Proton pump inhibitor monotherapy and the risk of cardiovascular events in patients with gastro-esophageal reflux disease: a meta-analysis
Z. Cui
Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
Search for more papers by this authorCorresponding Author
G. Cheng
Shenyang Pharmaceutical University, Shenyang, China
Correspondence
Gang Cheng, Shenyang Pharmaceutical University, Shenhe District, Shenyang, Liaoning Province, China.
Email: [email protected]
Search for more papers by this authorZ. Cui
Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
Search for more papers by this authorCorresponding Author
G. Cheng
Shenyang Pharmaceutical University, Shenyang, China
Correspondence
Gang Cheng, Shenyang Pharmaceutical University, Shenhe District, Shenyang, Liaoning Province, China.
Email: [email protected]
Search for more papers by this authorAbstract
Background and Purpose
Proton pump inhibitors (PPIs) are commonly used as potent gastric acid secretion antagonists for gastro-esophageal disorders and their overall safety in patients with gastro-esophageal reflux disease (GERD) is considered to be good and they are well-tolerated. However, recent studies have suggested that PPIs may be a potential independent risk factor for cardiovascular adverse events. The aim of our meta-analysis was to examine the association between PPI monotherapy and cardiovascular events in patients with GERD.
Methods
A literature search involved examination of relevant databases up to July 2015 including PubMed, Cochrane Library, EMBASE, and ClinicalTrial.gov, as well as selected randomized controlled trials (RCTs) reporting cardiovascular events with PPI exposure in GERD patients. In addition, the pooled risk ratio (RR) and heterogeneity were assessed based on a fixed effects model of the meta-analysis and the I2 statistic, respectively.
Key Results
Seventeen RCTs covering 7540 patients were selected. The pooled data suggested that the use of PPIs was associated with a 70% increased cardiovascular risk (RR=1.70, 95% CI: [1.13–2.56], P=.01, I2=0%). Furthermore, higher risks of adverse cardiovascular events in the omeprazole subgroup (RR=3.17, 95% CI: [1.43–7.03], P=.004, I2=25%) and long-term treatment subgroup (RR=2.33, 95% CI: [1.33–4.08], P=.003, I2=0%) were found.
Conclusion & Inferences
PPI monotherapy can be a risk factor for cardiovascular adverse events. Omeprazole could significantly increase the risk of cardiovascular events and, so, should be used carefully.
Supporting Information
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References
- 1Kahrilas PJ. Clinical practice. Gastroesophageal reflux disease. N Engl J Med. 2008; 359: 1700–1707.
- 2Berardi RR, Welage LS. Proton-pump inhibitors in acid-related diseases. Am J Health Syst Pharm. 1998; 55: 2289–2298.
- 3Stedman CA, Barclay ML. Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment Pharmacol Ther. 2000; 14: 963–978.
- 4Katz MH. Failing the acid test: benefits of proton pump inhibitors may not justify the risks for manyusers. Arch Intern Med. 2010; 170: 747–748.
- 5Howden CW, Larsen LM, Perez MC, et al. Clinical trial: efficacy and safety of dexlansoprazole MR 60 and 90 mg in healed erosive oesophagitis – maintenance of healing and symptom relief. Aliment Pharmacol Ther. 2009; 30: 895–907.
- 6Peura DA, Pilmer B, Hunt B, et al. Distinguishing the impact of dexlansoprazole on heartburn vs. regurgitation in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2013; 38: 1303–1311.
- 7Armstrong D, Pare P, Pericak D, et al. Symptom relief in gastroesophageal reflux disease: a randomized, controlled comparison of pantoprazole and nizatidine in a mixed patient population with erosive esophagitis or endoscopy-negative reflux disease. Am J Gastroenterol. 2001; 96: 2849–2857.
- 8Lundell L, Attwood S, Ell C, Fiocca R, et al. Comparing laparoscopic antireflux surgery with esomeprazole in the management of patients with chronic gastro-oesophageal reflux disease: a 3-year interim analysis of the lotus trial. Gut. 2008; 57: 1207–1213.
- 9Flook NW, Moayyedi P, Dent J, et al. Acid-suppressive therapy with esomeprazole for relief of unexplained chest pain in primary care: a randomized, double-blind, sal. Am J Gastroenterol. 2013; 108: 56–64.
- 10Venables TL, Newland RD, Patel AC, et al. Omeprazole 10 milligrams once daily, omeprazole 20 milligrams once daily, or ranitidine 150 milligrams twice daily, evaluated as initial therapy for the relief of symptoms of gastro-oesophageal reflux disease in general practice. Scand J Gastroenterol. 1997; 32: 965–973.
- 11Mearin F, Ponce J. Potent acid inhibition: summary of the evidence and clinical application. Drugs 2005; 65(suppl): 113–126.
- 12Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitorsand clopidogrel. CMAJ. 2009; 180: 713–718.
- 13Ho 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: 937–944.
- 14Dunn SP, Macaulay TE, Brennan DM, et al. Abstract 3999: Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO Trial. Circulation. 2008; 118: S815.
- 15Rassen JA, Choudhry NK, Avorn J, et al. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation. 2009; 120: 2322–2329.
- 16 Food and Drug Administration. Public Health Advisory 17 November 2009:updated Safety Information about a drug interaction between Clopidogrel Bisulfate (marketed as Plavix) and Omeprazole (marketed as Prilosec and Prilosec OTC). http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm190825.htm. Accessed December 15, 2009.
- 17Sibbing D, Kastrati A. Risk of combining PPIs with thienopyridines: fact or fiction? Lancet. 2009; 374: 952–954.
- 18Laine L, Hennekens C. Proton pump inhibitor and clopidogrel interaction: fact or fiction? Am J Gastroenterol. 2010; 105: 34–41.
- 19Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013; 108: 308–328.
- 20Charlot M, Grove EL, Hansen PR, et al. Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study. BMJ. 2011; 342: d2690.
- 21Charlot M, Ahlehoff O, Norgaard ML, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use. Ann Intern Med. 2010; 53: 378–386.
- 22Goodman SG, Clare R, Pieper KS, et al. Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from PLATO. Circulation. 2012; 125: 978–986.
- 23Juurlink DN, Dormuth CR, Huang A, et al. Proton pump inhibitors and the risk of adverse cardiac events. PLoS ONE. 2013; 8: e84890.
- 24Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009; 151: 264–269.
- 25 Cochrane Collaboration. Cochrane Handbook for Systematic Reviews of Interventions, 2009. Available at www.cochrane-handbook.org. Accessed August 28, 2013.
- 26Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.0 [updated February 2008]. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org randomised trials. BMJ. 2011; 343: d5928.
- 27Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011; 64: 383–394.
- 28Friedlander EA, Pallentino J, Miller SK, et al. The evolution of proton pump inhibitors for the treatment of gastroesophageal reflux disease. J Am Acad Nurse Pract. 2010; 22: 674–683.
- 29Richter JE, Sabesin SM, Kogut DG, et al. Omeprazole versus ranitidine or ranitidine/metoclopramide in poorly responsive symptomatic gastroesophageal reflux disease. Am J Gastroenterol. 1996; 91: 1766–1772.
- 30Richter JE, Peura D, Benjamin SB, et al. Efficacy of omeprazole for the treatment of symptomatic acid reflux disease without esophagitis. Arch Intern Med. 2000; 160: 1810–1816.
- 31Lundell L, Miettinen P, Myrvold HE, et al. Comparison of outcomes twelve years after antireflux surgery or omeprazole maintenance therapy for reflux esophagitis. Clin Gastroenterol Hepatol 2009; 7: 1292–1298.
- 32Bigard MA, Genestin E. Treatment of patients with heartburn without endoscopic evaluation: on-demand treatment after effective continuous administration of lansoprazole 15 mg. Aliment Pharmacol Ther. 2005; 22: 635–643.
- 33Talley NJ, Lauritsen K, Tunturi-Hihnala H, et al. Esomeprazole 20 mg maintains symptom control in endoscopy-negative gastro-oesophageal reflux disease: a controlled trial of ‘on-demand’ therapy for 6 months. Aliment Pharmacol Ther. 2001; 15: 347–354.
- 34Sugisaki N, et al. A comparative study on the efficacy and safety of E3810 in patients with non-erosive gastroesophageal reflux disease.ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00165646?term=NCT00165646&rank=1. (June 1, 2015)
- 35Attwood SE, Ell C, Galmiche JP, et al. Long-term safety of proton pump inhibitor therapy assessed under controlled, randomised clinical trial conditions: data from the SOPRAN and LOTUS studies. Aliment Pharmacol Ther. 2015; 41: 1162–1174.
- 36Kovacs TO, Freston JW, Haber MM, et al. Long-term quality of life improvement in subjects with healed erosive esophagitis: treatment with lansoprazole. Dig Dis Sci. 2010; 55: 1325–1336.
- 37Kiljander TO, Junghard O, Beckman O, et al. Effect of esomeprazole 40 mg once or twice daily on asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2010; 181: 1042–1048.
- 38Shih CJ, Chen YT, Ou SM, et al. Proton pump inhibitor use represents an independent risk factor for myocardial infarction. Int J Cardiol. 2014; 177: 292–297.
- 39Shah NH, LePendu P, Bauer-Mehren A, et al. Proton pump inhibitor usage and the risk of myocardial infarction in the general population. PLoS ONE. 2015; 10: e0124653.
- 40Cardoso RN, Benjo AM, DiNicolantonio JJ, et al. Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis. Open Heart. 2015; 2: e000248.
- 41Ghebremariam YT, Cooke JP, Khan F, et al. Proton pump inhibitors and vascular function: a prospective cross-over pilot study. Vasc Med. 2015; 20: 309–316.
- 42Ghebremariam YT, LePendu P, Lee JC, et al. An unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor ADMA. Circulation. 2013; 128: 845–853.
- 43Mittermayer F, Krzyzanowska K, Exner M, et al. Asymmetric dimethylarginine predicts major adverse cardiovascular events in patients with advanced peripheral artery disease. Arterioscler Thromb Vasc Biol. 2006; 26: 2536–2540.
- 44Wilson AM, Shin DS, Weatherby C, et al. Asymmetric dimethylarginine correlates with measures of disease severity, major adverse cardiovascular events and all-cause mortality in patients with peripheral arterial disease. Vasc Med. 2010; 15: 267–274.
- 45Lu TM, Chung MY, Lin MW, et al. Plasma asymmetric dimethylarginine predicts death and major adverse cardiovascular events in individuals referred for coronary angiography. Int J Cardiol. 2011; 153: 135–140.
- 46Ari H, Ari S, Erdogan E, et al. A novel predictor of restenosis and adverse cardiac events: asymmetric dimethylarginine. Heart Vessels. 2010; 25: 19–26.
- 47Boger RH, Sullivan LM, Schwedhelm E, et al. Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community. Circulation. 2009; 119: 1592–1600.
- 48Wanby P, Teerlink T, Brudin L, et al. Asymmetric dimethylarginine (ADMA) as a risk marker for stroke and TIA in a Swedish population. Atherosclerosis. 2006; 185: 271–227.