This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was developed prior to initiation of the review and followed standardized methodological frameworks for evidence synthesis in clinical medicine.

A comprehensive literature search was conducted using the following electronic databases: PubMed/MEDLINE; Embase; Cochrane Central Register of Controlled Trials (CENTRAL). The search included studies published between January 1, 2005, and December 31, 2025. The search strategy combined controlled vocabulary (Medical Subject Headings [MeSH]) and free-text terms including: “gastroprotection”, “proton pump inhibitors”, “anticoagulants”, “antiplatelet therapy”, “dual therapy”, “triple therapy”, “gastrointestinal bleeding”, “direct oral anticoagulants”, “warfarin”, “peptic ulcer”, “bleeding prevention”.

Boolean operators (AND, OR) were used to optimize search specificity and sensitivity. Additional studies were identified through manual review of reference lists of included articles and major clinical guidelines.

Studies were included if they met the following criteria:

1. Population: Adult patients (≥18 years) receiving combined anticoagulant and antiplatelet therapy.
2. Interventions: Gastroprotective strategies including: Proton pump inhibitors, Histamine-2 receptor antagonists, Mucosal protective agents, Helicobacter pylori eradication strategies
3. Comparators: No gastroprotection or alternative gastroprotective therapy.
4. Outcomes: Gastrointestinal bleeding (upper and lower), Mortality, Rebleeding, Hospitalization, Adverse drug events.
5. Study Designs: Randomized controlled trials, Prospective cohort studies, Retrospective cohort studies, Case-control studies, Meta-analyses, Evidence-based clinical guidelines.

Studies were excluded if they met any of the following: Pediatric populations (<18 years), Single-agent antithrombotic therapy without combination therapy, Case reports or small case series (<50 participants), Animal or in vitro studies, Studies lacking relevant clinical outcomes.

Two independent reviewers screened titles and abstracts for eligibility. Full-text articles were subsequently reviewed for inclusion. Disagreements were resolved through consensus discussion or adjudication by a third reviewer. Study selection performed followed PRISMA flow methodology.

Data were extracted using standardized forms including: Study design, Population characteristics, Type of anticoagulant, Type of antiplatelet agent, Gastroprotective intervention, Bleeding outcomes, Mortality, Duration of follow-up, Where available, subgroup analyses involving high-risk populations were recorded.

Risk of bias was assessed using:

• Cochrane Risk of Bias Tool for randomized controlled trials
• Newcastle–Ottawa Scale for observational studies

Studies were categorized as: Low risk of bias; Moderate risk of bias; High risk of bias

Due to heterogeneity in study design and outcome reporting, a qualitative synthesis approach was primarily used. Where appropriate, pooled risk estimates from published meta-analyses were incorporated. Key outcomes were synthesized across: Patients receiving gastroprotection; Patients not receiving gastroprotection; Patients with established gastrointestinal bleeding; Patients without prior gastrointestinal bleeding

Primary outcomes: Incidence of gastrointestinal bleeding; Recurrent bleeding.

Secondary outcomes: All-cause mortality; Cardiovascular mortality; Hospitalization duration; Adverse drug reactions; Therapy discontinuation rates.

Antiplatelet agents impair primary hemostasis through inhibition of platelet aggregation, thereby reducing clot formation at sites of mucosal injury. Acetylsalicylic acid (aspirin) remains one of the most widely used antiplatelet agents and is strongly associated with upper GI mucosal injury. Aspirin irreversibly inhibits cyclooxygenase-1 (COX-1), reducing prostaglandin synthesis in gastric mucosa. Prostaglandins play a critical role in maintaining mucosal defense through stimulation of mucus and bicarbonate secretion, maintenance of mucosal blood flow, and promotion of epithelial regeneration ^[17]. Reduction in prostaglandin-mediated mucosal protection predisposes the gastric epithelium to erosion, ulceration, and bleeding. Chronic aspirin use has been associated with a twofold to fourfold increased risk of peptic ulcer disease and upper GI bleeding, particularly in elderly populations and those receiving concurrent anticoagulation ^[18,19].

P2Y12 receptor inhibitors, including clopidogrel, prasugrel, and ticagrelor, impair platelet activation through inhibition of adenosine diphosphate (ADP)-mediated signaling. Although these agents do not directly injure mucosa, they impair platelet-mediated hemostasis, increasing bleeding risk from preexisting lesions ^[20].

Anticoagulants disrupt secondary hemostasis by inhibiting coagulation cascade pathways. Vitamin K antagonists (VKAs), such as warfarin, reduce synthesis of vitamin K-dependent clotting factors (II, VII, IX, and X). Direct oral anticoagulants (DOACs) exert their effects through selective inhibition of thrombin or factor Xa. Warfarin has historically been associated with increased GI bleeding risk due to its narrow therapeutic window and variability in anticoagulation intensity. Supratherapeutic international normalized ratio (INR) values are strongly correlated with bleeding risk ^[21].

DOACs, including dabigatran, rivaroxaban, apixaban, and edoxaban, demonstrate predictable pharmacokinetics and fewer drug interactions compared with VKAs. However, certain DOACs exhibit increased gastrointestinal bleeding risk compared with warfarin, particularly at higher doses and in elderly patients ^[22,23].

Local anticoagulant activity within the gastrointestinal lumen has also been proposed as a contributing factor. Dabigatran, for example, undergoes partial conversion within the GI tract, potentially increasing mucosal exposure to anticoagulant effects ^[24].

The combination of anticoagulant and antiplatelet therapy produces synergistic effects on bleeding risk through simultaneous impairment of primary and secondary hemostasis. When mucosal injury occurs, platelet aggregation is impaired, and fibrin clot formation is inhibited, resulting in prolonged bleeding duration and increased severity ^[25].

Triple therapy (oral anticoagulant plus dual antiplatelet therapy) is associated with the highest risk of GI bleeding. Observational studies suggest that triple therapy increases bleeding risk by approximately threefold compared with anticoagulation alone ^[26]. Additionally, the risk of bleeding increases exponentially with the duration of combined therapy. Extended exposure beyond 6 to 12 months is associated with cumulative mucosal injury and impaired healing ^[27].

Gastric acid contributes significantly to mucosal injury and ulcer progression. Acid-mediated degradation of fibrin clots prevents stabilization of hemostasis at sites of injury. Furthermore, acidic environments impair platelet aggregation and reduce clot strength ^[28].

Proton pump inhibitors (PPIs) exert protective effects by suppressing gastric acid secretion, thereby promoting clot stabilization and enhancing mucosal healing. Acid suppression is particularly beneficial in preventing upper GI bleeding associated with ulcerative lesions ^[29].

Helicobacter pylori infection remains an important independent risk factor for peptic ulcer disease and upper GI bleeding. In patients receiving antithrombotic therapy, the presence of H. pylori infection significantly increases bleeding risk due to mucosal inflammation and ulcer formation ^[30]. Eradication therapy has been shown to reduce recurrent bleeding risk in patients with prior ulcer disease, particularly among those receiving aspirin therapy ^[31].

Although upper GI bleeding predominates in patients receiving combined therapy, lower GI bleeding represents a significant proportion of events. Mechanisms include diverticular hemorrhage, angiodysplasia, ischemic colitis, and colorectal neoplasia ^[32].

DOAC-associated lower GI bleeding has been increasingly recognized, potentially due to incomplete drug absorption and local anticoagulant effects within the colon ^[33].

Gastrointestinal bleeding represents one of the most frequent complications of antithrombotic therapy. The global burden of bleeding-related hospitalizations continues to increase as antithrombotic therapy becomes more widely used in aging populations with multiple comorbidities.

The incidence of GI bleeding varies depending on the number and type of antithrombotic agents used. Monotherapy with aspirin is associated with an annual upper GI bleeding incidence of approximately 0.5% to 1.0%. When combined with anticoagulant therapy, this risk increases substantially ^[34]. Patients receiving dual therapy (oral anticoagulant plus single antiplatelet agent) experience an annual GI bleeding incidence ranging from 2% to 4%. Triple therapy increases this risk further, with reported annual bleeding rates of 5% to 10% ^[35,36]. Recent population-based cohort studies demonstrate that approximately 30% to 40% of major bleeding events in anticoagulated patients involve the gastrointestinal tract ^[37].

The introduction of DOACs has altered bleeding epidemiology. Although DOACs reduce intracranial hemorrhage risk compared with VKAs but gastrointestinal bleeding risk remains comparable or slightly higher depending on the specific agent ^[38]. Large registry data suggest that GI bleeding incidence has increased in recent years due to expanded use of antithrombotic therapy in elderly populations and patients with cardiovascular disease ^[39].

GI bleeding in patients receiving combined therapy is associated with increased mortality, particularly in elderly patients and those with multiple comorbidities. Mortality rates following major GI bleeding events range from 5% to 15%, depending on severity and patient characteristics ^[40]. Rebleeding events further increase mortality risk and are associated with prolonged hospitalization and increased resource utilization ^[41].

Hospitalization rates for GI bleeding related to antithrombotic therapy have increased substantially over the past two decades. Such hospitalizations are associated with increased length of stay, requirement for transfusion, endoscopic intervention, and intensive care unit admission ^[42]. Economic analyses demonstrate that GI bleeding represents a major contributor to healthcare expenditures associated with antithrombotic therapy ^[43].

Risk stratification plays a central role in determining the need for gastroprotective therapy. Identification of high-risk patients allows targeted intervention while minimizing unnecessary medication exposure.

Several patient-related factors are consistently associated with increased risk of GI bleeding:

Age greater than 65 years is one of the strongest predictors of GI bleeding risk. Elderly patients exhibit reduced mucosal resilience, impaired healing capacity, and increased prevalence of comorbid conditions ^[44]. Age-related pharmacokinetic changes may also increase drug exposure, particularly in patients receiving DOACs.

Prior GI bleeding represents the most significant predictor of recurrent bleeding. Patients with previous ulcer bleeding exhibit recurrence rates exceeding 10% annually without appropriate gastroprotection ^[45].

Chronic kidney disease, liver cirrhosis, malignancy, and cardiovascular disease are associated with increased bleeding risk. Renal impairment affects drug clearance and increases systemic anticoagulant exposure ^[46]. Liver disease contributes to coagulopathy and portal hypertension, further increasing bleeding risk.

Several clinical risk scores have been developed to estimate bleeding risk in patients receiving antithrombotic therapy.

The HAS-BLED score is widely used to assess bleeding risk in patients with atrial fibrillation receiving anticoagulation. Components include hypertension, abnormal renal/liver function, stroke history, bleeding history, labile INR, elderly age, and drug or alcohol use ^[50]. Although not specific to gastrointestinal bleeding, the HAS-BLED score provides valuable insight into overall bleeding risk.

Additional predictive models incorporate GI-specific variables such as prior ulcer disease, NSAID use, and Helicobacter pylori infection ^[51]. Emerging models integrating laboratory biomarkers and clinical parameters may further improve risk prediction accuracy.

Patients receiving combined therapy can be broadly categorized into:

• Low risk: No prior GI bleeding; Age <65 years; No additional risk factors.
• Moderate risk: Age ≥65 years; Single additional risk factor.
• High risk: Prior GI bleeding; Triple antithrombotic therapy; Multiple comorbidities.

High-risk patients derive the greatest benefit from gastroprotective therapy, particularly with proton pump inhibitors ^[52].

Proton pump inhibitors (PPIs) represent the cornerstone of pharmacologic gastroprotection in patients receiving combined antithrombotic therapy. These agents irreversibly inhibit the hydrogen-potassium ATPase enzyme in gastric parietal cells, resulting in profound suppression of gastric acid secretion and elevation of intragastric pH levels ^[53].

PPIs reduce bleeding risk through several mechanisms: Reduction of gastric acidity; Stabilization of fibrin clots; Promotion of ulcer healing; Prevention of mucosal erosion; Enhancement of platelet aggregation at neutral pH.

Elevated gastric pH reduces proteolytic degradation of fibrin clots, thereby improving hemostasis and reducing recurrent bleeding risk ^[54].

Multiple randomized controlled trials and meta-analyses demonstrate significant reductions in upper GI bleeding risk among patients receiving PPIs concurrently with antithrombotic therapy. Relative risk reductions of approximately 30% to 60% have been reported across high-risk populations ^[55–57]. Evidence supporting routine PPI use is strongest in: Patients receiving dual antithrombotic therapy; Patients receiving triple therapy; Patients with prior GI bleeding; Elderly populations. Guidelines from major cardiovascular and gastroenterology societies recommend PPI co-therapy in high-risk individuals receiving dual or triple antithrombotic regimens ^[58].

Commonly used PPIs include: Omeprazole; Pantoprazole; Esomeprazole; Lansoprazole; Rabeprazole

Pantoprazole is often preferred in patients receiving clopidogrel due to reduced interaction potential through the cytochrome P450 2C19 pathway ^[59].

The duration of PPI therapy depends on risk category: Short-term therapy (4–8 weeks) for acute ulcer healing; Long-term therapy for ongoing dual or triple antithrombotic therapy; Indefinite therapy for patients with recurrent bleeding risk.

Continued therapy should be reassessed periodically to minimize unnecessary long-term exposure ^[60].

Histamine-2 receptor antagonists (H2RAs) provide moderate suppression of gastric acid secretion by blocking histamine-mediated stimulation of parietal cells ^[61].

Screening for Helicobacter pylori infection is recommended in patients with a history of ulcer disease prior to initiating long-term antithrombotic therapy ^[64]. Eradication therapy significantly reduces the risk of recurrent ulcer bleeding. Randomized trials demonstrate that H. pylori eradication lowers long-term recurrence rates in patients receiving aspirin therapy ^[65].

Testing modalities include: Urea breath test; Stool antigen testing; Endoscopic biopsy. Eradication regimens typically involve combination antibiotic therapy and acid suppression ^[66].

Agents such as sucralfate and misoprostol provide mucosal protection through enhancement of protective barriers and stimulation of prostaglandin synthesis ^[67]. Misoprostol has demonstrated effectiveness in preventing NSAID-induced ulcers; however, its use is limited by adverse effects such as diarrhea and abdominal cramping ^[68]. These agents are generally considered adjunctive therapies rather than primary prophylactic options in combined antithrombotic therapy.

Non-pharmacologic interventions play an important role in reducing bleeding risk.

Risk factor modification key interventions include: Avoidance of NSAIDs; Limitation of corticosteroid use; Reduction of alcohol intake; Smoking cessation; Optimization of renal and hepatic function. Such measures reduce mucosal injury and improve overall patient outcomes ^[69].

Adjustments to antithrombotic therapy duration and intensity significantly influence bleeding risk. Recommended strategies include: Minimization of triple therapy duration; Transition to dual therapy when clinically appropriate; Use of lower aspirin doses (≤100 mg daily); Selection of anticoagulants with lower bleeding risk profiles. These modifications have been associated with improved safety outcomes ^[70].

Preventive gastroprotection is particularly important in patients without prior GI bleeding but with identifiable risk factors. Primary prevention focuses on reducing the risk of first-time GI bleeding in patients receiving combined therapy.

Prophylactic PPI therapy is recommended in patients with: Age ≥65 years; History of peptic ulcer disease; Concomitant NSAID use; Corticosteroid therapy; Triple antithrombotic therapy; Helicobacter pylori infection. Risk-based prophylaxis significantly reduces hospitalization rates associated with bleeding ^[71].

Risk stratification tools guide clinical decision-making. Patients classified as moderate or high risk derive the greatest benefit from PPI therapy. Low-risk patients may not require routine gastroprotection but should undergo periodic reassessment ^[72]. Management strategies differ substantially in patients presenting with active or prior GI bleeding.

Acute GI bleeding in patients receiving combined therapy represents a medical emergency requiring rapid assessment and intervention. Key steps include: Hemodynamic stabilization; Intravenous fluid resuscitation; Blood transfusion when indicated; Temporary discontinuation of antithrombotic therapy. Early resuscitation reduces mortality risk and improves clinical outcomes ^[73].

Urgent endoscopy remains the primary diagnostic and therapeutic modality. Common endoscopic interventions include: Injection therapy; Thermal coagulation; Mechanical clipping. Endoscopic hemostasis achieves bleeding control in the majority of cases ^[74].

Intravenous PPI therapy is recommended in patients with suspected upper GI bleeding. High-dose infusion regimens promote clot stabilization and reduce rebleeding risk ^[75].

Restarting antithrombotic therapy after bleeding presents a significant clinical challenge. Delayed resumption increases thrombotic risk, while early resumption increases rebleeding risk. Current evidence supports: Resumption of anticoagulation within 7–14 days in most patients; Earlier resumption in high thrombotic risk patients; Individualized assessment based on bleeding severity and thrombotic risk ^[76]. Concurrent PPI therapy significantly reduces recurrence risk following resumption of antithrombotic therapy.

Patients with prior GI bleeding require long-term preventive strategies. Recommended interventions include: Long-term PPI therapy; H. pylori eradication; Endoscopic surveillance when indicated; Modification of antithrombotic therapy intensity. Secondary prevention significantly reduces recurrent bleeding events ^[77].

Gastroprotection strategies must be tailored to specific high-risk populations receiving combined anticoagulant and antiplatelet therapy. Certain patient subgroups exhibit unique pharmacologic and physiologic considerations that influence bleeding risk and response to therapy.

Advanced age is associated with increased susceptibility to gastrointestinal bleeding due to diminished mucosal defense mechanisms, polypharmacy, and comorbidities such as chronic kidney disease and cardiovascular disease ^[78]. Elderly patients benefit significantly from proton pump inhibitor (PPI) prophylaxis, particularly when receiving dual or triple antithrombotic therapy ^[79]. Regular assessment of renal function and drug interactions is essential to avoid overexposure to acid-suppressive therapy and potential adverse effects.

Patients with a history of gastrointestinal bleeding are at highest risk for recurrent events. Secondary prevention strategies include long-term PPI therapy, eradication of Helicobacter pylori, and endoscopic monitoring when indicated. Observational studies indicate that PPI therapy reduces recurrent bleeding risk by up to 70% in these patients ^[84]. Individualized antithrombotic therapy adjustment, including consideration of DOACs with lower GI bleeding risk, is recommended ^[85].

Patients receiving triple therapy (oral anticoagulant plus dual antiplatelet therapy) experience the highest bleeding rates. Guidelines recommend limiting the duration of triple therapy to the minimum necessary for thrombotic protection and initiating PPI prophylaxis early ^[86]. Transition to dual therapy with ongoing PPI therapy is advised when clinically feasible.

While PPIs and other gastroprotective agents significantly reduce bleeding risk, long-term use may be associated with adverse effects.

• Clostridioides difficile infection: Acid suppression alters gut microbiota, increasing infection risk ^[87].
• Hypomagnesemia: Chronic PPI use may reduce magnesium absorption, leading to arrhythmias and neuromuscular complications ^[88].
• Bone fractures: Long-term therapy is associated with decreased calcium absorption and increased risk of osteoporotic fractures ^[89].
• Drug interactions: PPIs may interfere with clopidogrel metabolism via CYP2C19 inhibition, although clinical significance varies among specific PPIs ^[90].

H2RAs are generally well tolerated but may cause headache, dizziness, diarrhea, or rare hepatic enzyme elevation. Compared to PPIs, efficacy in high-risk populations is limited ^[91].

Agents such as misoprostol and sucralfate are limited by gastrointestinal side effects (e.g., diarrhea, abdominal pain) and poor patient adherence ^[92].

Overall, the benefit-risk balance strongly favors PPI use in high-risk patients, while periodic reassessment is recommended to minimize long-term adverse effects.