Management of Peptic Ulcer Disease in Patients Taking Antithrombotic Agents

Abstract

The management of peptic ulcer disease (PUD) in patients receiving antithrombotic therapy requires balancing bleeding and thrombotic risk. The shift from Helicobacter pylori-dominant to drug-induced PUD combined with increasing antithrombotic use has created a new high-risk population that demands particular attention. In this review, we synthesize the current evidence from Korean and international guidelines, focusing on practical management strategies for the acute treatment and long-term prevention of PUD. Key recommendations include individualized risk assessment of bleeding and thrombotic risks, timely resumption of antithrombotic agents following successful hemostasis, and mandatory proton pump inhibitor co-therapy for high-risk patients. Multidisciplinary collaboration and evidence-based approaches are necessary to optimize patient outcomes while minimizing gastrointestinal and cardiovascular complications.

INTRODUCTION

Peptic ulcer disease (PUD) is a mucosal defect that extends through the muscularis mucosa into the submucosa or deeper layers of the gastrointestinal (GI) wall, predominantly occurring in the stomach and duodenum [1]. The pathophysiology fundamentally reflects an imbalance between aggressive factors (e.g., gastric acid, pepsin, Helicobacter pylori, and nonsteroidal anti-inflammatory drugs [NSAIDs]) and mucosal defensive mechanisms (e.g., mucus-bicarbonate barrier, epithelial cell renewal, blood flow to mucosa, and prostaglandin synthesis) [2,3]. Historically, H. pylori infection has been the predominant etiology [4]. NSAIDs have emerged as a major etiologic factor, causing mucosal injury through both direct topical irritation and systemic inhibition of prostaglandin synthesis, thereby compromising mucosal defense mechanisms [5,6].

The management of PUD has entered a new era of complexity as the global population ages and the cardio-cerebrovascular disease burden expands, driving unprecedented increases in antithrombotic agent use [7]. This creates a clinical paradox: the use of medications that prevent life-threatening thrombotic events significantly increases the risk of GI complications. Gastroenterologists should now make intricate decisions regarding when to interrupt antithrombotic therapy, when to resume it after bleeding, and how to prevent recurrence, while coordinating with cardiology and neurology colleagues who bring different risk-benefit perspectives to these shared patients.

Antithrombotic agents encompass two principal pharmacological classes—antiplatelet agents and anticoagulants—each targeting distinct components of the hemostatic pathway [8]. Antiplatelet agents inhibit platelet activation and aggregation, thereby preventing arterial thrombosis, whereas anticoagulants interfere with the coagulation cascade to prevent fibrin clot formation, primarily addressing venous thromboembolism and cardioembolic events [9]. Antiplatelet agents are further subdivided based on their mechanism of action. Aspirin, the most widely used antiplatelet agent, irreversibly inhibits cyclooxygenase-1 (COX-1), thereby preventing the synthesis of thromboxane A2, a potent mediator of platelet aggregation and vasoconstriction [10]. Because of the irreversible nature of COX-1 acetylation, the antiplatelet effect of aspirin persists for the lifespan of the platelet (approximately 7 to 10 days). P2Y12 receptor inhibitors constitute the second major class of antiplatelet agents, blocking the adenosine diphosphate-mediated pathway of platelet activation. This class includes thienopyridines (clopidogrel and prasugrel), which are prodrugs that require hepatic biotransformation to generate active metabolites that irreversibly bind to the P2Y12 receptor, and ticagrelor, a cyclopentyl-triazolo-pyrimidine that directly and reversibly inhibits the P2Y12 receptor without requiring metabolic activation [11]. The combination of aspirin with a P2Y12 receptor inhibitor, termed dual antiplatelet therapy (DAPT), provides synergistic inhibition of platelet function and constitutes the standard of care following acute coronary syndrome.

Anticoagulants are classified into vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). Warfarin, the prototypical VKA, inhibits vitamin K epoxide reductase, thereby impairing hepatic synthesis of vitamin K-dependent coagulation factors (II, VII, IX, and X) and anticoagulant proteins C and S [12]. The anticoagulant effect of warfarin requires several days to manifest fully, exhibits substantial inter-individual variability due to genetic polymorphisms and dietary vitamin K intake, and necessitates regular monitoring of the international normalized ratio (INR). DOACs are mechanistically subdivided into direct thrombin (factor IIa) inhibitor, dabigatran, and direct factor Xa inhibitors, including rivaroxaban, apixaban, and edoxaban [13]. These agents achieve rapid onset of anticoagulation within hours of administration and possess relatively short half-lives, although their elimination is significantly affected by renal function, particularly for dabigatran.

The landscape of PUD has shifted from the traditional H. pylori-dominant etiology toward drug-induced mucosal injury, with antithrombotic agents now implicated in a considerable proportion of PUD cases [14]. Simultaneously, the pharmacologic armamentarium has expanded dramatically, in that DOACs have largely replaced warfarin and the durations of DAPT have evolved [15-17]. In this review, we synthesize the current evidence and guidelines to provide a comprehensive framework for managing PUD in this high-risk population.

DIAGNOSIS

PUD is definitively diagnosed by endoscopic examination, which allows direct visualization, biopsy for histopathology and H. pylori testing, and therapeutic intervention for bleeding lesions [18]. The endoscopic diagnosis of PUD in patients on antithrombotic therapy follows standard protocols, with the Forrest classification system guiding the management of bleeding lesions [19]. However, pre-endoscopic evaluation requires additional specific considerations. A thorough medication history assessment is essential, yet often challenging. Many patients fail to recognize, report, or accurately disclose their use of antithrombotic agents [20]. Critical pre-procedural assessments include determining the timing of the last antithrombotic dose, validating the INR in anticoagulant users, and obtaining the creatinine level for DOAC users because renal impairment, particularly for dabigatran, prolongs elimination.

Current evidence is reassuring regarding the safety of diagnostic endoscopy with biopsy (Table 1 and Fig. 1) [21,22]. Diagnostic endoscopy with biopsy is classified as a low-risk hemorrhage procedure across all major guidelines [8,23-25]. The British Society of Gastroenterology and the European Society of Gastrointestinal Endoscopy guidelines specifically note no increased bleeding risk with aspirin, clopidogrel, or warfarin continuation for biopsy [23]. Guidelines for DOACs suggest omitting the morning dose on the day of the procedure as a precautionary measure, although supporting data remain limited [23,25].

Table 1.

Recommendation for stopping antithrombotic agents before elective endoscopic procedures with low and high risk of bleeding

	Low-risk procedures	High-risk procedures
	Diagnostic endoscopy with/without biopsy	Polypectomy (>1 cm)
	Cold snare polypectomy of colon polyp ≤1 cm	EUS with needle aspiration or biopsy
	EUS without needle aspiration or biopsy	ERCP with sphincterotomy
	ERCP with stent placement or papillary balloon dilation	Dilation of strictures
	Diagnostic enteroscopy	Percutaneous endoscopic gastrostomy or jejunostomy
	Capsule endoscopy	Injection or band ligation of varices
	Enteral stenting without significant dilation	Endoscopic hemostasis
		EMR/ESD
		Endoscopic papillectomy
		POEM
		Tumor ablation or coagulation
Aspirin	Continue	Continue (consider stopping before ultra-high-risk procedures*)
P2Y12 receptor inhibitors	Continue	Stop 5–7 days before (5 days for clopidogrel and ticagrelor, and 7 days for prasugrel)
DAPT	Continue	Stop P2Y12 receptor inhibitors 5–7 days before, continue aspirin
Warfarin	Continue	Low thromboembolic risk: stop 5 days before
		Heparin bridging is recommended only in patients with high thromboembolic risk
DOACs	Omit morning dose	Stop 2–4 days before†

^*Ultra-high-risk procedures include ESD, EMR of large colon polyps (≥2 cm), endoscopic papillectomy25;

^†Evaluating creatinine clearance and DOAC type.

DAPT, dual antiplatelet therapy; DOACs, direct oral anticoagulants; EMR, endoscopic mucosal resection; ERCP, endoscopic retrograde cholangiopancreatography; ESD, endoscopic submucosal dissection; EUS, endoscopic ultrasonography; POEM, peroral endoscopic myotomy.

Fig. 1.

Management of antithrombotic agents for elective endoscopic procedures. *Warfarin can be resumed on the evening of the procedure for most patients at the patient’s usual maintenance dose. CrCl, creatinine clearance; DAPT, dual antiplatelet agent; DOACs, direct oral anticoagulants.

TREATMENT AND PREVENTION

Anti-ulcer therapy

Acid-suppressive therapy forms the cornerstone of ulcer treatment and prevention, following the same protocols used in non-user of antithrombotic agents [26]. For uncomplicated PUD, standard-dose proton pump inhibitor (PPI) therapy for 4–8 weeks could achieve ulcer healing in most cases. Potassium-competitive acid blockers (P-CABs), such as vonoprazan and tegoprazan, represent a new class of antisecretory agents that provide more rapid and consistent acid suppression, independent of the CYP2C19 genotype [26]. Tegoprazan, commercially available in Korea, is a benzimidazole derivative with a potent and reversible K⁺/H⁺-ATPase inhibitory effect, which has demonstrated efficacy in gastric ulcer treatment [27,28].

Mucoprotective agents are adjunctive therapeutic strategies that enhance mucosal defense mechanisms through prostaglandin-independent and prostaglandin-dependent pathways [29]. Traditional agents, such as sucralfate and misoprostol, have been used for gastric mucosal protection, whereas newer agents, including rebamipide, teprenone, and eupatilin, are increasingly prescribed in clinical practice, particularly in East Asian countries [30].

Management of peptic ulcer bleeding

Bleeding is the most common PUD-associated complication. Aspirin confers an increased risk of upper GI bleeding, with a clear dose-response relationship [31,32]. The risk of bleeding further increases with the addition of clopidogrel, anticoagulants, NSAIDs, or steroids and in old age [33-36]. Anticoagulants do not directly cause gastric mucosal injury but can promote bleeding from pre-existing lesions [37-39].

The management of antithrombotic therapy in GI bleeding represents the most complex aspect of care, requiring the integration of bleeding and thromboembolic risk (Fig. 2) [40]. For thrombotic risk assessment, the CHA₂DS₂-VASc score guides anticoagulation decisions in atrial fibrillation (scores ≥2 mandate anticoagulation) [8]. Concurrent HAS-BLED scores ≥3 indicate high bleeding risk that requires careful monitoring [41-43]. The risk of thromboembolism associated with anticoagulant discontinuation depends largely on the underlying disease for which the anticoagulant was indicated [25]. High thrombotic risk scenarios requiring antithrombotic treatment include recent cardioembolic stroke within 3 months, recent venous thromboembolism within 3 months, atrial fibrillation with rheumatic valvular heart disease, mechanical heart valve, CHA2DS2-VASc score ≥6, and severe thrombophilia [25,44,45]. In patients with acute coronary syndrome, the risk of stent thrombosis is highest in the first 4 to 6 weeks after coronary artery stenting with bare metal stent and in the first 3 months after drug-eluting stent implantation [8,44,45]. These patients require antithrombotic therapy despite the risk of bleeding. Since thromboembolic risk increases substantially when both antiplatelet agents are discontinued during DAPT [46], current guidelines recommend continuing aspirin if P2Y12 receptor inhibitor interruption is necessary [23-25,47].

Fig. 2.

Management of antithrombotic agents in patients with peptic ulcer bleeding with high risk (A), and low risk (B) endoscopic stigmata. DAPT, dual antiplatelet therapy; DOACs, direct oral anticoagulants; P-CAB, potassium-competitive acid blocker; PPI, proton pump inhibitor.

The evidence in the literature to guide the proper timing of restarting antithrombotic agents in patients with peptic ulcer bleeding is limited. Guidelines strongly recommend restarting aspirin and thienopyridine, including clopidogrel, for secondary prevention of cardiovascular or cerebrovascular diseases, as soon as endoscopic hemostasis is confirmed [25,44]. For DAPT, aspirin should be continued without interruption, when possible, with P2Y12 receptor inhibitor resumption at proper timing based on bleeding risk assessment [25,37]. In most cases of GI bleeding in patients with atrial fibrillation indicated for anticoagulation therapy, restarting oral anticoagulants after the hemorrhage can have a positive net clinical benefit, particularly in those at the highest thromboembolic risk [48]. Therefore, anticoagulants should be resumed as soon as possible for patients who need long-term anticoagulation once peptic ulcer bleeding has been successfully controlled [25,44].

The timing of resumption should be individualized based on the pharmacokinetic properties of specific agents, the severity of the bleeding episode, and the urgency of restoring anticoagulation, often necessitating multidisciplinary consultation with a cardiologist or neurologist. Considering that the onset of antiplatelet activity usually requires 3–5 days after the resumption of its administration, antiplatelet agent should be resumed as soon as possible if adequate hemostasis is achieved [37]. As the onset time of prasugrel or ticagrelor is fast and the antiplatelet potency is greater than that of clopidogrel, the timing of restarting these P2Y12 receptor inhibitors should be determined carefully [23,49]. When warfarin is restarted after interruption, achieving full anticoagulant effects can require several days. Therefore, warfarin can be restarted at the previous therapeutic dose once hemostasis is achieved. In most patients, peak levels and a therapeutic anticoagulation effect are achieved within several hours after DOAC initiation. DOACs should be resumed when full anticoagulation is clinically appropriate once adequate hemostasis has been secured [25,45]. The guidelines also underscore the need for standardized bleeding and thrombotic risk assessment through multidisciplinary collaboration and the establishment of institutional protocols for consistent management across specialties.

Long-term preventive strategies

The prevention of ulcer recurrence in patients requiring ongoing antithrombotic therapy centers on PPI maintenance and H. pylori eradication. The guidelines recommend PPI therapy in combination with antiplatelet therapy in patients with a history of peptic ulcer (Table 2) [36,37,40,44,50-52]. Specifically, the 2020 revised Korean guidelines strongly recommend PPI co-therapy for patients with long-term low-dose aspirin therapy for secondary prevention with a history of peptic ulcer [44]. Robust evidence supports PPI maintenance in patients with antiplatelet therapy. A randomized trial demonstrated that lansoprazole in addition to H. pylori eradication therapy significantly reduced the recurrence in long-term low-dose aspirin users [53]. Another randomized trial demonstrated that aspirin plus esomeprazole resulted in a cumulative incidence of recurrent bleeding rate of only 0.7% versus 8.6% with clopidogrel alone in patients who took aspirin to prevent vascular diseases, confirming that PPI co-therapy with aspirin is superior to switching to an alternative antiplatelet agent [54]. The Clopidogrel and the Optimization of Gastrointestinal Events Trial confirmed an 87% relative reduction in overt upper GI bleeding with omeprazole co-administration in patients on DAPT [55]. Meta-analyses of randomized controlled trials have also demonstrated that PPIs are effective in reducing PUD and ulcer bleeding in low-dose aspirin ulcers [56].

Table 2.

Recommendations regarding proton pump inhibitor co-therapy in patients with antithrombotic therapy

Guideline	Statement	Class of recommendation	Level of evidence
ACCF/ACG/AHA 2008 expert consensus document on reducing the GI risk of antiplatelet therapy and NSAID use [40]
	The combination of ASA and anticoagulant therapy (including unfractionated heparin, low-molecular-weight heparin, and warfarin) is associated with a clinically meaningful and significantly increased risk of major extracranial bleeding events, a large proportion from the upper GI tract. This combination should be used with established vascular, arrhythmic, or vascular indication; patients should receive concomitant PPIs as well.	Expert consensus
	PPIs are the preferred agents for the therapy and prophylaxis of NSAID- and ASA-associated GI injury.	Expert consensus
ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of PPIs and thienopyridines: a focused update of the 2008 expert consensus document [36]
	Use of a PPI or H2RA reduces the risk of upper GI bleeding compared with no therapy. PPIs reduce upper GI bleeding to a greater degree than do H2RAs.	Expert consensus
	PPIs are recommended to reduce GI bleeding in patients with a history of upper GI bleeding. PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy.	Expert consensus
	Routine use of either a PPI or an H2RA is not recommended for patients at lower risk of upper GI bleeding, who have much less potential to benefit from prophylactic therapy.	Expert consensus
	Clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both cardiovascular and GI complications.	Expert consensus
2017 ESC focused update on DAPT in coronary artery disease developed in collaboration with EACTS [50]
	A PPI in combination with DAPT is recommended.	I*	B†
Clinical guidelines for drug-related peptic ulcers, 2020 revised edition [44]
	We recommend that patients who have a history of PU receiving long-term LDA therapy are co-administered PPI to prevent PU and rebleeding.	Strong for	Moderate
	We suggest high-risk patients who are taking anticoagulants to be administered PPIs to prevent upper GI hemorrhage.	Weak for	low
Endoscopic diagnosis and management of NVUGIH, ESGE guideline update 2021 [37]
	ESGE recommends that in patients who have had acute NVUGIH and require ongoing DAPT, PPI should be given as co-therapy.	Strong	Moderate
	ESGE recommends PPIs for gastroduodenal prophylaxis in patients requiring ongoing anticoagulation and with a history of NVUGIH.	Strong	Low
2023 ESC guidelines for the management of acute coronary syndromes [51]
	Therapy with a PPI is indicated for patients receiving any antithrombotic regimen who are at high risk of GI bleeding.	No corresponding recommendation was made
2025 ACC/AHA/ACEP/NAEMSP/SCAI guidelines for the management of patients with acute coronary syndrome [52]
	In patients at high risk of GI bleeding, a PPI is recommended in combination with DAPT, oral anticoagulants, or both to reduce risk of bleeding.	I*	A†

^*Class of recommendation is graded as I, II, or III in this guideline;

^†Level of evidence is graded as A, B, or C in this guideline.

ACC, The American College of Cardiology; ACCF, The American College of Cardiology Foundation; ACEP, The American College of Emergency Physicians; ACG, The American College of Gastroenterology; AHA, The American Heart Association; ASA, acetylsalicylic acid (aspirin); DAPT, dual antiplatelet therapy; EACTS, The European Association for Cardio-Thoracic Surgery; ESC, The European Society of Cardiology; ESGE, The European Society of Gastrointestinal Endoscopy; GI, gastrointestinal; H2RA, histamine H₂ receptor antagonist; LDA, lowdose aspirin; NAEMSP, National Association of EMS Physicians; NSAID, nonsteroidal anti-inflammatory drug; NVUGIH, nonvariceal upper gastrointestinal hemorrhage; PPI, proton pump inhibitor; PU, peptic ulcer; SCAI, Society for Cardiovascular Angiography and Interventions.

PPI therapy is also recommended in high-risk patients (history of PUD and concomitant use of antiplatelet agents and NSAIDs) taking anticoagulants to prevent GI bleeding [37,44,51,52]. An observational study demonstrated that concomitant use of PPIs in oral anticoagulant users was associated with a 34% risk reduction in hospitalization for upper GI bleeding [57]. Another retrospective cohort study reported that PPI and histamine 2-receptor antagonists significantly reduced the risk of upper GI bleeding in patients taking dabigatran with a history of peptic ulcers or GI bleeding [58]. A recent meta-analysis also indicated that PPI co-therapy in anticoagulant users was associated with a lower total and major GI bleeding [59]. For patients on anticoagulants, the COMPASS trial, which investigated pantoprazole versus placebo in patients with stable atherosclerotic vascular disease who were treated with aspirin, rivaroxaban, or both, provided important nuance [60]. In this study, routine pantoprazole did not significantly reduce composite upper GI events compared with placebo but significantly reduced bleeding from gastroduodenal lesions. Thus, the benefits of PPI are greater in patients with additional GI risk factors than in all patients receiving anticoagulants.

The potential interaction between clopidogrel and PPIs has generated substantial concern because the conversion of clopidogrel to its active metabolite and the metabolism of certain PPIs depend on common CYP isoenzymes, mainly CYP2C19 [36]. Several studies have reported that clopidogrel-induced platelet inhibition is attenuated with the use of certain PPIs, a pharmacodynamic effect that is most pronounced with omeprazole [61,62]. In line with this, the U.S. Food and Drug Administration (FDA) issued a boxed warning in March 2010 advising against concomitant use of clopidogrel with omeprazole or esomeprazole, citing reduced effectiveness in CYP2C19 poor metabolizers [63]. Nonetheless, results from a double-blind, placebo-controlled randomized trial have indicated no significant differences in ischemic events between omeprazole and placebo among patients treated with clopidogrel, although PPI use markedly decreased the risk of GI bleeding [55]. Moreover, post hoc analyses from several randomized trials have shown that ischemic risk is not increased when a clinically indicated PPI is used with clopidogrel [64,65]. The PLATO sub-study revealed the association of PPI use with similar cardiovascular risk in both clopidogrel and ticagrelor groups despite ticagrelor not requiring CYP2C19 activation, thus strongly suggesting confounding rather than true drug interaction [66].

P-CABs represent an alternative class of antisecretory agents with CYP2C19-independent acid suppression [26]. A randomized trial demonstrated that vonoprazan was non-inferior to lansoprazole in preventing ulcer recurrence in patients with a history of peptic ulcer requiring long-term low-dose aspirin therapy [67]. However, contrary to initial expectations based on in vitro CYP2C19 inhibition data, a clinical pharmacokinetic study demonstrated that compared with esomeprazole, vonoprazan attenuated clopidogrel-induced platelet inhibition more potently across all CYP2C19 genotype groups [68]. The U.S. FDA also classifies vonoprazan as a CYP2C19 inhibitor and warns that co-administration may reduce plasma concentrations of the active metabolite of clopidogrel, resulting in reduced platelet inhibition [69]. The current international guidelines have not yet specifically recommended P-CABs for gastroprotection in patients on antithrombotic therapy.

H. pylori eradication is another important aspect of PUD management that allows healing and reduces recurrence, and is also indicated in patients receiving antithrombotic therapy. The 2020 revised Korean guideline strongly recommends H. pylori eradication in patients with a history of PUD receiving long-term low-dose aspirin therapy to prevent peptic ulcer and its complications [44]. This approach is based on studies demonstrating that successful H. pylori eradication significantly reduces the recurrence of ulcer complications in long-term aspirin users [70,71].

CONCLUSION

As the burden of cardio-cerebrovascular disease continues to rise, an increasing number of patients require long-term antithrombotic therapy and are consequently at elevated risk of GI complications. The epidemiology of PUD has fundamentally shifted from H. pylori infection to a drug-induced etiology, making the assessment of antithrombotic medication history as important as H. pylori testing in diagnostic evaluation. The management of PUD in patients taking antithrombotic agents requires sophisticated integration of GI bleeding risk, thrombotic risk, pharmacological interactions, and guideline recommendations from multiple specialties. It is imperative to balance these competing risks through multidisciplinary collaboration. In high-risk patients, long-term prevention of recurrence relies primarily on H. pylori eradication and concomitant PPI therapy in those receiving antithrombotic agents. As the population ages and antithrombotic indications continue to expand, this complex patient population will continue to grow, making mastery of these management principles essential for contemporary gastroenterology practice.