- •The use of PPIs increase cardiovascular events in patients with hemodialysis.
- •The use of PPIs link to QTc interval prolongation in patients with hemodialysis.
- •Bleeding events do not decrease with the use of PPIs in patients with hemodialysis.
Proton pump inhibitors (PPIs) are known to increase the risk of mortality and cardiovascular events in the general population. However, in patients with maintenance hemodialysis, PPI effects are under investigated.
We analyzed the risk of PPIs for cardiovascular events using the Kagoshima Dialysis (KIDS) registry, a prospective, multicenter, observational study in patients with maintenance hemodialysis in Japan.
In all, 531 patients were enrolled from June 2015 to December 2018. One-year follow-up data were available for 376 patients (Use of PPIs at baseline (PPI group): 217 patients and without PPIs (No PPI group): 159 patients). The incidence of a composite outcome (all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke) was higher in patients in the PPI group than the No PPI group (15.2% vs. 4.4%; hazard ratio (HR): 3.65, 95% confidence interval (CI): 1.61–8.23, P = 0.002). In the multivariate analysis, even after adjustment for covariates, the use of PPIs was an independent risk factor for a composite outcome (HR: 2.38, 95% CI: 1.02–5.54, P = 0.045). We performed propensity score matching analysis as a sensitivity analysis, showing a consistent result. The incidence of bleeding showed no difference between the two groups (15.7% vs. 11.3%; HR: 1.46, 95% CI: 0.83–2.59, P = 0.19).
These results indicate that the use of PPIs in patients with maintenance hemodialysis might increase mortality and cardiovascular events without decreasing the risk of bleeding. Therefore, it should always be analyzed if a patient truly needs PPIs.
Abbreviations:ACC (American college of cardiology), ADMA (asymmetrical dimethylarginine), AHA (American heart association), BW (body weight), CABG (coronary artery bypass grafting), CI (confidence interval), CV (cardiovascular), GERD (gastroesophageal reflex disease), GNRI (geriatric nutrition risk index), GUSTO (global use of strategies to open occluded coronary arteries), HR (hazard ratio), LVEF (left ventricular ejection fraction), MI (myocardial infarction), n-PCR (normalized protein catabolic rate), NSAIDs (non-steroidal anti-inflammatory drugs), PCI (percutaneous coronary intervention, PPIs, proton pump inhibitors), PSM (propensity score matching), spKt/V (single-pool Kt/V), TIMI (thrombolysis in myocardial infarction), URL (upper reference limit), URR (urea reduction rate)
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- We are using too many PPIs, and we need to stop: a European perspective.Am J Gastroenterol. 2016; 111: 1085-1086https://doi.org/10.1038/ajg.2016
- The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association.Gastroenterology. 2017; 152: 706-715https://doi.org/10.1053/j.gastro.2017.01.031
- Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case-control study.Aliment Pharmacol Ther. 2010; 32: 1124-1128https://doi.org/10.1111/j.1365-2036.2010.04453.x
- Association of gastric acid suppression with recurrent clostridium difficile infection: a systematic review and meta-analysis.JAMA Intern Med. 2017; 177: 784-791https://doi.org/10.1001/jamainternmed.2017.0212
- Proton pump inhibitors and risk of incident CKD and progression to ESRD.J Am Soc Nephrol. 2016; 27: 3153-3163https://doi.org/10.1681/ASN.2015121377
- Associations of proton-pump inhibitors and H2 receptor antagonists with chronic kidney disease: a meta-analysis.Dig Dis Sci. 2017; 62: 2821-2827https://doi.org/10.1007/s10620-017-4725-5
- The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis.Nephrol Dial Transplant. 2018; 33: 331-342https://doi.org/10.1093/ndt/gfw470
- Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative.Arch Intern Med. 2010; 170: 765-771https://doi.org/10.1001/archinternmed.2010.94
- Increased risk of bone fractures in hemodialysis patients treated with proton pump inhibitors in real world: results from the dialysis outcomes and practice patterns study (DOPPS).J Bone Miner Res. 2019; (31)https://doi.org/10.1002/jbmr.3842
- Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies.Ren Fail. 2015; 37: 1237-1241https://doi.org/10.3109/0886022X.2015.1057800
- Proton-pump inhibitor-induced hypomagnesemia: current research and proposed mechanisms.World J Nephrol. 2016; 5: 152-157https://doi.org/10.5527/wjn.v5.i2.152
- Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12).Ann Intern Med. 1994; 120: 211-215https://doi.org/10.7326/0003-4819-120-3-199402010-00006
- Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors.Aliment Pharmacol Ther. 2008; 27: 1110-1121https://doi.org/10.1111/j.1365-2036.2008.03658.x
- Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency.JAMA. 2013; 310: 2435-2442https://doi.org/10.1001/jama.2013.280490
- Proton pump inhibitor usage and the risk of myocardial infarction in the general population.PLoS ONE. 2015; 10e0124653https://doi.org/10.1371/journal.pone.0124653
- Proton-pump inhibitor use and the risk of first-time ischemic stroke in the general population: a nationwide population-based study.Am J Gastroenterol. 2017; 112: 1084-1093https://doi.org/10.1038/ajg.2017.101
- Risk of death among users of proton pump inhibitors: a longitudinal observational cohort study of United States veterans.BMJ Open. 2017; 7https://doi.org/10.1136/bmjopen-2016-015735
- Large variations in prescriptions of gastrointestinal medications in hemodialysis patients on three continents: the dialysis outcomes and practice patterns study (DOPPS).Hemodial Int. 2006; 10: 180-188https://doi.org/10.1111/j.1542-4758.2006.00092.x
- A province-wide cross-sectional study of demographics and medication use of patients in hemodialysis units across Ontario.Can J Kidney Health Dis. 2018; 52054358118760832https://doi.org/10.1177/2054358118760832
- Determination of Kt/V and protein catabolic rate using pre- and postdialysis blood urea nitrogen concentrations.Nephron. 1994; 67: 280-290https://doi.org/10.1159/000187980
- Japanese society for dialysis therapy clinical guideline for “Maintenance hemodialysis: hemodialysis prescriptions.”.Ther Apher Dial. 2015; 19: 67-92https://doi.org/10.1111/1744-9987.12294
- Simplified nutritional screening tools for patients on maintenance hemodialysis.Am J Clin Nutr. 2008; 87: 106-113https://doi.org/10.1093/ajcn/87.1.106
- Thrombolysis in Myocardial Infarction (TIMI) trial – Phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase.J Am Coll Cardiol. 1988; 11: 1-11https://doi.org/10.1016/0735-1097(88)90158-1
- An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.N Engl J Med. 1993; 329: 673-682https://doi.org/10.1056/NEJM199309023291001
- 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: d2690https://doi.org/10.1136/bmj.d2690
- Proton pump inhibitors and risk of 1-year mortality and rehospitalization in older patients discharged from acute care hospitals.JAMA Intern Med. 2013; 173: 518-523https://doi.org/10.1001/jamainternmed.2013.2851
- Proton pump inhibitors and cardiovascular events: a systematic review.Heart Lung Circ. 2018; 27: 443-450https://doi.org/10.1016/j.hlc.2017.10.020
- Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome: a systematic review.Heart. 2013; 99: 520-527https://doi.org/10.1136/heartjnl-2012-302371
- Is there a relationship between hypomagnesemia and proton-pump inhibitors in patients on chronic hemodialysis?.Eur J Intern Med. 2016; 30: 99-103https://doi.org/10.1016/j.ejim.2016.01.026
- Proton pump inhibitor use and magnesium concentrations in hemodialysis patients: a cross-sectional study.PLoS ONE. 2015; 10e0143656https://doi.org/10.1371/journal.pone.0143656
- The relationship between proton pump inhibitor use and serum magnesium concentration among hemodialysis patients: a cross-sectional study.BMC Nephrol. 2015; 16: 136https://doi.org/10.1186/s12882-015-0139-9
- Hypomagnesemia in hemodialysis patients: role of proton pump inhibitors.Am J Nephrol. 2014; 39: 204-209https://doi.org/10.1159/000360011
- Lower serum magnesium is associated with cardiovascular risk factors and mortality in haemodialysis patients.Blood Purif. 2014; 38: 244-252https://doi.org/10.1159/000366124
- Prevalence of the risk factors for QT prolongation and associated drug-drug interactions in a cohort of medical inpatients.J Formos Med Assoc. 2019; 118: 109-115https://doi.org/10.1016/j.jfma.2018.01.016
- Low serum magnesium is associated with vascular calcification in peritoneal dialysis patients: a cross sectional study.BMC Nephrol. 2017; 18: 129https://doi.org/10.1186/s12882-017-0549-y
- Long-term proton pump inhibitor use is associated with vascular calcification in chronic kidney disease: a cross-sectional study using propensity score analysis.Drug Saf. 2013; 36: 635-642https://doi.org/10.1007/s40264-013-0062-6
- Proton pump inhibitor as an independent factor of progression of abdominal aortic calcification in patients on maintenance hemodialysis.PLoS ONE. 2018; 13e0199160https://doi.org/10.1371/journal.pone.0199160
- Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740https://doi.org/10.1093/ndt/gfg414
- Progressive vascular calcification over 2 years is associated with arterial stiffening and increased mortality in patients with stages 4 and 5 chronic kidney disease.Clin J Am Soc Nephrol. 2007; 2: 1241-1248https://doi.org/10.2215/CJN.02190507
- PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis.Am J Kidney Dis. 2006; 47: 149-156https://doi.org/10.1053/j.ajkd.2005.09.024
- Temporal trends in fracture rates and post-discharge outcomes among hemodialysis patients.J Am Soc Nephrol. 2013; 24: 1461-1469https://doi.org/10.1681/ASN.2012090916
- High rates of death and hospitalization follow bone fracture among hemodialysis patients.Kidney Int. 2014; 85: 166-173https://doi.org/10.1038/ki.2013.279
- Proton pump inhibitors accelerate endothelial senescence.Circ Res. 2016; 118: e36-e42https://doi.org/10.1161/CIRCRESAHA.116.308807
- Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine.Circulation. 2013; 128: 845-853https://doi.org/10.1161/CIRCULATIONAHA.113.003602
- Asymmetric dimethylarginine and all-cause mortality: a systematic review and meta-analysis.Sci Rep. 2017; 7: 44692https://doi.org/10.1038/srep44692
- Relationship between serum asymmetric dimethylarginine and left ventricular structure and function in patients with end-stage renal disease treated with hemodialysis.Pol Arch Med Wewn. 2012; 122: 226-234https://doi.org/10.20452/pamw.1222
- Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs.JAMA. 2004; 292: 1955-1960https://doi.org/10.1001/jama.292.16.1955
- Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study.Arch Intern Med. 2007; 167: 950-955https://doi.org/10.1001/archinte.167.9.950
- Proton-pump inhibitor use and the risk of community-acquired pneumonia.Ann Intern Med. 2008; 149: 391-398https://doi.org/10.7326/0003-4819-149-6-200809160-00005
- Association between proton pump inhibitors and respiratory infections: a systemic review and meta-analysis of clinical trials.Can J Gastroenterol. 2008; 22: 761-766https://doi.org/10.1155/2008/821385
- Rabeprazole reduces the recurrence of peptic ulcers associated with low-dose aspirin in patients with cardiovascular or cerebrovascular disease: a prospective randomized active-controlled trial.J Gastroenterol. 2012; 47: 1186-1197https://doi.org/10.1007/s00535-012-0588-x
- Multinational, double-blind, randomized, placebo-controlled, prospective study of esomeprazole in the prevention of recurrent peptic ulcer in low-dose acetylsalicylic acid users: the Lavender study.Gut. 2014; 63: 1061-1068https://doi.org/10.1136/gutjnl-2013-304722
- Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. [Omeprazole versus Misoprostol for NSAID-Induced Ulcer Management (OMNIUM) study group.].N Engl J Med. 1998; 338: 727-734https://doi.org/10.1056/NEJM199803123381105
- A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs [Acid Suppression Trial: ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment (ASTRONAUT) Study Group.].N Engl J Med. 1998; 338: 719-726https://doi.org/10.1056/NEJM199803123381104
- Investigation of small intestinal lesions in dialysis patients using capsule endoscopy.Hemodial Int. 2019; 23: 77-80https://doi.org/10.1111/hdi.12683
Published online: November 14, 2019
Accepted: November 6, 2019
Received in revised form: October 4, 2019
Received: July 9, 2019
© 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.