1 The Risks and Benefits ofLong-term Use of Proton Pump inhibitors

2 Gastroenterological Association ( 2016 ) Expert Review and BestPractice Advice From the American Gastroenterological Association ( 2016 )

3 evaluate the risks associated with long-term use of proton BACKGROUND & AIMS: The purpose of this review is to evaluate the risks associated with long-term use of proton pump inhibitors (PPIs), focusing on long-term use of PPIs for three common indications: gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE), and non-steroidal anti-inflammatory drug (NSAID) bleeding prophylaxis.

4 What Are the Potential RisksAssociated With Long-term Use of PPIs?

5 Kidney Disease Case reports have linked PPIs to acuteinterstitial nephritis (AIN) and acute kidney injury (AKI) since 1992.

6 In 2016, two studies received widespreadattention because they connected PPIs to an excess risk for chronic kidney disease (CKD) not explained solely by risk for AKI.

7 The first of these studies, by Lazarus et al,examined a cohort of 10,482 patients who were actively followed and a larger cohort of 249,751 patients whose data was retrieved retrospectively.

8 After adjusting for confounders, the authorsfound that PPIs were associated with a 50% increase in the risk for CKD in the smaller cohort and a 17% risk increase in the larger cohort.

9 The second study, by Xie et al,compared 173,321 PPI users with 20,270 H2RA users in a VA dataset.

10 The authors included only patients whohad a normal eGFR at baseline, and followed patients for up to 5 years for incident CKD, defined as an eGFR of less than 60 ml/min/1.73 m2

11 They found a 1.8% absolute annualexcess risk for CKD associated with PPIs compared to H2RAs.

12 Also, the PPI-CKD relationship persisteddespite adjusting for AKI, implying that not all of the observed risk could be attributed to AIN.

13 Dementia Build-up of amyloid-b (A -Beta) proteinpredisposes to Alzheimer’s disease.

14 Microglial cells use V-type ATPasesto degrade amyloid-b, and PPIs may block V-ATPases to increase isoforms of amyloid-b in mice.

15 Haenisch et al followed 3,327 non-institutionalized German adults aged 75 years or more with serial neuropsychiatric examinations. PPIs were associated with a 38% increased risk for dementia, with similar risk increases for Alzheimer’s and non-Alzheimer’s dementia

16 Gomm et al extended these results byretrospectively querying an insurance database covering more than half of the German population over 75 years old. They found a 44% higher risk for dementia in regular users of PPIs compared to non-users.

17 Bone Fracture A link between PPIs and increased fracture risk ishypochlorhydria-associated malabsorption of calcium or vitamin B12, gastrin-induced parathyroid hyperplasia, and osteoclastic vacuolar proton pump inhibition.

18 The results regarding the presence of a dose- orduration-based response have also been inconsistent, as have studies that investigated the effect of PPI therapy on bone mineral density (BMD) based on dual-energy X-ray absorptiometry (DXA).

19 Using peripheral quantitative computertomography (QCT), a small crosssectional study reported that PPIs were associated with lower trabecular BMD but not cortical BMD.

20 By contrast, another cohort studyreported no effect of PPI therapy on hip v BMD based on QCT.

21 Currently, there are no data tosupport the routine use of bone mineral density monitoring among PPI users.

22 Myocardial InfarctionPPIs are primarily metabolized by the cytochrome P450 isoenzyme CYP2C19.

23 Because the anti-platelet drug clopidogrel isactivated by CYP2C19, there has been concern that PPIs may decrease clopidogrel’s anti- platelet effect.

24 The COGENT study, a randomizedcontrolled trial published in 2010, provided reassurance that PPIs do not meaningfully interact with clopidogrel.

25 COGENT randomized patientswho were receiving daily aspirin to a combination pill containing omeprazole and clopidogrel versus placebo.

26 When results from 3761 patients wereanalyzed, there was no difference in the cardiovascular event rate between omeprazole-clopidogrel (4.9%) compared to clopidogrel alone (5.7%).

27 Subsequently, it was postulated that PPIsmight increase risk for MI based on a different mechanism, ie, that they may directly blockade vascular nitric oxide synthase to enhance vascular contractivity

28 Infections Small intestinal bacterial overgrowth:Gastric acid is bactericidal and PPIs increase bacterial counts in the stomach and in the proximal small bowel.

29 Two studies used duodenal aspirates for thediagnosis of small intestinal bacterial overgrowth (SIBO) and a rigorous, self-controlled study design in which within-individual changes in bacterial counts were assessed before versus after PPIs.

30 Pereira et al found that PPIs increased theduodenal bacterial load but that participants remained asymptomatic whereas Lewis et al found both that PPIs increased bacterial counts and symptoms.

31 In these two studies, PPIs wereassociated with an over 20-fold relative risk for SIBO.

32 Overall, studies that have classified SIBOusing aspirates have found an 8-fold relative risk associated with PPIs whereas studies using breath testing have found a 2-fold relative risk.

33 Non-typhoidal Salmonella and Campylobacter.Patients with hypochlorhydria from pernicious anemia or from gastric surgery have increased rates of Salmonella infections.

34 Retrospective case-control studiesshow an approximately 3-fold relative risk for Salmonella or Campylobacter infections after exposure to PPIs.

35 is contradictory evidence from a retrospective study byBrophy et al which used a modified self-control study design to compare patients during the period before PPIs versus the period after PPIs.27 Inaccurate ascertainment of PPI exposure during the period before initiation of PPIs (eg, from intermittent use) would invalidate this study’s result, and all of the other studies have reached the opposite

36 Spontaneous bacterial peritonitis.Alterations in gut bacteria due to hypochlorhydria may lead to changes in intestinal permeability and translocation of bacteria across the gut wall.

37 Studies show a 2-fold relative risk forspontaneous bacterial peritonitis associated with exposure to PPIs.

38 Clostridium difficile infection. Although PPIs have no direct effect on pH in the colon, they appear to exert a significant “downstream” effect on colonic bacteria.

39 Bacterial taxa associated withClostridium difficile infection (CDI) were increased in the stool of healthy volunteers after 4-8 weeks of high-dose PPIs.

40 Observational studies show an approximately 50%relative risk for CDI associated with PPIs.

41 The risk associated with PPIs is modestcompared to traditional risk factors such as antibiotics, but some studies suggest that PPIs may be more important within specific populations—for example, in children.

42 Pneumonia. It has been hypothesized that, just as PPIsmay have a downstream effect on the colonic microbiome, they may have an “upstream” effect on the oropharyngeal microbiome which increases risk for pneumonia.

43 In observational studies, PPIs have beenassociated with increased risk for community-acquired pneumonia (CAP).

44 However, this risk is borne largely bythose who recently started PPIs rather than those using long-term PPIs.

45 This suggests either that PPIs are markersfor uncaptured acute events (eg, hospitalizations) or that they are being prescribed for early symptoms of undiagnosed pneumonia.

46 The OBERON study randomized 2426ambulatory adults to a PPI versus placebo for 26 weeks for the purpose of ulcer prevention and found similar rates of pneumonia (0.9% with PPIs vs 1.9% with placebo).

47 In a post hoc, manufacturer-sponsoredanalysis of 24 short-term RCTs, incidence of pneumonia was similar in patients randomized to PPIs compared to placebo.

48 Randomized studies of PPIs for stressulcer prophylaxis in the ICU have not shown an association between PPIs and ventilator-associated pneumonia.

49 Micronutrient DeficienciesGastric acidity is important for the absorption of minerals (eg, calcium, iron, magnesium) ingested as salts and dietary protein-bound vitamin B12.

50 A number of studies have investigatedwhether PPI-induced hypochlorhydria might result in clinically important micronutrient deficiencies.

51 Calcium. The existing data generallysupport the notion that profound acid suppression may interfere with calcium absorption.

52 However, this effect is not relevant forwater-soluble calcium salts or calcium contained in milk or cheese.

53 Furthermore, the malabsorption of waterinsolublecalcium in the setting of achlorhydria can be completely reversed when calcium is taken with a slightly acidic meal

54 Iron. Few studies have specificallyevaluated the potential association between PPIs and iron deficiency.

55 In patients with Zollinger-Ellison Syndrome, sixyears of PPIs was not associated with decreased total body iron stores or with iron deficiency.

56 On the other hand, in patients with hereditaryhemochromatosis, PPI use was associated with asignificant reduction in the absorption of non- heme iron in the short-term as well as a significant reduction in annual phlebotomy requirements in the long-term

57 Magnesium. Cases of profound hypomagnesemiaassociated with chronic PPI therapy have been reported since 2006

58 The relative rarity of these cases in theface of highly prevalent PPI use suggests that they may represent a form of idiosyncratic reaction.

59 Nevertheless, several observational studies havereported a modest positive association between PPI use and hypomagnesemia

60 Vitamin B12. Several studies have examined the associationbetween long-term PPI use and the risk of developing vitamin B12 deficiency; most48 but not all49 reported a 2-4-fold increased risk of B12 deficiency associated with PPI therapy.

61 Gastrointestinal MalignanciesPPIs have the potential to increase risk for gastrointestinal malignancies by facilitating gastric pan-colonization by Helicobacter pylori and by causing hypergastrinemia.

62 Studies in humans have not confirmedan association between PPIs and gastric cancer or gastric NETs.

63 In a population-based study, rates ofgastric cancer were elevated 5-fold in patients with GERD and similar diagnoses; in these patients, treatment with PPIs appeared to be a marker for cancer risk rather than a causative factor

64 In a pooled analysis of four RCTs, PPIswere not associated with gastric atrophy or other pre-malignant changes

65 In the SOPRAN and LOTUS trials, 812adults were randomized to antireflux surgery versus PPIs and followed with serial study biopsies.

66 After up to 12 years of follow-up, therewas no difference between groups in gastric pre-malignant changes or in gastric NETs.

67 There were few events in these trials, butthey mean that any absolute risk for gastric tumors related to PPIs would be very small.

68 Gastrin has a trophic effect on colonicepithelial cells in mice and on human colorectal cancers in vitro.

69 Thorburn et al analyzed gastrin levels in bankedserum from 250 patients with colorectal cancer and matched controls; median gastrin levels were similar in both groups, but an elevated gastrin was associated with a 4-fold relative increase in risk for colorectal cancer.

70 Subsequent population-basedretrospective studies have explored this and have uniformly failed to confirm that PPIs increase risk for colorectal cancer.

71 Colon cancers grow slowly, but therewas no change when these results were restricted to patients with 7 years of PPIs

72 What Are the Benefits of Using PPIsEvidence for the benefits of PPIs for GERD, Barrett’s, and NSAID bleeding prophylaxis is given in Table 3

73 Gastroesophageal Reflux DiseaseGastric acid has an inflammatory effect on the distal esophagus and short-term PPIs are highly effective in treating gastroesophageal reflux disease (GERD).

74 In complicated GERD, long-termmaintenance with PPIs prevents recurrence of esophagitis (80% PPIs vs 49% H2RAs) and esophageal strictures (46% PPIs vs 30% H2RAs).

75 In uncomplicated GERD, there is lesscertainty regarding the need for daily long-term maintenance with PPIs.

76 In a trial of patients with uncomplicated GERDwho responded to short-term PPIs and were subsequently randomized to “on-demand” PPIs versus placebo, 83% of patients using PPIs were symptom-free after six months compared to 56% of patients using placebo

77 Barrett’s esophagus For patients with symptomatic GERD andBarrett’s, PPI therapy is highly effective for symptom relief and may potentially offer a chemopreventive effect, particularly since symptomatic reflux is a known risk factor for esophageal adenocarcinoma (EAC).

78 In patients with Barrett’s esophagus whohave no symptoms of GERD, PPIs are prescribed primarily to reduce the risk of progression to EAC.

79 Epidemiologic studies generally support thispractice, but there is currently no randomized data directly demonstrating that PPIs prevent progression of Barrett’s to EAC.

80 Bleeding Prophylaxis in High-RiskPatients Who Take Nonsteroidal Anti-Inflammatory Drugs

81 Nonsteroidal anti-inflammatory drugs(NSAIDs) cause gastrointestinal mucosal damage through multiple mechanisms including inhibition of cyclooxygenase and a reduction in prostaglandins.

82 Acid suppression with PPIs reducesthis damage and thus reduces ulcer formation and ulcer related bleeding

83 In RCTs, there was a 10-15% absoluterisk reduction in ulcer formation and in ulcer-related bleeding in high-risk patients after 6-12 months of PPIs compared to placebo.

84 Balancing the Risks andBenefits of Long-term PPIs

85 Despite the long list of potential adverseeffects associated with PPI therapy, the quality of evidence underlying these associations is consistently low to very low

86 In addition, the magnitudes of absoluterisk increase for individual patients are modest, particularly at once daily dosing

87 We recommend that patients take long-term PPIs for complicated GERD, uncomplicated GERD with objective evidence of excess acid, Barrett’s esophagus with GERD symptoms, and NSAID bleeding prophylaxis if high-risk.

88 What Measures Can Be Used toMitigate the Potential Risks of Long-term PPI Therapy

89 Most patients with uncomplicated GERDcan be reduced from twice- to once- daily PPIs.

90 Patients with complicated GERD, on theother hand, are usually unable to successfully reduce PPIs

91 Perhaps the most challenging categoryof patients are those who respond symptomatically to a daily PPI but cannot reduce below this

92 Because such patients face lifelong PPItherapy, we recommend that evidence be sought for an acid-related disorder (eg, by performing ambulatory esophageal pH/ impedance monitoring).

93 This testing is likely to reveal a subset ofpatients who have a very poor correlation between symptoms and acidic reflux events; in these patients, strenuous efforts should be made to discontinue or reduce PPIs.

94 The literature regarding the use ofsupplements to ameliorate potential PPI risks is also limited.

95 Probiotics have shown a modest benefitin preventing antibiotic-associated diarrhea but have never been tested to prevent infections in long-term users of PPIs

96 Because the absolute rates of infectionsare extremely low, probiotics are unlikely to confer a benefit in this setting.

97 Supplementation of calcium andvitamin D does not conclusively decrease risk for fracture

98 Therefore, it is unlikely that a policy of routinelysupplementing long-term users of PPIs with calcium, vitamin D, or other vitamins would be of benefit

99 Similarly, we cannot recommend routineBMD testing, or routine monitoring of vitamin or mineral levels in long-term users of PPIs

100 In sum, the best current strategies for mitigatingthe potential risks of long-term PPIs are to avoid prescribing them when they are not indicated and to reduce them to their minimum dose when they are indicated

101 Conclusions Baseline differences between PPI usersand non-users make it challenging to study potential PPI adverse effects retrospectively.

102 Despite a large number of studies, theoverall quality of evidence for PPI adverse effects is low to very low.

103 When PPIs are appropriately prescribed,their benefits are likely to outweigh their risks.

104 When PPIs are inappropriatelyprescribed, modest risks become important because there is no potential benefit.

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