Preventing major gastrointestinal bleeding in elderly patients
Authors: Hans-Christoph Diener
Journal: The Lancet (2017)

Antiplatelet therapy is the most frequently recommended treatment to prevent recurrent ischaemic events in patients who have had an ischaemic stroke, an acute coronary syndrome, or symptomatic peripheral arterial disease. The most frequently used drugs are aspirin or clopidogrel. Most guidelines recommend lifelong intake of antiplatelet therapy. However, randomised trials that have investigated the benefit of antiplatelet therapy had an observation period of between 2 years and 4 years.1Vandvik PO Lincoff AM Gore JM et al.Primary and secondary prevention of cardiovascular disease: antithrombotic therapy and prevention of thrombosis, 9th edn: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2012; 141: e637S-e668SSummary Full Text Full Text PDF PubMed Scopus (431) Google Scholar Therefore, we lack data on the long-term benefit and risk of antiplatelet therapy across long time periods, particularly in elderly patients. In The Lancet, Linxin Li and colleagues2Li L Geraghty OC Mehta Z Rothwell PM on behalf of the Oxford Vascular StudyAge-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study.Lancet. 2017; (published online June 5.)http://dx.doi.org/10.1016/S0140-6736(17)30770-5Google Scholar report bleeding events and outcomes in 3166 patients with first transient ischaemic attack, ischaemic stroke, or myocardial infarction who were treated with antiplatelet drugs (mainly aspirin) and were followed prospectively for 10 years. Half of the patients (n=1582) were aged 75 years or older. Major bleeding and fatal bleeding were significantly related to age and showed a steep increase in incidence above the age of 75 years. The hazard ratio for major upper gastrointestinal bleeds was 4·13 for age 75 years or older and 10·26 for those bleeds that were disabling or fatal. The proportion of gastrointestinal bleeding events that were disabling or fatal was higher than the proportion of ischaemic stroke or intracerebral haemorrhage. At age 75 years or older, most major upper gastrointestinal bleeds were disabling or fatal (62% vs 25% of patients younger than 75 years), outnumbering disabling or fatal intracerebral haemorrhage (45 vs 18), with an absolute risk of 9·15 (95% CI 6·67–12·24) per 1000 patient-years. 1 year after the qualifying ischaemic event, 33% of the survivors were on proton-pump inhibitors (PPIs). The number needed to treat to prevent one disabling or fatal upper gastrointestinal bleed over 5 years with the use of PPIs was 338 for individuals younger than 65 years and 25 for individuals aged 85 years or older. What are the practical consequences of this important study? In patients with stroke with a cardiac source of embolism who qualify for oral anticoagulation we obsess about the association between benefit and bleeding risk. Specific risk scores were developed to assess the bleeding risk for patients with atrial fibrillation who qualified for anticoagulation (HAS-BLED).3Kirchhof P Benussi S Kotecha D et al.2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.Eur Heart J. 2016; 37: 2893-2962Crossref PubMed Scopus (5160) Google Scholar, 4Heidbuchel H Verhamme P Alings M et al.Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: executive summary—revision 1.Eur Heart J. 2016; (published online June 9)https://doi.org/10.1093/eurheartj/ehw058Crossref Scopus (190) Google Scholar Similar risk scores are not applied for patients who undergo long-term prevention with antiplatelet therapy. We have learned from the studies in elderly patients with atrial fibrillation that aspirin carries a similar risk of major bleeding than warfarin.5Mant J Hobbs F Fletcher K et al.Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.Lancet. 2007; 370: 493-503Summary Full Text Full Text PDF PubMed Scopus (1417) Google Scholar Therefore, the first consequence of Li and colleagues' study is that the benefit–risk association in long-term antiplatelet therapy should be evaluated every 3–5 years in patients older than 75 years. We need to consider that patients on dual antiplatelet therapy have a higher risk of bleeding than patients on monotherapy.6Berger PB Bhatt DL Fuster V et al.Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.Circulation. 2010; 121: 2575-2583Crossref PubMed Scopus (199) Google Scholar, 7Tan S Xiao X Ma H et al.Clopidogrel and aspirin versus aspirin alone for stroke prevention: a meta-analysis.PLoS One. 2015; 10: e0135372Google Scholar The bleeding risk is further increased if patients with atrial fibrillation and atherosclerotic disease receive a combination of anticoagulation and antiplatelet therapy. The second consequence of Li and colleagues' study2Li L Geraghty OC Mehta Z Rothwell PM on behalf of the Oxford Vascular StudyAge-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study.Lancet. 2017; (published online June 5.)http://dx.doi.org/10.1016/S0140-6736(17)30770-5Google Scholar is its support for the need to use PPIs in patients on antiplatelet therapy aged 75 years or older or in patients with a history of gastrointestinal bleeds. PPIs are underused in patients on antiplatelet therapy,8de Jong HJ Korevaar JC van Dijk L Voogd E van Dijk CE van Oijen MG Suboptimal prescribing of proton-pump inhibitors in low-dose aspirin users: a cohort study in primary care.BMJ Open. 2013; (published online July 24)https://doi.org/10.1136/bmjopen-2013-003044Crossref Scopus (31) Google Scholar perhaps because the consequences of upper gastrointestinal bleeds were underestimated in elderly patients who were treated with aspirin. Both physicians and patients were shocked by a small underpowered publication in 2016,9Gomm W von Holt K Thome F et al.Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis.JAMA Neurol. 2016; 73: 410-416Crossref PubMed Scopus (398) Google Scholar which assumed a correlation between the use of PPIs and dementia. Unfortunately, this paper was reported widely in the media and created a lot of confusion and angst. Finally physicians are much more influenced by what they observe in their clinical practice than by what they read in the medical literature. Cardiologists will rarely see intracranial bleeds, and neurologists and cardiologists will rarely see major gastrointestinal bleeds. Therefore, they might underestimate the real risk in patients on antithrombotic therapy. In summary, major bleeding complications are a major issue in elderly patients with ischaemic vascular disease treated with antiplatelet therapy. PPIs are recommended to reduce the risk of upper gastrointestinal bleeds in patients aged 75 years or above. I have received honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from AstraZeneca, Bayer Vital, Boehringer Ingelheim, Bristol–Myers Squibb, Daiichi Sankyo, Sanofi Aventis, and Servier, related to antiplatelet therapy or proton-pump inhibitors, and from Abbott, Allergan, CoAxia, Corimmun, Covidien, D-Pharm, Fresenius, GlaxoSmithKline (GSK), Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, Medtronic, Merck, Sharp, & Dohme, MindFrame, Neurobiological Technologies, Novartis, Novo Nordisk, Paion, Parke-Davis, Pfizer, Schering-Plough, Solvay, St Jude, Syngis, Talecris, Thrombogenics, WebMD Global, Wyeth, and Yamanouchi. I have received financial support for research projects from AstraZeneca, Boehringer Ingelheim, GSK, Janssen-Cilag, Lundbeck, Novartis, Sanofi Aventis, Syngis, and Talecris. The Department of Neurology at the University Duisburg-Essen (Duisburg and Essen, Germany) received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, National Institute of Health USA, Bertelsmann Foundation, and Heinz Nixdorf Foundation. I have no ownership interest and do not own stocks of any pharmaceutical company. Within the past year, I have served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerz News, Stroke News, and as coeditor of Cephalalgia, and on the editorial board of Lancet Neurology, European Neurology, and Cerebrovascular Disorders. I chair the Treatment Guidelines Committee of the German Society of Neurology and have contributed to the European Heart Rhythm Association and European Society of Cardiology guidelines for the treatment of atrial fibrillation. Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort studyIn 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 gastrointestinal bleeding. Given that half of the major bleeds in patients aged 75 years or older were upper gastrointestinal, the estimated NNT for routine PPI use to prevent such bleeds is low, and co-prescription should be encouraged. Full-Text PDF Open Access