rpcardioRational Pharmacotherapy in CardiologyРациональная Фармакотерапия в Кардиологии1819-64462225-3653«SILICEA-POLIGRAF» LLC10.20996/1819-6446-2014-10-6-665-671rpcardio-307Research ArticleCURRENT QUESTIONS OF CLINICAL PHARMACOLOGYАКТУАЛЬНЫЕ ВОПРОСЫ КЛИНИЧЕСКОЙ ФАРМАКОЛОГИИСONCOMITANT ADMINISTRATION OF CLOPIDOGREL AND PROTON PUMP INHIBITORS: ARE THERE ANY OPEN QUESTIONS LEFT TODAY?СОВМЕСТНОЕ ИСПОЛЬЗОВАНИЕ КЛОПИДОГРЕЛА И ИНГИБИТОРОВ ПРОТОННОЙ ПОМПЫ: ЕСТЬ ЛИ НЕРЕШЕННЫЕ ВОПРОСЫ СЕГОДНЯМарцевичС. Ю.MartsevichS. Yu.

д.м.н., профессор, руководитель отдела профилактической фармакотерапии

101990, Москва, Петроверигский пер., 10

Petroverigsky per. 10, Moscow, 101990 Russia

СуворовА. Ю.SuvorovA. Yu.

м.н.с. того же отдела

101990, Москва, Петроверигский пер., 10

Petroverigsky per. 10, Moscow, 101990 Russia

asuvorov@gnicpm.ruГосударственный научно-исследовательский центр профилактической медициныРоссияState Research Centre for Preventive MedicineRussian Federation201425092015106665671Copyright © Martsevich S.Y., Suvorov A.Y., 20152015Марцевич С.Ю., Суворов А.Ю.Martsevich S.Y., Suvorov A.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rpcardio.online/jour/article/view/307

Concomitant administration of clopidogrel and proton pump inhibitors (PPI), the possible influence of PPI on the effectiveness of clopidogrel often raises questions among practitioners. Massive antithrombotic therapy increases the risk of upper gastrointestinal tract lesions. Concomitant administration of these drugs is studied in a large number of trials. Results of the most significant of these trials are considered. Safety of concomitant administration of clopidogrel and PPI, its impact on long-term outcomes of cardiovascular diseases, and a choice of particular PPI are also discussed.

Совместное применение клопидогрела и ингибиторов протонной помпы (ИПП), возможное влияние ИПП на эффективность клопидогрела часто вызывает вопросы у практикующих врачей. Тем не менее, массивная антитромботическая терапия значительно повышает риск поражения верхних отделов желудочно-кишечного тракта. Сегодня известно о большом количестве исследований, в которых изучалось совместное применение этих препаратов. Рассмотрены результаты наиболее крупных из этих исследований, а также обсуждаются вопросы безопасности совместного использования клопидогрела и ИПП, влияние на отдаленные исходы кардиологических заболеваний и выбор определенного ИПП.

клопидогрелингибиторы протонной помпыбезопасность леченияclopidogrelproton pump inhibitorssafety of treatmentReferencesNational guidelines for the treatment of acute coronary syndromes without persistent ST elevation on ECG. Kardiovaskulyarnaya Terapiya i Profilaktika 2006; 5 (8): 411-40. Russian (Национальные рекомендации по лечению острого коронарного синдрома без стойкого подъема ST на ЭКГ. Кардиоваскулярная Терапия и Профилактика 2006;5(8):411-40).National guidelines for the treatment of acute coronary syndromes without persistent ST elevation on ECG. Kardiovaskulyarnaya Terapiya i Profilaktika 2006; 5 (8): 411-40. Russian (Национальные рекомендации по лечению острого коронарного синдрома без стойкого подъема ST на ЭКГ. Кардиоваскулярная Терапия и Профилактика 2006;5(8):411-40).National guidelines for diagnosis and treatment of patients with acute myocardial infarction with ST segment elevation ECG. Kardiovaskulyarnaya Terapiya i Profilaktika 2007; 6 (8): 415-500. Russian (Национальные рекомендации по диагностике и лечению больных острым инфарктом миокарда с подъемом сегмента ST ЭКГ. Кардиоваскулярная Терапия и Профилактика 2007;6(8):415-500).National guidelines for diagnosis and treatment of patients with acute myocardial infarction with ST segment elevation ECG. Kardiovaskulyarnaya Terapiya i Profilaktika 2007; 6 (8): 415-500. Russian (Национальные рекомендации по диагностике и лечению больных острым инфарктом миокарда с подъемом сегмента ST ЭКГ. Кардиоваскулярная Терапия и Профилактика 2007;6(8):415-500).Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33(20):2569-619.Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33(20):2569-619.O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127(4):e362-425.O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127(4):e362-425.Patrono C, Bachmann F, Baigent C, et al. Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European society of cardiology. Eur Heart J 2004;25(2):166-81.Patrono C, Bachmann F, Baigent C, et al. Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European society of cardiology. Eur Heart J 2004;25(2):166-81.O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. JACC 2013;61(4):e78-140.O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. JACC 2013;61(4):e78-140.Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988;2(8607):349-60.Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988;2(8607):349-60.Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. NEJM 2001;345(7):494-502.Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. NEJM 2001;345(7):494-502.Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366(9497):1607-21.Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366(9497):1607-21.U.S. Food and Drug Administration. Information for Healthcare Professionals: Update to the Labelling of Clopidogrel Bisulfate (Marketed as Plavix) to Alert Healthcare Professionals About a Drug Interaction With Omeprazole (Marketed as Prilosec and Prilosec OTC). Available at: http://wwwfdagov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand-Providers/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm. Accessed by 24.10.2014.U.S. Food and Drug Administration. Information for Healthcare Professionals: Update to the Labelling of Clopidogrel Bisulfate (Marketed as Plavix) to Alert Healthcare Professionals About a Drug Interaction With Omeprazole (Marketed as Prilosec and Prilosec OTC). Available at: http://wwwfdagov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand-Providers/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm. Accessed by 24.10.2014.European Medicines Agency. PublicStatement on Possible InteractionBetween Clopidogrel and Proton-PumpInhibitors. Available at: http://wwwemaeuropaeu/humandocs/PDFs/EPAR/Plavix/32895609en.pdf. Accessed by 24.10.2014.European Medicines Agency. PublicStatement on Possible InteractionBetween Clopidogrel and Proton-PumpInhibitors. Available at: http://wwwemaeuropaeu/humandocs/PDFs/EPAR/Plavix/32895609en.pdf. Accessed by 24.10.2014.Pereillo JM, Maftouh M, Andrieu A, et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug metabolism and disposition: the biological fate of chemicals 2002;30(11):1288-95.Pereillo JM, Maftouh M, Andrieu A, et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug metabolism and disposition: the biological fate of chemicals 2002;30(11):1288-95.Richter T, Murdter TE, Heinkele G, et al. Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. The Journal of pharmacology and experimental therapeutics 2004;308(1):189-97.Richter T, Murdter TE, Heinkele G, et al. Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. The Journal of pharmacology and experimental therapeutics 2004;308(1):189-97.De Miguel A, Ibanez B, Badimon JJ. Clinical implications of clopidogrel resistance. Thrombosis and haemostasis 2008;100(2):196-203.De Miguel A, Ibanez B, Badimon JJ. Clinical implications of clopidogrel resistance. Thrombosis and haemostasis 2008;100(2):196-203.Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. JACC 2008;51(3):256-60.Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. JACC 2008;51(3):256-60.Gilard M, Arnaud B, Le Gal G, et al. Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin. JTH 2006;4(11):2508-9.Gilard M, Arnaud B, Le Gal G, et al. Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin. JTH 2006;4(11):2508-9.Mehran R, Pocock SJ, Stone GW, et al. Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial. Eur Heart J 2009;30(12):1457-66.Mehran R, Pocock SJ, Stone GW, et al. Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial. Eur Heart J 2009;30(12):1457-66.Spencer FA, Moscucci M, Granger CB, et al. Does comorbidity account for the excess mortality in patients with major bleeding in acute myocardial infarction? Circulation 2007;116(24):2793-801.Spencer FA, Moscucci M, Granger CB, et al. Does comorbidity account for the excess mortality in patients with major bleeding in acute myocardial infarction? Circulation 2007;116(24):2793-801.Martsevich SY, KutishenkoN.P., Tolpygina SN, et al. Efficacy and safety of drug therapy for primary and secondary prevention of cardiovascular disease. Ration Pharmacother Cardiol 2011; 7 (5) suppl: 2-72. Russian (Марцевич С.Ю., КутишенкоН.П., Толпыгина С.Н., и др. Эффективность и безопасность лекарственной терапии при первичной и вторичной профилактике сердечно-сосудистых заболеваний. Рациональная Фармакотерапия в Кардиологии 2011;7(5) приложение:2-72).Martsevich SY, KutishenkoN.P., Tolpygina SN, et al. Efficacy and safety of drug therapy for primary and secondary prevention of cardiovascular disease. Ration Pharmacother Cardiol 2011; 7 (5) suppl: 2-72. Russian (Марцевич С.Ю., КутишенкоН.П., Толпыгина С.Н., и др. Эффективность и безопасность лекарственной терапии при первичной и вторичной профилактике сердечно-сосудистых заболеваний. Рациональная Фармакотерапия в Кардиологии 2011;7(5) приложение:2-72).AbrahamNS, HlatkyMA, AntmanEM, et al. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation 2010;122(24):2619-33.AbrahamNS, HlatkyMA, AntmanEM, et al. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation 2010;122(24):2619-33.Sung JJ, Lau JY, Ching JY, et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Annals of internal medicine 2010;152(1):1-9.Sung JJ, Lau JY, Ching JY, et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Annals of internal medicine 2010;152(1):1-9.Lanas A, Garcia-Rodriguez LA, Arroyo MT, et al. Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. The American journal of gastroenterology 2007;102(3):507-15.Lanas A, Garcia-Rodriguez LA, Arroyo MT, et al. Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. The American journal of gastroenterology 2007;102(3):507-15.Ng FH, Lam KF, Wong SY, et al. Upper gastrointestinal bleeding in patients with aspirin and clopidogrel co-therapy. Digestion 2008;77(3-4):173-7.Ng FH, Lam KF, Wong SY, et al. Upper gastrointestinal bleeding in patients with aspirin and clopidogrel co-therapy. Digestion 2008;77(3-4):173-7.Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. NEJM 2010;363(20):1909-17.Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. NEJM 2010;363(20):1909-17.Wentworth JK, Pula G, Poole AW. Vasodilator-stimulated phosphoprotein (VASP) is phosphorylated on Ser157 by protein kinase C-dependent and -independent mechanisms in thrombin-stimulated human platelets. The Biochemical journal 2006;393(Pt 2):555-64.Wentworth JK, Pula G, Poole AW. Vasodilator-stimulated phosphoprotein (VASP) is phosphorylated on Ser157 by protein kinase C-dependent and -independent mechanisms in thrombin-stimulated human platelets. The Biochemical journal 2006;393(Pt 2):555-64.Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory effects of the proton pumpinhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug metabolism and disposition: the biological fate of chemicals 2004;32(8):821-7.Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory effects of the proton pumpinhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug metabolism and disposition: the biological fate of chemicals 2004;32(8):821-7.Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. Journal of clinical pharmacology 2008;48(4):475-84.Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. Journal of clinical pharmacology 2008;48(4):475-84.Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. JACC 2009;54(13):1149-53.Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. JACC 2009;54(13):1149-53.Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301(9):937-44.Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301(9):937-44.Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180(7):713-8.Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180(7):713-8.Aubert AE, Epstein RS, Teagarden JR et al. Proton Pump Inhibitors Effect on Clopidogrel Effectiveness: The Clopidogrel Medco Outcomes Study. Circulation 2008;118:S815.Aubert AE, Epstein RS, Teagarden JR et al. Proton Pump Inhibitors Effect on Clopidogrel Effectiveness: The Clopidogrel Medco Outcomes Study. Circulation 2008;118:S815.Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. JACC 2008;52(12):1038-9.Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. JACC 2008;52(12):1038-9.Mistry SD, Trivedi HR, Parmar DM, et al. Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence. Indian journal of pharmacology 2011;43(2):183-6.Mistry SD, Trivedi HR, Parmar DM, et al. Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence. Indian journal of pharmacology 2011;43(2):183-6.O'Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 2009;374(9694):989-97.O'Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 2009;374(9694):989-97.Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009;120(23):2322-9.Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009;120(23):2322-9.Zairis MN, Tsiaousis GZ, Patsourakos NG, et al. The impact of treatment with omeprazole on the effectiveness of clopidogrel drug therapy during the first year after successful coronary stenting. The Canadian journal of cardiology 2010;26(2):e54-7.Zairis MN, Tsiaousis GZ, Patsourakos NG, et al. The impact of treatment with omeprazole on the effectiveness of clopidogrel drug therapy during the first year after successful coronary stenting. The Canadian journal of cardiology 2010;26(2):e54-7.Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. NEJM 2009;360(4):363-75.Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. NEJM 2009;360(4):363-75.Wayne A, Ray KTM, Griffin MR, et al. Outcomes with Concurrent Use of Clopidogrel and Proton-Pump Inhibitors: A Cohort Study. Ann Intern Med 2010;152 (6):337-45.Wayne A, Ray KTM, Griffin MR, et al. Outcomes with Concurrent Use of Clopidogrel and Proton-Pump Inhibitors: A Cohort Study. Ann Intern Med 2010;152 (6):337-45.Foundation ACoC. The Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effect (SPICE) Trial. J Am Coll Cardiol 2011;58(20s1):B219-BFoundation ACoC. The Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effect (SPICE) Trial. J Am Coll Cardiol 2011;58(20s1):B219-BWiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007;116(25):2923-32.Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007;116(25):2923-32.Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. NEJM 2007;357(20):2001-15.Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. NEJM 2007;357(20):2001-15.Yano H, Tsukahara K, Morita S, et al. Influence of omeprazole and famotidine on the antiplatelet effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes: a prospective, randomized, multicenter study. Circulation 2012;76(11):2673-80.Yano H, Tsukahara K, Morita S, et al. Influence of omeprazole and famotidine on the antiplatelet effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes: a prospective, randomized, multicenter study. Circulation 2012;76(11):2673-80.Tunggal P, Ng FH, Lam KF, et al. Effect of esomeprazole versus famotidine on platelet inhibition by clopidogrel: a double-blind, randomized trial. American Heart Journal 2011;162(5):870-4.Tunggal P, Ng FH, Lam KF, et al. Effect of esomeprazole versus famotidine on platelet inhibition by clopidogrel: a double-blind, randomized trial. American Heart Journal 2011;162(5):870-4.Jones DB, Howden CW, Burget DW, et al. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987;28(9):1120-7.Jones DB, Howden CW, Burget DW, et al. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987;28(9):1120-7.Taha AS, McCloskey C, Prasad R, Bezlyak V. Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomised, double-blind, placebo-controlled trial. Lancet 2009;374(9684):119-25.Taha AS, McCloskey C, Prasad R, Bezlyak V. Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomised, double-blind, placebo-controlled trial. Lancet 2009;374(9684):119-25.

The authors declare that there are no conflicts of interest present.