Review Article | Published:

Proton-pump inhibitors: understanding the complications and risks

Nature Reviews Gastroenterology & Hepatology volume 14, pages 697710 (2017) | Download Citation

Abstract

Proton-pump inhibitors (PPIs) are the most effective therapy for the full spectrum of gastric-acid-related diseases. However, in the past decade, a steadily increasing list of complications following long-term use of PPIs has been reported. Their potent acid-suppressive action induces several structural and functional changes within the gastric mucosa, including fundic gland polyps, enterochromaffin-like cell hyperplasia and hypergastrinaemia, which can be exaggerated in the presence of Helicobacter pylori infection. As discussed in this Review, most associations of PPIs with severe adverse events are not based on sufficient evidence because of confounding factors and a lack of plausible mechanisms. Thus, a causal relationship remains unproven in most associations, and further studies are needed. Awareness of PPI-associated risks should not lead to anxiety in patients but rather should induce the physician to consider the appropriate dosing and duration of PPI therapy, including long-term monitoring strategies in selected groups of patients because of their individual comorbidities and risk factors.

Key points

  • Proton-pump inhibitors (PPIs) induce structural and functional changes in the gastric mucosa related to potent acid suppression, which are exaggerated during Helicobacter pylori infection; PPIs alone are unlikely to be related to gastric and gastrointestinal malignancies

  • The list of adverse events associated with PPI intake is increasing; few of these associations are plausible or proven to have a causal relationship

  • The risk of bacterial enteric infections with Clostridium difficile, Salmonella and Campylobacter is increased in patients on PPI therapy — this risk is low to modest

  • PPI use can rarely cause acute kidney injury and other morbid conditions related to idiosyncratic effects

  • Long-term PPI intake interferes with magnesium and calcium homeostasis in small subsets of patients with chronic kidney disease on diuretic therapy; the prevalence of bone fractures attributable to PPIs in older patients is low

  • The debate on whether PPIs increase the risk of coronary events in patients on clopidogrel seems to be resolved; the FDA recommends avoiding omeprazole in patients taking clopidogrel

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References

  1. 1.

    Proton pump inhibitors. Drugwatch (2017).

  2. 2.

    Statista. Top 20 pharmaceutical products by sales worldwide in 2014 (in billions US dollars). Statista (2017).

  3. 3.

    Omeprazole (correction of omepraxole) and ocular damage. Concerns on safety of drug are unwarranted. BMJ 316, 7124–7167 (1998).

  4. 4.

    , , & Omeprazole-induced pseudohypertrophy of gastric parietal cells. Z. Gastroenterol. 30, 134–138 (1992).

  5. 5.

    et al. Gastric exocrine and endocrine cell morphology under prolonged acid inhibition therapy: results of a 5-year follow-up in the LOTUS trial. Aliment. Pharmacol. Ther. 36, 959–971 (2012). A controlled study on the long-term effect of PPIs on endocrine and exocrine gastric cells.

  6. 6.

    et al. Parietal cell protrusions and fundic gland cysts during omeprazole maintenance treatment. Hum. Pathol. 31, 684–690 (2000).

  7. 7.

    , & Effects of very long (up to 10 years) proton pump blockade on human gastric mucosa. Digestion 64, 205–213 (2001).

  8. 8.

    , , , & Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology. Aliment. Pharmacol. Ther. 42, 649–663 (2015). This systematic review reports on long-term PPI-induced moderate hypergastrinaemia in most patients and an increased prevalence of enterochromaffin-like cell hyperplasia; Helicobacter pylori-positive patients receiving long-term PPI therapy were exposed to a higher risk of corpus atrophy than were H. pylori-negative patients.

  9. 9.

    Gastric acid secretion. Curr. Opin. Gastroenterol. 32, 452–460 (2016).

  10. 10.

    , , & Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 137, 80–87 (2009).

  11. 11.

    , & Gastric Polyps Study Group. Incidence and risk factor of fundic gland polyp and hyperplastic polyp in long-term proton pump inhibitor therapy: a prospective study in Japan. J. Gastroenterol. 45, 618–624 (2010).

  12. 12.

    , & Systematic review with meta-analysis: fundic gland polyps and proton pump inhibitors. Aliment. Pharmacol. Ther. 44, 915–925 (2016).

  13. 13.

    , , , & Use of proton pump inhibitors and risks of fundic gland polyps and gastric cancer: systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 14, 1706–1719 (2016). The latest systematic review and meta-analysis reporting that PPI use increases the incidence of fundic gland polyps; a small effect on gastric cancer is biased by confounding factors.

  14. 14.

    et al. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome. Gut 61, 774–779 (2012).

  15. 15.

    et al. Familial fundic gland polyposis with gastric cancer. Gut 61, 1103–1104 (2012).

  16. 16.

    et al. Serum chromogranin A as a screening test for gastric enterochromaffin-like cell hyperplasia during acid-suppressive therapy. Eur. J. Clin. Invest. 31, 802–811 (2001).

  17. 17.

    , & Are proton pump inhibitors really so dangerous? Dig. Liver Dis. 48, 851–859 (2016).

  18. 18.

    , , , & Does long-term profound inhibition of gastric acid secretion increase the risk of ECL cell-derived tumors in man? Scand. J. Gastroenterol. 51, 767–773 (2016).

  19. 19.

    et al. Gastric carcinoids after long-term use of a proton pump inhibitor. Aliment. Pharmacol. Ther. 36, 644–649 (2012).

  20. 20.

    et al. Effect of proton-pump inhibitor therapy on serum chromogranin a level. Digestion 84, 22–28 (2011).

  21. 21.

    et al. PPI-delayed diagnosis of gastrinoma: oncologic victim of pharmacologic success. Pathol. Oncol. Res. 16, 87–91 (2010).

  22. 22.

    et al. Role of proton pump inhibitors in preventing hypergastrinemia-associated carcinogenesis and in antagonizing the trophic effect of gastrin. J. Physiol. Pharmacol. 66, 159–167 (2015). Experimental evidence of anti-carcinogenetic effects of PPIs — these results are awaiting clinical confirmation.

  23. 23.

    et al. Proton pump inhibitors and risk of gastric cancer: a population-based cohort study. Br. J. Cancer. 100, 1503–1507 (2009).

  24. 24.

    , , & Long-term use of proton pump inhibitors does not affect the frequency, growth, or histologic caracteristics of colon adenomas. Aliment. Pharmacol. Ther. 26, 1051–1061 (2007).

  25. 25.

    et al. Proton pump inhibitor use and risk of colorectal cancer: a population-based, case-control study. Gastroenterology 133, 755–760 (2007).

  26. 26.

    , & Proton pump inhibitors on pancreatic cancer risk and survival. Cancer Epidemiol. 46, 80–84 (2017).

  27. 27.

    et al. Increase of Helicobacter pylori-associated corpus gastritis during acid suppressive therapy: implications for long-term safety. Am. J. Gastroenterol. 90, 1401–1406 (1995).

  28. 28.

    , & Peptic ulcer disease. Lancet 374, 1449–1461 (2009).

  29. 29.

    et al. The stomach in health and disease. Gut 64, 1650–1668 (2015). A comprehensive update on all aspects of gastric functions.

  30. 30.

    et al. Changes in the intragastric distribution of H. pylori during treatment with omeprazole. Gut 36, 12–16 (1995).

  31. 31.

    , , , & Changes in Helicobacter pylori-induced gastritis in the antrum and corpus during 12 months of treatment with omeprazole and lansoprazole in patients with gastro-oesophageal reflux disease. Aliment. Pharmacol. Ther. 12, 247–253 (1998).

  32. 32.

    et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N. Engl. J. Med. 334, 1018–1022 (1996).

  33. 33.

    , , , & Gastric mucosa during treatment with lansoprazole: Helicobacter pylori is a risk factor for argyrophil cell hyperplasia. Gastroenterology 112, 707–717 (1997).

  34. 34.

    et al. Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial. Aliment. Pharmacol. Ther. 23, 639–647 (2006).

  35. 35.

    et al. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 66, 6–30 (2017). This manuscript presents the latest recommendations on the management of Helicobacter pylori infection and the role of PPIs.

  36. 36.

    , , De , & Double gastric infection with Helicobacter pylori and non-Helicobacter pylori bacteria during acid-suppressive therapy: increase of pro-inflammatory cytokines and development of atrophic gastritis. Aliment. Pharmacol. Ther. 8, 1163–1175 (2001).

  37. 37.

    , , , & H. pylori and its modulation of gastrointestinal microbiota. J. Dig. Dis. 16, 109–117 (2015).

  38. 38.

    et al. Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology 149, 883–885 (2015).

  39. 39.

    et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut 65, 749–756 (2016). References 37 and 38 provide novel insights into the effect of PPIs on gut microbiota composition.

  40. 40.

    et al. Proton pump inhibitors affect the gut microbiome. Gut 65, 740–748 (2016).

  41. 41.

    et al. A comparison of the gut microbiome between long-term users and non-users of proton pump inhibitors. Aliment. Pharmacol. Ther. 43, 974–984 (2016).

  42. 42.

    , , & Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin. Gastroenterol. Hepatol. 8, 504–508 (2010).

  43. 43.

    et al. Proton pump inhibitor therapy use does not predispose to small intestinal bacterial overgrowth. Am. J. Gastroenterol. 107, 730–735 (2012).

  44. 44.

    & Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin. Gastroenterol. Hepatol. 11, 483–490 (2013).

  45. 45.

    , , , & Dysmotility and proton pump inhibitor use are independent risk factors for small intestinal bacterial and/or fungal overgrowth. Aliment. Pharmacol. Ther. 37, 1103–1111 (2013).

  46. 46.

    , , , & Small intestinal bacterial overgrowth is associated with irritable bowel syndrome and is independent of proton pump inhibitor usage. BMC Gastroenterol. 16, 67 (2016).

  47. 47.

    , & Systematic review of the risk of enteric infection in patients taking acid suppression. Am. J. Gastroenterol. 102, 2047–2056 (2007).

  48. 48.

    , , , & Risk factors for Salmonella Enteritidis and Typhimurium (DT104 and non-DT104) infections in the Netherlands: predominant roles for raw eggs in Enteritidis and sandboxes in Typhimurium infections. Epidemiol. Infect. 134, 617–626 (2006).

  49. 49.

    & Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment. Pharmacol. Ther. 34, 1269–1281 (2011).

  50. 50.

    , , , & Proton pump inhibitors and gastroenteritis. Eur. J. Epidemiol. 31, 1057–1063 (2016).

  51. 51.

    et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am. J. Gastroenterol. 107, 1011–1019 (2012).

  52. 52.

    et al. Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis. PLoS ONE 7, e50836 (2012).

  53. 53.

    et al. Assessing the risk of hospital-acquired Clostridium difficile infection with proton pump inhibitor use: a meta-analysis. Infect. Control Hosp. Epidemiol. 28, 1–10 (2016). A meta-analysis suggesting an almost twofold increased risk of hospital-acquired Clostridium difficile infection in patients on PPIs.

  54. 54.

    , , , & Reducing co-administration of proton pump inhibitors and antibiotics using a computerized order entry alert and prospective audit and feedback. BMC Infect. Dis. 16, 355 (2016).

  55. 55.

    & Microscopic colitis associated with lansoprazole: report of two cases and a review of the literature. Scand. J. Gastroenterol. 42, 530–533 (2007).

  56. 56.

    & Microscopic colitis associated with omeprazole and esomeprazole exposure. J. Clin. Gastroenterol. 43, 551–553 (2009).

  57. 57.

    et al. Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case-control study. Aliment. Pharmacol. Ther. 32, 1124–1128 (2010).

  58. 58.

    et al. High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors. Aliment. Pharmacol. Ther. 43, 1004–1013 (2016).

  59. 59.

    et al. Proton pump inhibitor use and risk of spontaneous bacterial peritonitis in cirrhotic patients: a systematic review and meta-analysis. Genet. Mol. Res. 14, 7490–7501 (2015).

  60. 60.

    et al. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study. J. Hepatol. 62, 1056–1060 (2015).

  61. 61.

    , , & Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites. Hepatology 64, 1265–1272 (2016). A relevant study showing that PPIs increase the risk of developing hepatic encephalopathy and spontaneous bacterial peritonitis in patients with liver cirrhosis.

  62. 62.

    & Proton pump inhibitor-associated pneumonia: not a breath of fresh air after all? World J. Gastrointest. Pharmacol. Ther. 2, 17–26 (2011).

  63. 63.

    et al. Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis of randomized trials. Crit. Care 20, 120 (2016).

  64. 64.

    , , & Gastric acid-suppressive therapy and community-acquired respiratory infections. Aliment. Pharmacol. Ther. 18, 847–851 (2003).

  65. 65.

    et al. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis. CMAJ 183, 310–319 (2011).

  66. 66.

    et al. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis. Gut 63, 552–558 (2014).

  67. 67.

    & Frequency and time to onset of community-acquired respiratory tract infections in patients receiving esomeprazole: a retrospective analysis of patient-level data in placebo-controlled studies. Aliment. Pharmacol. Ther. 42, 607–613 (2015). A large cohort study of a PPI (esomeprazole) that disproves the risk of community-acquired pneumonia.

  68. 68.

    et al. Adverse event reporting for proton pump inhibitor therapy: an overview of systematic reviews. Otolaryngol. Head Neck Surg. 155, 547–554 (2016).

  69. 69.

    et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 73, 410–416 (2016). This study was an adverse event report showing a significantly increased risk of incident dementia in conjunction with PPI use; this report caused great concern in the general public.

  70. 70.

    , , , & Risk factors for dementia diagnosis in German primary care practices. Int. Psychogeriatr. 28, 1059–1065 (2016).

  71. 71.

    & Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors? Eur. J. Clin. Pharmacol. 62, 473–479 (2006).

  72. 72.

    , & Acute interstitial nephritis due to omeprazole. Am. J. Med. 93, 472–473 (1992).

  73. 73.

    & Drug-induced acute interstitial nephritis. Nat. Rev. Nephrol. 6, 461–470 (2010).

  74. 74.

    et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am. J. Kidney Dis. 64, 558–566 (2014).

  75. 75.

    , & PPIs and kidney disease: from AIN to CKD. J. Nephrol. 29, 611–616 (2016).

  76. 76.

    , , & A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int. 86, 837–844 (2014).

  77. 77.

    et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open 3, E166–E171 (2015).

  78. 78.

    , , & Proton pump inhibitors and acute interstitial nephritis. Clin. Gastroenterol. Hepatol. 4, 597–604 (2006).

  79. 79.

    et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern. Med. 176, 238–246 (2016). This study report comprehensive data showing that PPI use is associated with a low risk of incident chronic kidney disease.

  80. 80.

    et al. Proton pump inhibitors and risk of incident CKD and progression to ESRD. J. Am. Soc. Nephrol. 10, 3153–3163 (2016).

  81. 81.

    et al. Proton pump inhibitors and risk of 1-year mortality and rehospitalization in older patients discharged from acute care hospitals. JAMA Intern. Med. 173, 518–523 (2013).

  82. 82.

    , & Proton pump inhibitor therapy for peptic ulcer bleeding: Cochrane collaboration meta-analysis of randomized controlled trials. Mayo Clin. Proc. 82, 286–296 (2007).

  83. 83.

    , , & Proton pump inhibitor and histamine 2 receptor antagonist use and vitamine B12 deficiency. JAMA 310, 2435–2442 (2013).

  84. 84.

    Effect of proton pump inhibitors on vitamins and iron. Am. J. Gastroenterol. 104, S5–S9 (2009).

  85. 85.

    et al. Oxyntic gastric atrophy in Helicobacter pylori gastritis is distinct from autoimmune gastritis. J. Clin. Pathol. 69, 677–685 (2016).

  86. 86.

    , & Magnesium deficiency: pathophysiologic and clinical overview. Am. J. Kidney Dis. 24, 737–752 (1994).

  87. 87.

    , & Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N. Engl. J. Med. 355, 1834–1836 (2006).

  88. 88.

    et al. A case series of proton pump inhibitor-induced hypomagnesemia. Am. J. Kidney Dis. 56, 112–116 (2010).

  89. 89.

    & Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM 103, 387–395 (2010).

  90. 90.

    , , & Proton pump inhibitor-associated hypomagnesemia: what do FDA data tell us? Ann. Pharmacother. 47, 773–780 (2013).

  91. 91.

    Recent developments in intestinal magnesium absorption. Curr. Opin. Gastroenterol. 24, 230–235 (2008).

  92. 92.

    et al. TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J. Biol. Chem. 279, 19–25 (2004).

  93. 93.

    et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat. Genet. 31, 166–170 (2002).

  94. 94.

    et al. Proton pump inhibitors and hospitalization with hypomagnesemia: a population-based case-control study. PLoS Med. 11, e1001736 (2014). A population-based case–control study showing an increased risk of hospitalization with hypomagnesaemia in patients on PPIs that are also receiving diuretics.

  95. 95.

    , & Proton pump inhibitors are associated with lower magnesium levels in older people with chronic kidney disease. J. Am. Geriatr. Soc. 60, 392–393 (2012).

  96. 96.

    et al. Proton-pump inhibitor use is associated with low serum magnesium concentrations. Kidney Int. 83, 692–699 (2013).

  97. 97.

    , , & The relationship between proton pump inhibitor use and serum magnesium concentration among hemodialysis patients: a cross-sectional study. BMC Nephrol. 16, 136 (2015).

  98. 98.

    et al. Low prevalence of hypomagnesemia in long-term recipients of proton pump inhibitors in a managed care cohort. Clin. Gastroenterol. Hepatol. 14, 317–321 (2016). An important study showing that, in the absence of known precipitating factors (concomitant diuretic intake, chronic diarrhoea, chronic kidney disease and malignancies), chronic PPI use is not associated with hypomagnesaemia.

  99. 99.

    et al. Hypomagnesemia among outpatient long-term proton pump inhibitor users. Am. J. Ther. 24, e52–e55 (2017).

  100. 100.

    & Hypomagnesaemia/hypokalemia associated with the use of esomeprazole. Curr. Drug Saf. 6, 204–206 (2011).

  101. 101.

    , , , & Severe acute neurological symptoms related to proton pump inhibitors induced hypomagnesemia responsible for profound hypoparathyroidism with hypocalcemia. Clin. Res. Hepatol. Gastroenterol. 38, e103–e105 (2014).

  102. 102.

    & Proton pump inhibitors and risk of bone fractures. Curr. Treat. Options Gastroenterol. 12, 414–423 (2014).

  103. 103.

    & Apical acidity decreases inhibitory effect of omeprazole on Mg(2+) absorption and claudin-7 and -12 expression in Caco-2 monolayers. Exp. Mol. Med. 44, 684–693 (2012).

  104. 104.

    , , , & Omeprazole enhances the colonic expression of the Mg(2+) transporter TRPM6. Pflugers Arch. 465, 1613–1620 (2013).

  105. 105.

    , , , & Dietary inulin fibers prevent proton-pump inhibitor (PPI)-induced hypocalcemia in mice. PLoS ONE 10, e0138881 (2015).

  106. 106.

    et al. Inhibiting gastric acid production does not affect intestinal calcium absorption in young, healthy individuals: a randomized, crossover, controlled clinical trial. J. Bone Miner. Res. 25, 2205–2211 (2010).

  107. 107.

    et al. Do proton pump inhibitors decrease calcium absorption? J. Bone Miner. Res. 25, 2786–2795 (2010).

  108. 108.

    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. 41, 1162–1174 (2015). This study shows data from controlled randomized trials with reassuring findings on long-term PPI use, electrolytes and micronutrients.

  109. 109.

    , & Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif. Tissue Int. 79, 76–83 (2006).

  110. 110.

    , , & Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296, 2947–2953 (2006).

  111. 111.

    et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 179, 319–326 (2008).

  112. 112.

    et al. Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis. Eur. J. Gastroenterol. Hepatol. 9, 794–800 (2011).

  113. 113.

    , , , & Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am. J. Gastroenterol. 106, 1209–1218 (2011).

  114. 114.

    , , & Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology 139, 93–101 (2010).

  115. 115.

    & Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 28, 951–959 (2008).

  116. 116.

    , , & Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 138, 896–904 (2010). An accurate study shedding light on the association between PPIs and osteoporosis or accelerated bone mineral density loss.

  117. 117.

    , & Gastroesophageal reflux disease with proton pump inhibitor use is associated with an increased risk of osteoporosis: a nationwide population-based analysis. Osteoporos. Int. 27, 2117–2126 (2016).

  118. 118.

    , & Clopidogrel-proton pump inhibitor drug-drug interaction and risk of adverse clinical outcomes among PCI-treated ACS patients: a meta-analysis. J. Manag. Care Spec. Pharm. 22, 939–947 (2016). A meta-analysis of randomized controlled trials and observational studies, showing that concomitant clopidogrel–PPI therapy following percutaneous coronary intervention is significantly associated with adverse cardiovascular events.

  119. 119.

    et al. Individual proton pump inhibitors and outcomes in patients with coronary artery disease on dual antiplatelet therapy: a systematic review. J. Am. Heart Assoc. 4, e002245 (2015).

  120. 120.

    et al. Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review. Circ. Cardiovasc. Qual. Outcomes 8, 47–55 (2015).

  121. 121.

    , , , & Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin. J. Thromb. Haemost. 4, 2508–2509 (2006).

  122. 122.

    et al. Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome: a systematic review. Heart 99, 520–527 (2013).

  123. 123.

    et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am. Heart J. 157, 148.e1–148.e5 (2009).

  124. 124.

    et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J. Clin. Pharmacol. 48, 475–484 (2008).

  125. 125.

    , et al. Clopidogrel with or without omeprazole in coronary artery disease. N. Engl. J. Med. 363, 1909–1917 (2010).

  126. 126.

    , , & Early use of omeprazole benefits patients with acute myocardial infarction. J. Thromb. Thrombolysis 28, 282–287 (2009).

  127. 127.

    FDA. FDA reminder to avoid concomitant use of Plavix (clopidogrel) and omeprazole. FDA (2016).

  128. 128.

    et al. Genetic determinants of response to clopidogrel and cardiovascular events. N. Engl. J. Med. 360, 363–375 (2009).

  129. 129.

    & The pharmacogenetics of CYP 2C9 and CYP2C19: ethnic variation and clinical significance. Curr. Clin. Pharmacol. 2, 93–109 (2007).

  130. 130.

    , & Dilemma between gastroprotection and cardiovascular prevention. Dtsch. Med. Wochenschr. 135, 2193–2198 (2010).

  131. 131.

    et al. Clinical outcomes associated with proton pump inhibitor use among clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial infarction. Pharmacogenomics J. 15, 20–25 (2015).

  132. 132.

    & Proton pump inhibitor and clopidogrel interaction: fact or fiction? Am. J. Gastroenterol. 105, 34–41 (2010).

  133. 133.

    FDA. Information for healthcare professionals: update to the labeling of clopidogrel bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). FDA (2009).

  134. 134.

    , & Systematic review: impaired drug absorption related to the co-administration of antisecretory therapy. Aliment. Pharmacol. Ther. 29, 1219–1229 (2009).

  135. 135.

    The absorption of warfarin from the rat stomach in situ. Med. Biol. 54, 260–263 (1976).

  136. 136.

    et al. Effective and safe proton pump inhibitor therapy in acid-related diseases - a position paper addressing benefits and potential harms of acid suppression. BMC Med. 14, 179 (2016). A position statement on the benefits, harms and appropriateness of PPI use.

  137. 137.

    , , , & Drug interaction studies with dexlansoprazole modified release (TAK-390MR), a proton pump inhibitor with a dual delayed-release formulation: results of four randomized, double-blind, crossover, placebo-controlled, single-centre studies. Clin. Drug Investig. 29, 35–50 (2009).

  138. 138.

    et al. The potential drug-drug interaction between proton pump inhibitors and warfarin. Pharmacoepidemiol. Drug Saf. 24, 1337–1340 (2015).

  139. 139.

    et al. Does gastric acid suppression affect sunitinib efficacy in patients with advanced or metastatic renal cell cancer? J. Oncol. Pharm. Pract. 21, 194–200 (2015).

  140. 140.

    et al. Gastric acid suppression is associated with decreased erlotinib efficacy in non-small-cell lung cancer. Clin. Lung Cancer 16, 33–39 (2015).

  141. 141.

    et al. Influence of the acidic beverage cola on the absorption of erlotinib in patients with non-small-cell lung cancer. J. Clin. Oncol. 34, 1309–1314 (2016).

  142. 142.

    et al. Association of proton pump inhibitors and capecitabine efficacy in advanced gastroesophageal cancer: secondary analysis of the TRIO-013/LOGiC randomized clinical trial. JAMA Oncol. 3, 767–773 (2017). A secondary analysis of a phase III randomized trial, showing that PPIs negatively affect capecitabine efficacy, possibly by raising gastric pH levels; PPI-treated patients with advanced gastro-oesophageal cancer receiving capecitabine-based polychemotherapy had poorer progression-free survival and overall survival than those not treated with PPIs.

  143. 143.

    et al. Effect of food and a proton pump inhibitor on the pharmacokinetics of S-1 following oral administration of S-1 in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 69, 753–761 (2012).

  144. 144.

    et al. Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation 128, 845–853 (2013).

  145. 145.

    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. 15, 267–274 (2010).

  146. 146.

    et al. Asymmetric dimethylarginine as an independent risk marker for mortality in ambulatory patients with peripheral arterial disease. J. Intern. Med. 269, 349–361 (2011).

  147. 147.

    et al. Proton pump inhibitors and vascular function: a prospective cross-over pilot study. Vasc. Med. 4, 309–316 (2015).

  148. 148.

    et al. Proton pump inhibitors accelerate endothelial senescence. Circ. Res. 118, e36–e42 (2016).

  149. 149.

    Pathogenesis of endothelial cell dysfunction in chronic kidney disease: a retrospective and what the future may hold. Kidney Res. Clin. Pract. 34, 76–82 (2015).

  150. 150.

    et al. Vascular dysfunction in the pathogenesis of Alzheimer's disease — a review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiol. Dis. 82, 593–606 (2015).

  151. 151.

    et al. The assessment of endothelial function: from research into clinical practice. Circulation 126, 753–767 (2012).

  152. 152.

    et al. Management of Helicobacter pylori infection — the Maastricht IV/ Florence Consensus Report. Gut 61, 646–664 (2012).

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Affiliations

  1. Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University Hospital, Leipziger Strasse 44, 39120 Magdeburg, Germany.

    • Peter Malfertheiner
    • , Arne Kandulski
    •  & Marino Venerito

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Contributions

All authors contributed equally to the writing and reviewing of the draft manuscript.

Competing interests

P.M. is a member of the advisory boards for Allergan, Alfa Wassermann and Bayer and has taken part in speakers' bureaus for Allergan, AstraZeneca, Reckitt Benckiser and Takeda. M.V. is a member of the advisory boards for Amgen, Lilly and Nordic and has taken part in a speakers' bureau for Bayer and Merck Serono. A.K. declares no competing interests.

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Correspondence to Peter Malfertheiner.

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DOI

https://doi.org/10.1038/nrgastro.2017.117

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