Analysis of postmarketing safety data for proton-pump inhibitors reveals increased propensity for renal injury, electrolyte abnormalities, and nephrolithiasis

Makunts, Tigran; Cohen, Isaac; Awdishu, Linda; Abagyan, Ruben

doi:10.1038/s41598-019-39335-7

Cited by 56 publications

(45 citation statements)

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“…The primary outcome of this study was to evaluate the difference in estimated glomerular filtration rate (eGFR) calculated via Modification of Diet in Renal Disease (MDRD)-4 equation at 1 year posttransplant between patients treated with a PPI and those treated with an H2RA; this functional end point was chosen because postmarketing surveillance of PPI therapy has centered around acute and chronic kidney injury, which heretofore has not been well described in the kidney transplant population. [6][7][8][9] Renal function was also assessed at 30 days, month 3, month 6, month 9, year 3, year 5, and year 9 posttransplant. Other secondary outcomes included biopsy-proven acute rejection (BPAR), magnesium supplementation requirements, thrombocytopenia, GI effects (including gastritis, GI ulcer and GI bleeding episodes), incidence of Clostridium difficile infection, osteoporosis, fractures, and pneumonia.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3] To prevent these GI side effects, patients are prescribed acid suppression therapy with a proton pump inhibitor (PPI) or histamine-2 receptor antagonist (H2RA). Both PPIs and H2RAs have been in use for decades but recent studies have shown long-term PPI use can cause acute and chronic kidney injury, [4][5][6][7][8][9] thrombocytopenia, hypomagnesemia, hypocalcemia, and osteoporosis when compared with H2RAs. [9][10][11] Previous studies of PPI use in the kidney transplant population have mainly evaluated the shortterm risk of rejection given that PPIs reduce gastric acidity and may alter absorption and serum levels of MPA.…”

mentioning

confidence: 99%

“…Both PPIs and H2RAs have been in use for decades but recent studies have shown long-term PPI use can cause acute and chronic kidney injury, [4][5][6][7][8][9] thrombocytopenia, hypomagnesemia, hypocalcemia, and osteoporosis when compared with H2RAs. [9][10][11] Previous studies of PPI use in the kidney transplant population have mainly evaluated the shortterm risk of rejection given that PPIs reduce gastric acidity and may alter absorption and serum levels of MPA. [12][13][14][15] Studies have demonstrated that the formulation of MPA may determine the effect of PPI co-administration, with mycophenolate mofetil (MMF) exhibiting significantly decreased area under the curve that has not been consistently seen with enteric-coated mycophenolate sodium (EC-MPS), although reductions in the active metabolite mycophenolic acid glucuronide have not been shown to consistently be impacted by PPI therapy with either formulation.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Choice of Acid Suppressant Therapy and Long‐Term Graft Outcomes After Kidney Transplantation

January¹,

Progar²,

Nesselhauf³

et al. 2020

Pharmacotherapy

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STUDY OBJECTIVE The purpose of this study was to comprehensively evaluate the long-term adverse effects of proton pump inhibitors (PPIs) compared with histamine-2 receptor antagonists (H2RAs) in kidney transplant recipients. METHODS This retrospective cohort compared 582 patients treated with PPI with 705 patients treated with H2RA and evaluated adverse effects throughout their course of acid suppressant therapy to a maximum of nine years posttransplant. The primary outcome of interest was renal function at 1 year posttransplant; secondary outcomes included renal function at 30 days, 3, 5, and 9 years posttransplant as well as rejection, electrolyte and laboratory abnormalities, osteoporosis, pneumonia, and Clostridium difficile infections. RESULTS Renal function did not significantly differ at any timepoint posttransplant. Rejection rates and Clostridium difficile infections were similar between groups; osteoporosis and pneumonia rates were numerically higher in the PPI treated arm but did not reach statistical significance. Proton pump inhibitor (PPI) treated patients were more likely to experience hypomagnesemia requiring supplementation. High dose PPI treated patients had significantly higher rates of pneumonia and osteoporosis compared with H2RA treated patients. Patients were maintained on PPI therapy for an average of 5 years and H2RA therapy for 3 years posttransplant, the majority without a clear indication for therapy. CONCLUSIONS There was no difference in renal function, rejection, or graft loss between PPI and H2RA treated patients. The majority of patients were maintained on PPI therapy for several years posttransplant without a clear indication; critical evaluation of ongoing need for acid suppressant therapy in the posttransplant course should be an area of future focus. KEY WORDS proton pump inhibitor, histamine-2 receptor antagonist, kidney transplantation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

See 1 more Smart Citation

Choice of Acid Suppressant Therapy and Long‐Term Graft Outcomes After Kidney Transplantation

January¹,

Progar²,

Nesselhauf³

et al. 2020

Pharmacotherapy

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“…Najnowsze doniesienia Makunts i wsp. [26] wskazują, że pacjenci, którzy stosowali preparaty IPP w monoterapii mają zwiększone ryzyko wystąpienia zarówno AKI, jak i rozwinięcia się przewlekłej choroby nerek. W swoich badaniach autorzy wykazali, że pacjenci przyjmujący omeprazol, esomeprazol, pantoprazol lub lanzoprazol w monoterapii mieli istotny wzrost częstości występowania incydentów AKI w porównaniu do osób stosujących H2-blokery.…”

Section: Schyłkowa Niewydolność Nerekunclassified

“…Publikacja wykazała statystycznie istotne 1,3-krotne zwiększenie ryzyka rozwinięcia przewlekłej choroby nerek oraz schyłkowej niewydolności nerek u pacjentów stosujących IPP, natomiast brak takiego ryzyka u pacjentów stosujących antagonistów H 2 R. Najnowsze badania Makunts i wsp. z 2019 r. [26] potwierdzają negatywny wpływ stosowania IPP na rozwój zarówno przewlekłej choroby nerek, jak i skrajnej ich niewydolności. Autorzy porównali dwie grupy pacjentów -przedstawiciele jednej z nich stosowali w monoterapii wyłącznie jeden z preparatów IPP, przedstawiciele drugiej -wybranego antagonistę receptora H 2 .…”

Section: Schyłkowa Niewydolność Nerekunclassified

The role of proton pump inhibitors in renal disease - the risk of using OTC drugs

Wolska¹,

Wolska²,

Kowalczyk³

et al. 2019

Farm Pol.

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Do proton pump inhibitors increase mortality? A systematic review and in‐depth analysis of the evidence

Ben‐Eltriki

Green

Maclure

et al. 2020

Pharmacology Res & Perspec

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Proton pump inhibitors (PPIs) were primarily approved for short‐term use (2 to 8 weeks). However, PPI use continues to expand. Widely believed to be safe, we reviewed emerging evidence on increased mortality with PPI long‐term use. Our 2016 systematic PPI drug class review found that mortality was not reported as an outcome in randomized controlled trials (RCTs) that directly compared different PPIs. We sought more recent and comprehensive data on PPI harm outcomes from research syntheses as a follow‐on. A search was conducted from January 2014 to January 2020. We searched MEDLINE, EMBASE, and Cochrane Central for evidence from systematic reviews (SRs) and primary studies reporting all‐cause mortality in adults treated with a PPI for any indication (duration >12 weeks) compared to patients without PPI treatment (no use, placebo, or H2RA use). Two independent investigators assessed study eligibility, synthesized evidence, and assessed the quality of the included studies. Data on all‐cause mortality were sought, analyzed, critically examined, and interpreted herein. From 1304 articles, one SR was identified that reported on all‐cause mortality. The SRs pooled three observational studies with data to 1 year: odds ratio, 95% confidence interval (CI) 1.53‐1.84. A RCT, the COMPASS (Cardiovascular Outcomes for People Using Anticoagulant Strategies) RCT with data to 3 years: hazard ratio (HR) 1.03, 95% CI 0.92‐1.15. The US Veterans Affairs cohort study using a large national dataset with data to 10 years found a HR of 1.17, 95% CI (1.10‐1.24) and (NNH) of 22. The most common causes of death were from cardiovascular and chronic kidney diseases, with an excess death of 15 and 4 per 1000 patients, respectively, over the 10‐year period. Harms arising from real‐world medication use are best evaluated using a pharmacovigilance “convergence of proof” approach using data from a variety of sources and various study designs. Given that most PPI indications for use recommended a treatment duration of less than 12 weeks, it seems clear that PPIs were significantly overused in older patients. The median exposure time to PPI ranged from 1 to 4.6 years. Signals of serious harms including increased mortality with long‐term PPI use are reported in observational studies. The COMPASS trial findings are not inconsistent with contemporaneous findings from observational studies. The COMPASS RCT was unlikely to detect an increase in mortality given the trial was not powered to detect this outcome. The potential increase in mortality in older patients associated with prolonged PPI exposure needs to be conveyed to health professionals. Clinicians and patients may be able to reverse the relentless expansion of long‐term PPI exposure by reviewing indications and considering potential harms as well as benefits.

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Analysis of postmarketing safety data for proton-pump inhibitors reveals increased propensity for renal injury, electrolyte abnormalities, and nephrolithiasis

Cited by 56 publications

References 50 publications

Choice of Acid Suppressant Therapy and Long‐Term Graft Outcomes After Kidney Transplantation

Choice of Acid Suppressant Therapy and Long‐Term Graft Outcomes After Kidney Transplantation

The role of proton pump inhibitors in renal disease - the risk of using OTC drugs

Do proton pump inhibitors increase mortality? A systematic review and in‐depth analysis of the evidence

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