Proton pump inhibitors in antithrombotic therapy: gastroprotection, drug interactions, and clinical management

Antithrombotic therapy is central to the prevention of thromboembolic and ischaemic events in patients with coronary artery disease, atrial fibrillation, and after percutaneous coronary intervention, but is accompanied by an increased risk of gastrointestinal bleeding (GIB). Proton pump inhibitors (PPIs) can reduce upper GIB, although their optimal use across different antithrombotic regimens, potential drug interactions, and inability to prevent lower GIB remain clinically relevant concerns. This structured narrative review examines PPI co-therapy in patients receiving antiplatelet agents, oral anticoagulants, or combined antithrombotic treatment. MEDLINE, Embase, and the Cochrane Library were searched from inception to August 2026, supplemented by contemporary cardiology and gastroenterology guidelines. Randomized trials, systematic reviews, meta-analyses, and large observational studies were prioritized. Evidence indicates that PPIs provide clinically meaningful protection against acid-related upper GIB, particularly in high-risk patients receiving aspirin-containing regimens, dual antiplatelet therapy, or intensified antithrombotic therapy, whereas evidence in isolated oral anticoagulation remains predominantly observational. PPI co-therapy should therefore be targeted according to gastrointestinal bleeding risk and antithrombotic intensity, with periodic reassessment as treatment changes, rather than used as universal gastrointestinal protection. Key points • Proton pump inhibitors can reduce the risk of upper gastrointestinal bleeding in patients receiving antithrombotic therapy, but their benefit is greatest in patients with additional gastrointestinal bleeding risk factors • Their use should therefore be individualized according to gastrointestinal risk and the intensity of antithrombotic treatment rather than prescribed routinely to all patients • The need for gastroprotection should be reassessed whenever the antithrombotic regimen or the patient’s bleeding risk changes