Prescribing Proton Pump Inhibitor and Clopidogrel Together

Current State of Recommendations

Neena S. Abraham


Curr Opin Gastroenterol. 2011;27(6):558-564. 

In This Article

Antiplatelet Regimens (Monotherapy and Dual Therapy) and the Risk of Gastrointestinal Bleeding

ASA monotherapy is associated with a two-fold to four-fold increase in gastrointestinal bleeding,[4] with greater risk associated with dose escalation.[4,5•] ASA dose reduction does not diminish antiplatelet benefits, but the CURRENT OASIS-7 trial has shown that it reduces gastrointestinal bleeding.[5•] Thus, it is recommended that ASA doses greater than 75–81 mg/day should not be prescribed. Dual prescription of ASA plus warfarin is commonly prescribed to high-risk cardiovascular patients, including those with atrial fibrillation, valve prostheses, intracardiac thrombi, recurrent thromboembolism and antiphospholipid syndrome.[6–8] The prescription of dual ASA plus warfarin is associated with an increased risk of extracranial bleeds [pooled odds ratio of 2.37; 95% confidence interval (CI) 1.37–4.10] when compared with ASA alone. The risk and benefit to the patient must carefully be considered, as these data suggest that treating 1000 patients with combination ASA and warfarin would avoid approximately 20 nonfatal myocardial infarctions (MIs) and 10 nonfatal thromboembolic strokes, while causing 10 major extracranial bleeds.[9]

The changing face of peptic ulcer disease is reflected in the emerging subgroup of cardiac patients with gastrointestinal bleeding. These individuals are commonly prescribed dual ASA and clopidogrel for the treatment of acute coronary syndrome and as a standard precaution following percutaneous coronary intervention (PCI) with stent insertion. Current evidence supports the prescription of ASA plus clopidogrel for up to 12 months following bare metal stent PCI, for at least 12 months following drug-eluting-stent PCI, for up to 12 months following unstable angina or non-ST elevation MI managed without PCI, and for at least 14 days following ST-elevation MI.[10••,11]

Evidence from pivotal cardiovascular randomized controlled trials (RCTs) highlights the increased gastrointestinal bleeding risk of dual-antiplatelet therapy with ASA plus clopidogrel when compared with ASA alone. Both the CURE and ACTIVE trials report an increased risk of gastrointestinal bleeding of relative risk (RR) 1.78 (95% CI 1.25–2.54) and RR 1.96 (95% CI 1.46–2.63), respectively.[12,13] The observed increase in risk associated with dual-antiplatelet therapy is presumably related to its potent antiplatelet activity, which promotes bleeding of clinically silent lesions caused by Helicobacter pylori and ASA. The CURRENT OASIS-7 trial also suggests that doubling the dose of clopidogrel may improve cardiac outcomes post-PCI; however, this benefit is associated with a 44% increased risk of major bleeding.[5•] In the CHARISMA trial,[14•] even moderate bleeding was associated with an increase in all-cause mortality (hazard ratio 2.6; 95% CI 1.7–3.8), MI (hazard ratio 2.9; 95% CI 2.0–4.2) and stroke (hazard ratio 4.2; 95% CI 3.1–5.8), highlighting that gastrointestinal bleeding can itself aggravate cardiovascular morbidity and mortality.


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