin and rebamipide. The latter was found to be as effective as misoprostol in preventing gastroduodenal lesions from aceclofenac, meloxicam and nabumetone [
      • Kim JH
      • Park SH
      • Cho CS
      • Lee ST
      • Yoo WH
      • Kim SK
      • et al.
      Preventive efficacy and safety of rebamipide in nonsteroidal anti-inflammatory drug-induced mucosal toxicity.
      ], but not from naproxen [
      • Gagliano-Jucá T
      • Moreno RA
      • Zaminelli T
      • Napolitano M
      • Magalhães AFN
      • Carvalhaes A
      • et al.
      Rebamipide does not protect against naproxen-induced gastric damage: A randomized double-blind controlled trial.
      ], and better tolerated. However, there are still no data in the literature to validate its efficacy in preventing gastrointestinal damage from antiplatelet agents or anticoagulants.

      Recommendations of the guidelines and regulatory indications: impact on the "real world"

      There are several guidelines on gastroprotection in patients taking antiplatelet and/or oral anticoagulant treatment, prepared by American, European and Italian societies of Cardiology, Gastroenterology, Pharmacology and General Practitioners [
      • Bhatt DL
      • Scheiman J
      • Abraham NS
      • Antman EM
      • Chan FK
      • Furberg CD
      • et al.
      ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.
      ,
      • Valgimigli M
      • Bueno H
      • Byrne RA
      ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Scarpignato C
      • Gatta L
      • Zullo A
      • Blandizzi C
      for the SIFA-FG, on behalf of the Italian Society of P, et al.
      ,
      • Malfertheiner P
      • Megraud F
      • O'Morain CA
      • Gisbert JP
      • Kuipers EJ
      • Axon AT
      • et al.
      Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.
      ,
      • Chey WD
      • Leontiadis GI
      • Howden CW
      • Moss SF
      ACG Clinical Guideline: Treatment of Helicobacter pylori Infection.
      ,
      • Abraham NS
      • Hlatky MA
      • Antman EM
      • Bhatt DL
      • Bjorkman DJ
      • Clark CB
      • et al.
      ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: A focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use.
      ,
      • Collet JP
      • Thiele H
      • Barbato E
      • Barthélémy O
      • Bauersachs J
      • Bhatt DL
      • et al.
      2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.
      ,
      • Ansell J
      • Hirsh J
      • Hylek E
      • Jacobson A
      • Crowther M
      • Palareti G
      Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      ,
      • Hindricks G
      • Potpara T
      • Dagres N
      • Arbelo E
      • Bax JJ
      • Blomström-Lundqvist C
      • et al.
      2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS).
      ]. The joint US guidelines of the American College of Cardiology Foundation, the American College of Gastroenterology, and the American Heart Association recommend the use of PPIs in patients taking DAT and in those who have multiple risk factors for GI bleeding [
      • Abraham NS
      • Hlatky MA
      • Antman EM
      • Bhatt DL
      • Bjorkman DJ
      • Clark CB
      • et al.
      ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: A focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use.
      ]. The ESC 2017 guidelines on DAT recommend gastroprotection with PPIs in all patients [
      • Valgimigli M
      • Bueno H
      • Byrne RA
      ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
      ], while the recent ESC guidelines on non-ST-segment elevation acute coronary syndrome [
      • Collet JP
      • Thiele H
      • Barbato E
      • Barthélémy O
      • Bauersachs J
      • Bhatt DL
      • et al.
      2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.
      ] recommend (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 gastrointestinal bleeding in order to reduce the risk of gastric bleeds. In particular, they suggest 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 non-steroidal anti-inflammatory drugs/corticosteroid use, or two or more of: age ≥ 65 years; dyspepsia; gastro-oesophageal reflux disease; H. pylori infection; chronic alcohol use [
      • Collet JP
      • Thiele H
      • Barbato E
      • Barthélémy O
      • Bauersachs J
      • Bhatt DL
      • et al.
      2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.
      ]. In Italy, a position paper issued by Italian Society of Pharmacology, the Italian Association of Hospital Gastroenterologists, and the Italian Federation of General Practitioners, recommend 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 years, concomitant use of steroids or anticoagulants, previous history of peptic ulcer) [
      • Scarpignato C
      • Gatta L
      • Zullo A
      • Blandizzi C
      for the SIFA-FG, on behalf of the Italian Society of P, et al.
      ]. In addition, it was suggested the use of pantoprazole or rabeprazole if clopidogrel was used, while there were no restrictions on the choice of PPIs with prasugrel and ticagrelor [
      • Scarpignato C
      • Gatta L
      • Zullo A
      • Blandizzi C
      for the SIFA-FG, on behalf of the Italian Society of P, et al.
      ]. The uncertainty of the evidence on the eradication of H. pylori is reflected in the recommendations of two recent international Consensus. In the European guideline, it is stated that the use of ASA and NSAIDs increases the risk of peptic disease in the presence of the infection and, therefore, the search for H. pylori should be performed in patients with a history of peptic disease who take NSAIDs or ASA [
      • Malfertheiner P
      • Megraud F
      • O'Morain CA
      • Gisbert JP
      • Kuipers EJ
      • Axon AT
      • et al.
      Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.
      ]. However, there were no specific recommendations on LDA since the evidence was considered controversial, as well as no recommendations were provided for non-aspirin antiplatelet agents and/or oral anticoagulants [
      • Malfertheiner P
      • Megraud F
      • O'Morain CA
      • Gisbert JP
      • Kuipers EJ
      • Axon AT
      • et al.
      Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.
      ]. In the Consensus of the American College of Gastroenterology [
      • Chey WD
      • Leontiadis GI
      • Howden CW
      • Moss SF
      ACG Clinical Guideline: Treatment of Helicobacter pylori Infection.
      ], despite the lack of prospective RCTs, it was suggested searching for the infection in patients starting ASA therapy, even if it was emphasized that the basis for this recommendation was weak. Furthermore, also in this case, there were no specific recommendations regarding non-aspirin antiplatelet agents and/or oral anticoagulants [
      • Chey WD
      • Leontiadis GI
      • Howden CW
      • Moss SF
      ACG Clinical Guideline: Treatment of Helicobacter pylori Infection.
      ]. Therapy with oral anticoagulants alone has not been shown to be harmful to the gastroduodenal mucosa, and therefore does not require therapy with PPIs if patients are not taking steroid and/or antiplatelet therapy. Indeed, a consensus of experts recommends the use of PPIs only in patients taking warfarin in combination with antiplatelet therapy and/or NSAIDs [
      • Bhatt DL
      • Scheiman J
      • Abraham NS
      • Antman EM
      • Chan FK
      • Furberg CD
      • et al.
      ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.
      ], while other guidelines do not address this aspect . According to 2020 ESC guidelines on the management of AF [
      • Hindricks G
      • Potpara T
      • Dagres N
      • Arbelo E
      • Bax JJ
      • Blomström-Lundqvist C
      • et al.
      2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS).
      ], apixaban or dabigatran 110 mg b.i.d. are not associated with an excess of gastrointestinal bleeding compared with warfarin. From a regulatory point of view, in Italy the prescription of PPIs paid by the National Health Service, and regulated by the Prescriptive Note 1 of the Italian Medicines Agency, is limited to the prevention of serious complications of the upper GI tract in antiplatelet therapy with LDA provided one of the following bleeding risk conditions exists: history of past digestive bleeding or peptic ulcer not healed with H. pylori eradication therapy; concomitant anticoagulant or steroid therapy; old age. However, according to the Note 1, the use of ranitidine and misoprostol - as an equal alternative to PPIs - is also suggested, while rabeprazole cannot be prescribed for this purpose in Italy. However, the FDA has not approved ranitidine to prevent GI injury from NSAIDs. In the real world, a recent Danish study including more than 46,000 patients treated with DAT after an acute MI showed an underutilisation of gastroprotection with PPIs, against an annual risk of gastrointestinal bleeding of about 1% in the general population, and 1.7% in patients at high risk of bleeding [
      • Sehested TSG
      • Carlson N
      • Hansen PW
      • Gerds TA
      • Charlot MG
      • Torp-Pedersen C
      • et al.
      Reduced risk of gastrointestinal bleeding associated with proton pump inhibitor therapy in patients treated with dual antiplatelet therapy after myocardial infarction.
      ]. The lack of gastroprotection in a portion of patients on antiplatelet therapy, at risk of GI bleeding, was also documented in Italy [
      • Morini S
      • Zullo A
      • Oliveti D
      • Chiriatti A
      • Marmo R
      • Chiuri DAE
      • et al.
      A very high rate of inappropriate use of gastroprotection for nonsteroidal anti-inflammatory drug therapy in primary care: A cross-sectional study.
      ]. In a retrospective study conducted in Spain on patients hospitalized for ACS, the totality of the patients received gastroprotective agents at the moment of discharge, most of them with PPIs [
      • Lozano I
      • Sanchez-Insa E
      • de Leiras SR
      • Carrillo P
      • Ruiz-Quevedo V
      • Pinar E
      • et al.
      Acute Coronary Syndromes, Gastrointestinal Protection, and Recommendations Regarding Concomitant Administration of Proton-Pump Inhibitors (Omeprazol/Esomeprazole) and Clopidogrel.
      ]. Nevertheless, in one every 3 cases of the patients who were on clopidogrel, the recommendation of the FDA and of the EMA were not followed as omeprazole or esomeprazole were prescribed [
      • Lozano I
      • Sanchez-Insa E
      • de Leiras SR
      • Carrillo P
      • Ruiz-Quevedo V
      • Pinar E
      • et al.
      Acute Coronary Syndromes, Gastrointestinal Protection, and Recommendations Regarding Concomitant Administration of Proton-Pump Inhibitors (Omeprazol/Esomeprazole) and Clopidogrel.
      ].

      10 Conclusions: when and how to use gastroprotectors in patients using antiplatelet and/or anticoagulant agents

      Antiplatelet and anticoagulant agents are effective for primary and secondary prevention of cardiovascular events in subjects at thrombotic risk. Unfortunately, both can cause bleeding in the GI tract, sometimes with a fatal outcome [
      • Hallas J
      • Dall M
      • Andries A
      • Andersen BS
      • Aalykke C
      • Hansen JM
      • et al.
      Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: Population based case-control study.
      ,
      • Lanas A
      • Carrera-Lasfuentes P
      • Arguedas Y
      • García S
      • Bujanda L
      • Calvet X
      • et al.
      Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants.
      ,
      • Antithrombotic Trialists C
      • Collins R
      • Peto R
      • Hennekens C
      • Doll R
      • Bubes V
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      ,
      • Serebruany VL
      • Dinicolantonio JJ
      • Can MM
      • Pershukov IV
      • Kuliczkowski W
      Gastrointestinal adverse events after dual Antiplatelet therapy: Clopidogrel is safer than Ticagrelor, but Prasugrel data are lacking or inconclusive.
      ,
      • Fahmy AI
      • Mekkawy MA
      • Abou-Ali A
      Evaluation of adverse events involving bleeding associated with oral P2Y12 inhibitors use in the Food and Drug Administration adverse event reporting system.
      ,
      • Wallentin L
      • Becker RC
      • Budaj A
      • Cannon CP
      • Emanuelsson H
      • Held C
      • et al.
      Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
      ,
      • Wiviott SD
      • Braunwald E
      • McCabe CH
      • Montalescot G
      • Ruzyllo W
      • Gottlieb S
      • et al.
      Prasugrel versus clopidogrel in patients with acute coronary syndromes.
      ,
      • Sahlén A
      • Varenhorst C
      • Lagerqvist B
      • Renlund H
      • Omerovic E
      • Erlinge D
      • et al.
      Outcomes in patients treated with ticagrelor or clopidogrel after acute myocardial infarction: Experiences from SWEDEHEART registry.
      ,
      • Ruff CT
      • Giugliano RP
      • Braunwald E
      • Hoffman EB
      • Deenadayalu N
      • Ezekowitz MD
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials.
      ,
      • Connolly SJ
      • Ezekowitz MD
      • Yusuf S
      • Eikelboom J
      • Oldgren J
      • Parekh A
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ,
      • Lip GYH
      • Clemens A
      • Noack H
      • Ferreira J
      • Connolly SJ
      • Yusuf S
      Patient outcomes using the European label for dabigatran: A post-hoc analysis from the RE-LY database.
      ,
      • Patel MR
      • Mahaffey KW
      • Garg J
      • Pan G
      • Singer DE
      • Hacke W
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ,
      • Giugliano RP
      • Ruff CT
      • Braunwald E
      • Murphy SA
      • Wiviott SD
      • Halperin JL
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      ,
      • Granger CB
      • Alexander JH
      • McMurray JJV
      • Lopes RD
      • Hylek EM
      • Hanna M
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ,
      • Holster IL
      • Valkhoff VE
      • Kuipers EJ
      • Tjwa ETTL
      New oral anticoagulants increase risk for gastrointestinal bleeding: A systematic review and meta-analysis.
      ,
      • Desai JC
      • Chatterjee P
      • Friedman K
      • Aisenberg J
      Incidence and clinical presentation of gastrointestinal bleeding in atrial fibrillation patients taking direct oral anticoagulants.
      ,
      • Abraham NS
      • Singh S
      • Caleb Alexander G
      • Heien H
      • Haas LR
      • Crown W
      • et al.
      Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: Population based cohort study.
      ,
      • Camporese G
      • Simioni P
      • Bernard E
      Primo anno di edoxaban in Italia: Dati di sicurezza dalla Rete Nazionale di Farmacovigilanza.
      ,
      • Noseworthy PA
      • Yao X
      • Abraham NS
      • Sangaralingham LR
      • McBane RD
      • Shah ND
      Direct Comparison of Dabigatran, Rivaroxaban, and Apixaban for Effectiveness and Safety in Nonvalvular Atrial Fibrillation.
      ,
      • Mazurek M
      • Lip GYH.
      Gastrointestinal Bleeding and Direct Oral Anticoagulants Amongst Patients With Atrial Fibrillation in the “Real World”.
      ,
      • Graham DJ
      • Reichman ME
      • Wernecke M
      • Hsueh YH
      • Izem R
      • Southworth MR
      • et al.
      Stroke, bleeding, and mortality risks in elderly medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation.
      ,
      • Chan YH
      • Kuo CT
      • Yeh YH
      • Chang SH
      • Wu LS
      • Lee HF
      • et al.
      Thromboembolic, Bleeding, and Mortality Risks of Rivaroxaban and Dabigatran in Asians With Nonvalvular Atrial Fibrillation.
      ]. Therefore, gastroprotection is required in patients at increased risk of GI bleeding (Fig. 3).
      Unlabelled image
      Fig. 1Incidence of major gastrointestinal bleeding observed n phase 3 approval trials of the four DOAC [
      • Connolly SJ
      • Ezekowitz MD
      • Yusuf S
      • Eikelboom J
      • Oldgren J
      • Parekh A
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ,
      • Patel MR
      • Mahaffey KW
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      • Pan G
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      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ,
      • Giugliano RP
      • Ruff CT
      • Braunwald E
      • Murphy SA
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      • Halperin JL
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      ,
      • Granger CB
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      • Lopes RD
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      • Hanna M
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ]
      Unlabelled image
      Fig. 2Incidence of bleeding from direct oral anticoagulant drugs, AIFA 2017 data
      [
      • Camporese G
      • Simioni P
      • Bernard E
      Primo anno di edoxaban in Italia: Dati di sicurezza dalla Rete Nazionale di Farmacovigilanza.
      ]
      Fig. 3
      Fig. 3General recommendations for use of proton pump inhibitors (PPI).
      Flow-chart 1
      Flow-chart 1Antiplatelet therapy, gastrointestinal (GI) risk factors and recommendations for use of proton pump inhibitors (PPI). (modified from
      • Hallas J
      • Dall M
      • Andries A
      • Andersen BS
      • Aalykke C
      • Hansen JM
      • et al.
      Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: Population based case-control study.
      )
      Flow-chart 2
      Flow-chart 2Oral anticoagulant therapy, gastrointestinal (GI) risk factors and recommendations for use of proton pump inhibitors (PPI) (modified from
      • Hallas J
      • Dall M
      • Andries A
      • Andersen BS
      • Aalykke C
      • Hansen JM
      • et al.
      Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: Population based case-control study.
      ).
      Antiplatelet therapy induces GI bleeding both by causing mucosal lesions (erosions and ulcers), and by promoting bleeding by reducing the formation of the platelet plug on the lesions [
      • Laine L
      • Maller ES
      • Yu C
      • Quan H
      • Simon T
      Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: A double-blind trial.
      ,
      • Khan MA
      • Howden CW.
      The role of proton pump inhibitors in the management of upper gastrointestinal disorders.
      ]. In patients taking one antiplatelet agent for the first time, standard dose of PPIs should be used if GI risk factors are present (Flow-chart 1) [
      • Sehested TSG
      • Carlson N
      • Hansen PW
      • Gerds TA
      • Charlot MG
      • Torp-Pedersen C
      • et al.
      Reduced risk of gastrointestinal bleeding associated with proton pump inhibitor therapy in patients treated with dual antiplatelet therapy after myocardial infarction.
      ,
      • Wolfe MM
      • Sachs G
      Acid suppression: Optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome.
      ,
      • Vigneri S
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      A comparison of five maintenance therapies for reflux esophagitis.
      ,
      • Lanas A
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      • Bujanda L
      • Gomollón F
      • Forné M
      • et al.
      Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants.
      ,
      • Almufleh A
      • Ramirez FD
      • So D
      • Le May M
      • Chong AY
      • Torabi N
      • et al.
      H2 Receptor Antagonists versus Proton Pump Inhibitors in Patients on Dual Antiplatelet Therapy for Coronary Artery Disease: A Systematic Review.
      ,
      • Scarpignato C
      • Gatta L
      • Zullo A
      • Blandizzi C
      for the SIFA-FG, on behalf of the Italian Society of P, et al.
      ,
      • Khan MA
      • Howden CW.
      The role of proton pump inhibitors in the management of upper gastrointestinal disorders.
      ]. If there are no risk factors, there is currently no evidence to recommend one antiplatelet agent to use for the first time in terms of safety for the risk of UGIB [
      • Hallas J
      • Dall M
      • Andries A
      • Andersen BS
      • Aalykke C
      • Hansen JM
      • et al.
      Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: Population based case-control study.
      ,
      • Luo PJ
      • Lin XH
      • Lin CC
      • Luo JC
      • Hu HY
      • Ting PH
      • et al.
      Risk factors for upper gastrointestinal bleeding among aspirin users: An old issue with new findings from a population-based cohort study.
      ,
      • Lanas A
      • Gargallo CJ.
      Management of low-dose aspirin and clopidogrel in clinical practice: A gastrointestinal perspective.
      ,
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      ,
      • Zheng SL
      • Roddick AJ.
      Association of Aspirin Use for Primary Prevention with Cardiovascular Events and Bleeding Events: A Systematic Review and Meta-analysis.
      ,
      • Hashash JG
      • Shamseddeen W
      • Skoury A
      • Aoun N
      • Barada K
      Gross lower gastrointestinal bleeding in patients on anticoagulant and/or antiplatelet therapy: Endoscopic findings, management, and clinical outcomes.
      ,
      • Yusuf S
      • Zhao F
      • Mehta SR
      • Chrolavicius S
      • Tognoni G
      • Fox KK
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      ,
      • De Abajo FJ
      • Gil MJ
      • Bryant V
      • Timoner J
      • Oliva B
      • García-Rodríguez LA
      Upper gastrointestinal bleeding associated with NSAIDs, other drugs and interactions: A nested case-control study in a new general practice database.
      ]. In patients receiving clopidogrel, choosing PPI lacking interference with the hepatic CYP450 enzymes might be preferred [
      • Juurlink DN
      • Gomes T
      • Ko DT
      • Szmitko PE
      • Austin PC
      • Tu JV
      • et al.
      A population-based study of the drug interaction between proton pump inhibitors and clopidogrel.
      ,
      • Bundhun PK
      • Teeluck AR
      • Bhurtu A
      • Huang WQ
      Is the concomitant use of clopidogrel and Proton Pump Inhibitors still associated with increased adverse cardiovascular outcomes following coronary angioplasty?: A systematic review and meta-analysis of recently published studies (2012 - 2016).
      ,
      • Cardoso RN
      • Benjo AM
      • DiNicolantonio JJ
      • Garcia DC
      • MacEdo FYB
      • El-Hayek G
      • et al.
      Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: An updated meta-analysis.
      ,
      • Scarpignato C
      • Gatta L
      • Zullo A
      • Blandizzi C
      for the SIFA-FG, on behalf of the Italian Society of P, et al.
      ]. Among patients with a history of aspirin-induced UGIB, we do not advise the substitution of clopidogrel for LDA to reduce the risk of recurrence UGIB, but recommend to use standard dose of PPI in association with LDA [
      • Chan FKL
      • Ching JYL
      • Hung LCT
      • Wong VWS
      • Leung VKS
      • Kung NNS
      • et al.
      Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding.
      ,
      • Lai KC
      • Chu KM
      • Hui WM
      • Wong BC
      • Hung WK
      • Loo CK
      • et al.
      Esomeprazole with aspirin versus clopidogrel for prevention of recurrent gastrointestinal ulcer complications.
      ,
      • Bhatt DL
      • Scheiman J
      • Abraham NS
      • Antman EM
      • Chan FK
      • Furberg CD
      • et al.
      ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.
      ]. It is important also to highlight that recent data report that third generation P2Y12 inhibitors were associated with higher risk of upper GI bleeding (RR 1.32, 95% CI 1.05‐1.67) compared to clopidogrel [
      • Guo CG
      • Chen L
      • Chan EW
      • Cheung KS
      • Isshiki T
      • Wong ICK
      • et al.
      Systematic review with meta-analysis: the risk of gastrointestinal bleeding in patients taking third-generation P2Y12 inhibitors compared with clopidogrel.
      ].
      Oral anticoagulants (VKAs and DOAC) favour the bleeding of pre-existing lesions (erosions, angiodysplasias, polyps, diverticula) [
      • Connolly SJ
      • Ezekowitz MD
      • Yusuf S
      • Eikelboom J
      • Oldgren J
      • Parekh A
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ,
      • Cheung KS
      • Leung WK.
      Gastrointestinal bleeding in patients on novel oral anticoagulants: Risk, prevention and management.
      ,
      • Heidbuchel H
      • Verhamme P
      • Alings M
      • Antz M
      • Diener HC
      • Hacke W
      • et al.
      Updated European Heart Rhythm Association Practical Guide on the use of non-Vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation.
      ]. As for antiplatelet therapy is concerned, the most effective gastroprotection is that with standard dosage of PPIs.
      For VKAs (Flow-chart 2), risk factors as considered age> 65 years, previous peptic ulcer disease (with or without complications), concomitant use of ≥ 1 antiplatelet agents, concomitant used of NSAIDs [
      • Lanas A
      • Gargallo CJ.
      Management of low-dose aspirin and clopidogrel in clinical practice: A gastrointestinal perspective.
      ,
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      ,
      • Scarpignato C
      • Gatta L
      • Zullo A
      • Blandizzi C
      for the SIFA-FG, on behalf of the Italian Society of P, et al.
      ], International Normalized Ratio monitoring is required when starting or stopping PPI therapy in VKA users [
      • Scarpignato C
      • Gatta L
      • Zullo A
      • Blandizzi C
      for the SIFA-FG, on behalf of the Italian Society of P, et al.
      ]. For DOACs (Flow-chart 2), risk factors as considered age> 75 years, previous peptic ulcer disease (with or without complications), concomitant use of ≥ 1 antiplatelet agents, concomitant used of NSAIDs [
      • Abraham NS
      • Noseworthy PA
      • Yao X
      • Sangaralingham LR
      • Shah ND
      Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study.
      ,
      • Miller CS
      • Dorreen A
      • Martel M
      • Huynh T
      • Barkun AN
      Risk of Gastrointestinal Bleeding in Patients Taking Non–Vitamin K Antagonist Oral Anticoagulants: A Systematic Review and Meta-analysis.
      ,
      • Hernandez I
      • Baik SH
      • Piñera A
      • Zhang Y
      Risk of bleeding with dabigatran in atrial fibrillation.
      ,
      • Desai JC
      • Chatterjee P
      • Friedman K
      • Aisenberg J
      Incidence and clinical presentation of gastrointestinal bleeding in atrial fibrillation patients taking direct oral anticoagulants.
      ]. In patients taking DAPT, DAT or TAT we recommend to use standard dose of PPI [
      • Bhatt DL
      • Scheiman J
      • Abraham NS
      • Antman EM
      • Chan FK
      • Furberg CD
      • et al.
      ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.
      ,
      • Valgimigli M
      • Bueno H
      • Byrne RA
      ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
      ]. Patients with cirrhosis should follow specific recommendations [
      • Qamar A
      • Vaduganathan M
      • Greenberger NJ
      • Giugliano RP
      Oral Anticoagulation in Patients With Liver Disease.
      ,
      • Ballestri S
      • Capitelli M
      • Fontana MC
      • Arioli D
      • Romagnoli E
      • Graziosi C
      • et al.
      Direct Oral Anticoagulants in Patients with Liver Disease in the Era of Non-Alcoholic Fatty Liver Disease Global Epidemic: A Narrative Review.
      ,
      • Steffel J
      • Verhamme P
      • Potpara TS
      • Albaladejo P
      • Antz M
      • Desteghe L
      • et al.
      The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
      ]. It should be stressed that PPIs are not effective in in preventing bleeding from the small intestine or from the colon [
      • Scarpignato C
      • Gatta L
      • Zullo A
      • Blandizzi C
      for the SIFA-FG, on behalf of the Italian Society of P, et al.
      ].
      The interaction between H. pylori infection and antiplatelet therapy also remains controversial [
      • Venerito M
      • Schneider C
      • Costanzo R
      • Breja R
      • Rohl FW
      • Malfertheiner P
      Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.
      ,
      • Moayyedi P
      • Eikelboom JW
      • Bosch J
      • Connolly SJ
      • Dyal L
      • Shestakovska O
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      Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin.
      ,
      • Lanas A
      • Chan FKL
      Peptic ulcer disease.
      ,
      • Sostres C
      • Carrera-Lasfuentes P
      • Benito R
      • Roncales P
      • Arruebo M
      • Arroyo MT
      • et al.
      Peptic Ulcer Bleeding Risk. The Role of Helicobacter pylori Infection in NSAID/Low-Dose Aspirin Users.
      ,
      • Fletcher EH
      • Johnston DE
      • Fisher CR
      • Koerner RJ
      • Newton JL
      • Gray CS
      Systematic review: Helicobacter pylori and the risk of upper gastrointestinal bleeding risk in patients taking aspirin.
      ,
      • Malfertheiner P
      • Megraud F
      • O'Morain CA
      • Gisbert JP
      • Kuipers EJ
      • Axon AT
      • et al.
      Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.
      ,
      • Chey WD
      • Leontiadis GI
      • Howden CW
      • Moss SF
      ACG Clinical Guideline: Treatment of Helicobacter pylori Infection.
      ,
      • Sarri GL
      • Grigg SE
      • Yeomans ND
      Helicobacter pylori and low-dose aspirin ulcer risk: A meta-analysis.
      ,
      • Ng JC
      • Yeomans ND.
      Helicobacter pylori infection and the risk of upper gastrointestinal bleeding in low dose aspirin users: systematic review and meta-analysis.
      ], and randomized prospective studies are required. Finally, there is no evidence on the efficacy of gastroprotective drugs other than PPIs in preventing damage from antiplatelet agents [
      • Yeomans ND
      • Tulassay Z
      • Juhász L
      • Rácz I
      • Howard JM
      • Van Rensburg CJ
      • et al.
      A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs.
      ,
      • Hawkey CJ
      • Karrasch JA
      • Szczepañski L
      • Walker DG
      • Barkun A
      • Swannell AJ
      • et al.
      Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs.
      ,
      • Chau SH
      • Sluiter RL
      • Kievit W
      • Wensing M
      • Teichert M
      • Hugtenburg JG
      Cost Effectiveness of Gastroprotection with Proton Pump Inhibitors in Older Low-Dose Acetylsalicylic Acid Users in the Netherlands.
      ,
      • Merki HS
      • Wilder-Smith CH.
      Do continuous infusions of omeprazole and ranitidine retain their effect with prolonged dosing?.
      ,
      • Bhatt DL
      • Cryer BL
      • Liu Y
      • Hsieh WH
      • Doros G
      • Cohen M
      • et al.
      Proton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy.
      ,
      • de Mendonça Furtado RH
      • Giugliano RP
      • Strunz CMC
      • Cavalheiro Filho C
      • Ramires JAF
      • Kalil Filho R
      • et al.
      Drug interaction between clopidogrel and ranitidine or omeprazole in stable coronary artery disease: A double- blind, double dummy, randomized study.
      ,
      • Lev EI
      • Ramabadran RS
      • Guthikonda S
      • Patel R
      • Kleiman A
      • Granada JF
      • et al.
      Effect of Ranitidine on the Antiplatelet Effects of Aspirin in Healthy Human Subjects.
      ,
      • Kawai T
      • Oda K
      • Funao N
      • Nishimura A
      • Matsumoto Y
      • Mizokami Y
      • et al.
      Vonoprazan prevents low-dose aspirin-associated ulcer recurrence: Randomised phase 3 study.
      ,
      • Sakurai Y
      • Shiino M
      • Horii S
      • Okamoto H
      • Nakamura K
      • Nishimura A
      • et al.
      Pharmacokinetic Drug–Drug Interactions Between Vonoprazan and Low-Dose Aspirin or Nonsteroidal Anti-inflammatory Drugs: A Phase 2, Open-Label, Study in Healthy Japanese Men.
      ,
      • Kim JH
      • Park SH
      • Cho CS
      • Lee ST
      • Yoo WH
      • Kim SK
      • et al.
      Preventive efficacy and safety of rebamipide in nonsteroidal anti-inflammatory drug-induced mucosal toxicity.
      ,
      • Gagliano-Jucá T
      • Moreno RA
      • Zaminelli T
      • Napolitano M
      • Magalhães AFN
      • Carvalhaes A
      • et al.
      Rebamipide does not protect against naproxen-induced gastric damage: A randomized double-blind controlled trial.
      ]. Our final recommendations are summarized in Table 4.
      Table 4Final recommendations.
      In patients taking one antiplatelet agent, standard dose of PPIs should be used if GI risk factors are present (Flow-chart 1)
      In patients without any risk factor for UGIB needing antiplatelet therapy there is no evidence for suggesting PPI.
      In patients receiving clopidogrel, choosing PPI lacking interference with the hepatic CYP450 enzymes might be preferred
      There are no restrictions on the choice of PPIs with prasugrel and ticagrelor
      Among patients with a history of aspirin-induced UGIB, we do not advise the substitution of clopidogrel for LDA to reduce the risk of recurrence UGIB, but recommend to use standard dose of PPI in association with LDA
      In patients taking VKAs or DOACs, PPIs should be used according to presence of risk factors (Flow-chart 2)
      • Patients with cirrhosis should follow specific recommendations
      • In patients taking DAPT, DAT or TAT we recommend to use standard dose of PPI.
      • Eradicating H. pylori is recommended in patients with previous peptic ulcer disease with or without complication (i.e. bleeding, perforation)
      In conclusion, treatment with PPIs should be considered mandatory in patients on antiplatelet therapy with an increased risk of gastrointestinal bleeding [
      • Scarpignato C
      • Gatta L
      • Zullo A
      • Blandizzi C
      for the SIFA-FG, on behalf of the Italian Society of P, et al.
      ,
      • Abraham NS
      • Hlatky MA
      • Antman EM
      • Bhatt DL
      • Bjorkman DJ
      • Clark CB
      • et al.
      ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: A focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use.
      ,
      • Collet JP
      • Thiele H
      • Barbato E
      • Barthélémy O
      • Bauersachs J
      • Bhatt DL
      • et al.
      2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.
      ]. Validated therapies to prevent bleeding from anticoagulants are not available [
      • Bhatt DL
      • Scheiman J
      • Abraham NS
      • Antman EM
      • Chan FK
      • Furberg CD
      • et al.
      ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.
      ,
      • Ansell J
      • Hirsh J
      • Hylek E
      • Jacobson A
      • Crowther M
      • Palareti G
      Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      ]. However, data from recent retrospective studies and a prospective study seem to demonstrate a benefit of the treatment of PPIs also in patients taking both VKAs and DOACs [
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy with Hospitalization for Upper Gastrointestinal Tract Bleeding.
      ,
      • Ray WA
      • Chung CP
      • Murray KT
      • Smalley WE
      • Daugherty JR
      • Dupont WD
      • et al.
      Association of Proton Pump Inhibitors With Reduced Risk of Warfarin-Related Serious Upper Gastrointestinal Bleeding.
      ,
      • Agewall S
      • Cattaneo M
      • Collet JP
      • Andreotti F
      • Lip GYH
      • Verheugt FWA
      • et al.
      Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy.