Bleeding Risks and Long-Term Antiplatelet Treatment After Vascular Events

Study Questions:

What are the risks, time course, and outcomes of bleeding on antiplatelet treatment for secondary prevention in patients of all ages, and the potential benefit of co-administration of proton-pump inhibitors (PPIs)?


A prospective population-based cohort study was conducted in patients with a first transient ischemic attack, ischemic stroke, or myocardial infarction treated with antiplatelet drugs (mainly aspirin based, without routine PPI use) after the event in the Oxford Vascular Study from 2002 to 2012, with follow-up until 2013. The study evaluated the type, severity, outcome (disability or death), and time course of bleeding requiring medical attention by face-to-face follow-up for 10 years. Estimated age-specific numbers needed to treat (NNT) to prevent upper gastrointestinal (GI) bleeding with routine PPI co-prescription was determined on the basis of Kaplan–Meier risk estimates and relative risk reduction estimates from previous trials.


A total of 3,166 patients (1,582 [50%] aged ≥75 years) had 405 first bleeding events (n = 218 GI, n = 45 intracranial, and n = 142 other) during 13,509 patient-years of follow-up. Risk of nonmajor bleeding was unrelated to age, but major bleeding significantly increased steeply with age (≥75 years hazard ratio [HR], 3.10; 95% confidence interval [CI], 2.27–4.24), particularly for fatal bleeds (HR, 5.53; 95% CI, 2.65–11.54), and was sustained during long-term follow-up. The same was true of major upper GI bleeds (≥75 years HR, 4.13; 95% CI, 2.60–6.57), particularly if disabling or fatal (HR, 10.26; 95% CI, 4.37–24.13). At age ≥75 years, major upper GI bleeds were mostly disabling or fatal (45 [62%] of 73 patients vs. 101 [47%] of 213 patients with recurrent ischemic stroke), and outnumbered disabling or fatal intracerebral hemorrhage (n = 45 vs. n = 18), with an absolute risk of 9.15 (95% CI, 6.67–12.24) per 1,000 patient-years. The estimated NNT for routine PPI use to prevent one disabling or fatal upper GI bleed over 5 years fell from 338 for individuals <65 years, to 25 for individuals aged ≥85 years.


In patients receiving aspirin-based antiplatelet treatment without routine PPI use, the long-term risk of major bleeding is higher and more sustained in older patients in practice than in the younger patients in previous trials, with a substantial risk of disabling or fatal upper GI bleeding. Given that half of the major bleeds in patients aged ≥75 years were upper GI, the estimated NNT for routine PPI use to prevent such bleeds is low, and co-prescription should be encouraged.


The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) study showed that PPIs safely reduce rates of GI events in patients requiring dual antiplatelet therapy even with low-dose aspirin. However, the trial was short-term and not powered to assess the potential adverse side effects and thus overall benefit/risk with PPIs, nor was this an observational study. Guidelines suggest adding PPIs to aspirin at any dose in patients at high risk, which based on this review, includes those ≥75 years old. Considering the prevalence of aspirin use for prevention of atherosclerotic cardiovascular disease events and the concern for drug interactions, dementia, kidney disease, and cardiovascular events with long-term PPIs, a large randomized clinical trial is warranted.

Clinical Topics: Geriatric Cardiology, Prevention

Keywords: Aspirin, Cerebral Hemorrhage, Gastrointestinal Hemorrhage, Geriatrics, Ischemic Attack, Transient, Myocardial Infarction, Platelet Aggregation Inhibitors, Primary Prevention, Proton Pump Inhibitors, Risk Assessment, Secondary Prevention, Stroke, Treatment Outcome, Vascular Diseases

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