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Proton Pump Proton Pump Inhibitors Inhibitors Tom Miller Tom Miller

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Page 1: Proton Pump Inhibitors

Proton Pump Proton Pump InhibitorsInhibitorsTom MillerTom Miller

Page 2: Proton Pump Inhibitors

PPIsPPIs Available since late 80’sAvailable since late 80’s One of the most frequently prescribed One of the most frequently prescribed

classes of drug worldwideclasses of drug worldwide £425m in England in 2006 (25m Rx)£425m in England in 2006 (25m Rx)11

OverprescribedOverprescribed2,32,3 Good efficacyGood efficacy Safe…Safe…

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BNFBNF Common: Common:

– GI, headache, dizziness.GI, headache, dizziness. Less common: Less common:

– Dry mouth, insomnia, drowsiness, malaise, blurred Dry mouth, insomnia, drowsiness, malaise, blurred vision, rash and pruritis.vision, rash and pruritis.

Rare: Rare: – Liver dysfunction, oedema, hypersensitivity Liver dysfunction, oedema, hypersensitivity

reactions, photosensitivity, photophobia, fever, reactions, photosensitivity, photophobia, fever, sweating, depression, interstitial nephritis, blood sweating, depression, interstitial nephritis, blood disorders, arthralgia, myalgia, skin reactions.disorders, arthralgia, myalgia, skin reactions.

May increase risk of gastro-intestinal May increase risk of gastro-intestinal infections infections

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A few extra…A few extra… C-difficileC-difficile Hip FracturesHip Fractures PneumoniaPneumonia B12 deficiencyB12 deficiency

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C-difficileC-difficile; The ; The EvidenceEvidence

Systematic reviewSystematic review Cohorts and case-controlsCohorts and case-controls Animal modelsAnimal models

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Systematic reviewSystematic review44Leonard Leonard et alet al. J Am Gastroenterology 2007;102:2047-. J Am Gastroenterology 2007;102:2047-

20562056

Objective – Evaluate associations between Objective – Evaluate associations between acid suppression and enteric infectionacid suppression and enteric infection

Data Sources – MEDLINE, EMBASE and Data Sources – MEDLINE, EMBASE and CINAHLCINAHL

Selection – Observational studies including Selection – Observational studies including cross-sectional, case control and cohort cross-sectional, case control and cohort that evaluated risk of enteric infection that evaluated risk of enteric infection associated with antisecretory therapy.associated with antisecretory therapy.

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Data SynthesisData Synthesis12 papers, 2948 patients with 12 papers, 2948 patients with C-diffC-diff.. Increased risk of taking antisecretory Increased risk of taking antisecretory

therapy therapy – Pooled OR 1.94 (95% CI 1.37-2.75) Pooled OR 1.94 (95% CI 1.37-2.75)

Significant heterogeneity p=0.0006Significant heterogeneity p=0.0006 Association greater for PPI vs. H2RAAssociation greater for PPI vs. H2RA

Salmonella and Compylobacter Salmonella and Compylobacter – OR 2.55 (95% CI 1.53-4.26) again with OR 2.55 (95% CI 1.53-4.26) again with

heterogeneity and greater for PPIsheterogeneity and greater for PPIs

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Cohort and Case Cohort and Case ControlControl

Risk of Risk of Clostridium difficileClostridium difficile diarrhoea among hospital diarrhoea among hospital inpatients prescribed proton inpatients prescribed proton pump inhibitorspump inhibitors

Dial Dial et alet al. CMAJ 2004;171(1):33-8. CMAJ 2004;171(1):33-8

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CohortCohort 1187 patients from pharmacy database 1187 patients from pharmacy database

receiving abx in an 8 month periodreceiving abx in an 8 month period 2 Medical and one Cardiothoracic 2 Medical and one Cardiothoracic

sugical wardsugical ward Analysis of meds, ward, number and Analysis of meds, ward, number and

type of abx and type of acid suppressive type of abx and type of acid suppressive therapytherapy

Positive toxin assay as recorded with Positive toxin assay as recorded with infection controlinfection control

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Case-controlCase-control To control for ‘sicker patients’ with added To control for ‘sicker patients’ with added

risk factors for risk factors for C-diffC-diff Separate hospital, same timeSeparate hospital, same time Cases (94) were consecutive patients with Cases (94) were consecutive patients with

history of diarrhoea and positive history of diarrhoea and positive C-diffC-diff toxin toxin assay (new patients).assay (new patients).

Controls (94) had abx but no Controls (94) had abx but no C-diff, C-diff, type type matched for age, type and number of abx, matched for age, type and number of abx, Charlston co-morbidity indexCharlston co-morbidity index

Average ages 75.5 and 73.0Average ages 75.5 and 73.0 PPI exposure at least 3 daysPPI exposure at least 3 days

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ResultsResults Cohort Cohort

– Those taking PPIs had RR of 2.1 (1.4-Those taking PPIs had RR of 2.1 (1.4-3.4) of developing 3.4) of developing C-diff C-diff diarrhoeadiarrhoea

– Remained significant after Remained significant after multivariate analysis for ward type multivariate analysis for ward type and abx numbersand abx numbers

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Case-controlCase-control– Unadjusted OR 3.1 (1.7-5.6), Unadjusted OR 3.1 (1.7-5.6),

significant after adjustment for other significant after adjustment for other significant factorssignificant factors

– Extended use >6 months OR 6.9 (2.3-Extended use >6 months OR 6.9 (2.3-20.8)20.8)

– Of 21 pts experiencing 1 or more Of 21 pts experiencing 1 or more relapse 19 (90%) were Rx PPI OR 5.2 relapse 19 (90%) were Rx PPI OR 5.2 (1.1-24.6)(1.1-24.6)

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DiscussionDiscussion Controlled for number of abx and Controlled for number of abx and

co-morbiditiesco-morbidities In cohort greater effect seen with In cohort greater effect seen with

low-risk abxlow-risk abx Time and dose relevanceTime and dose relevance Omeprazole and Pantoprazole = Omeprazole and Pantoprazole =

class effectclass effect

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Case-control 2Case-control 2 Proton pump inhibitor therapy is a Proton pump inhibitor therapy is a

risk factor of risk factor of Clostridium difficileClostridium difficile--associated diarrhoeaassociated diarrhoea

Yearsley Yearsley et alet al. Aliment Pharmacol . Aliment Pharmacol Ther 2006;24:613-619.Ther 2006;24:613-619.

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MethodsMethods 155 patients with CDAD, 153 155 patients with CDAD, 153

controls.controls. Controls chosen as patients on Controls chosen as patients on

same ward with closest DOBsame ward with closest DOB Mean age 79.1 and 78.7Mean age 79.1 and 78.7

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ResultsResults PPI: OR 2.03 (1.21-3.41) p=0.004PPI: OR 2.03 (1.21-3.41) p=0.004 Abx and acid suppression OR 1.84 Abx and acid suppression OR 1.84

(1.01-3.36) p=0.046(1.01-3.36) p=0.046 5 Cases PPI alone5 Cases PPI alone

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AnimalsAnimals Comparitive role of antibiotics Comparitive role of antibiotics

and proton pump inhibitor in and proton pump inhibitor in experimental experimental Clostridium difficileClostridium difficile infection in miceinfection in mice

Kaur Kaur et alet al. Microbiol. Immunol. . Microbiol. Immunol. 2007;51(12):1209-1214.2007;51(12):1209-1214.

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Human studies bedevilled by problems Human studies bedevilled by problems of sample size, uncertainties of how of sample size, uncertainties of how much and how often drugs taken, much and how often drugs taken, combination therapies and ignorance of combination therapies and ignorance of exposureexposure

Morphological findings in mice during c-Morphological findings in mice during c-diff similar to human intestine and diff similar to human intestine and successful model of c-diff infection used successful model of c-diff infection used for investigation of histological changesfor investigation of histological changes

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MethodsMethods 4 groups4 groups

– 1. Control1. Control– 2. 2. C-difficileC-difficile – 3. Ampicilln and 3. Ampicilln and C-difficileC-difficile– 4. 4. Lansoprazole andLansoprazole and C-difficile C-difficile

Assesed for C-difficile activity, MPO activity Assesed for C-difficile activity, MPO activity and histology.and histology.

BALB/c

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ResultsResults Groups 1, 2 and 3 colonisedGroups 1, 2 and 3 colonised Caecal contents of group 1 and 2 Caecal contents of group 1 and 2

negative for CDT A + Bnegative for CDT A + B Antibiotic (c) – 100% A, 83.3% BAntibiotic (c) – 100% A, 83.3% B PPI (d) – 83.3% A, 100 B PPI (d) – 83.3% A, 100 B

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Antibiotic and PPI groups Antibiotic and PPI groups significantly higher colonisation significantly higher colonisation than than C-difficileC-difficile group (and group (and control)control)

MPO activity significantly higher MPO activity significantly higher in antibiotic and PPI group vs. in antibiotic and PPI group vs. C-C-difficile difficile (and control)(and control)

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Antibiotic and PPI groups showed Antibiotic and PPI groups showed significant differences for epithelial significant differences for epithelial damage, oedema and neutrophil damage, oedema and neutrophil infiltrate in the colon against controls infiltrate in the colon against controls and and C-difficile groupC-difficile group

No significant difference between No significant difference between antibiotic and PPI group for antibiotic and PPI group for colonisation or histology (except for colonisation or histology (except for oedema)oedema)

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DiscussionDiscussion C-difficleC-difficle group adequately group adequately

colonised but no production of colonised but no production of toxin or histological change akin toxin or histological change akin to adult carriersto adult carriers

PPIs act as an independent factor PPIs act as an independent factor for C-difficile infection in for C-difficile infection in experimental animalsexperimental animals

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SummarySummary Cohort and case control human studies Cohort and case control human studies

show PPI use to have an increased risk show PPI use to have an increased risk of developing of developing C-difficileC-difficile diarrhoea in diarrhoea in those taking antibiotics and as an those taking antibiotics and as an independent risk factor, compounded independent risk factor, compounded by animal model evidence.by animal model evidence.

Evidence includes omeprazole, Evidence includes omeprazole, pantoprazole and lansoprazole pantoprazole and lansoprazole class class effect.effect.

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Food for thought…Food for thought… Indication for PPIIndication for PPI Consider reducing or stopping Consider reducing or stopping

with antibioticswith antibiotics Acid suppressant guidelines??Acid suppressant guidelines??

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Also in the newsAlso in the news Use of acid suppressants increase the Use of acid suppressants increase the

risk of community acquired risk of community acquired C-difficileC-difficile by by 3 fold3 fold88, but is not a risk for hospitalisation , but is not a risk for hospitalisation in community dwelling older patientsin community dwelling older patients99

Recent PPI increases the risk of Recent PPI increases the risk of community acquired pneumonia, community acquired pneumonia, especially in the under 40’sespecially in the under 40’s1010

PPIs mayPPIs may1111 or may not or may not1212 cause a decline cause a decline in B12 status with prolonged usein B12 status with prolonged use

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FinallyFinally PPIs also to blame for broken hips…PPIs also to blame for broken hips… In a nested case control study the In a nested case control study the

adjusted odds ratio for hip fracture adjusted odds ratio for hip fracture associated with PPI use over 1 year associated with PPI use over 1 year was 1.44 (1.30-1.59), increased in was 1.44 (1.30-1.59), increased in long term high dosage to AOR 2.65 long term high dosage to AOR 2.65 (1.80-3.90), strength of association (1.80-3.90), strength of association increasing with duration of therapy.increasing with duration of therapy.

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ReferencesReferences1.1. NHS PACT centre pages. Drugs for dyspepsia 2006.NHS PACT centre pages. Drugs for dyspepsia 2006.2.2. Walker NM, Mc Donald. An evolution of the use of proton pump inhibitors. Pharm World Walker NM, Mc Donald. An evolution of the use of proton pump inhibitors. Pharm World

Sci 2001;23:116-7.Sci 2001;23:116-7.3.3. Grube RR May DB. Stress Ulcer prophylaxis in hospitalised patients not in intensive care Grube RR May DB. Stress Ulcer prophylaxis in hospitalised patients not in intensive care

untis. Am J Health Syst Pharm 2007;64:1396-400.untis. Am J Health Syst Pharm 2007;64:1396-400.4.4. Leonard Leonard et alet al. J Am Gastroenterology 2007;102:2047-2056. J Am Gastroenterology 2007;102:2047-20565.5. Dial Dial et alet al. CMAJ 2004;171(1):33-8. CMAJ 2004;171(1):33-86.6. Yearsley Yearsley et alet al. Aliment Pharmacol Ther 2006;24:613-619. Aliment Pharmacol Ther 2006;24:613-6197.7. Kaur Kaur et alet al. Microbiol. Immunol. 2007;51(12):1209-1214. Microbiol. Immunol. 2007;51(12):1209-12148.8. Dial Dial et alet al. Use of gastric-acid suppressive agents and the risk of community-acquired . Use of gastric-acid suppressive agents and the risk of community-acquired C-C-

diff-diff-associated disease. JAMA 2005;294:2989-2995.associated disease. JAMA 2005;294:2989-2995.9.9. PPI and hospitalisation for PPI and hospitalisation for C-diffC-diff-associated disease: A population based study. CID -associated disease: A population based study. CID

2006;43:1272-1276.2006;43:1272-1276.10.10. Use of PPIs and the risk of community acquired pneumonia. Gulmez Use of PPIs and the risk of community acquired pneumonia. Gulmez et alet al. Arch Intern . Arch Intern

Med. 2007;167:950-955.Med. 2007;167:950-955.11.11. Do acid lowering agents affect vitamin B12 status in older adults? Dharmarajan Do acid lowering agents affect vitamin B12 status in older adults? Dharmarajan et alet al. J . J

AM Med Dir Assoc. 2008;9(3):162-7.AM Med Dir Assoc. 2008;9(3):162-7.12.12. Long term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Long term use of proton pump inhibitors and vitamin B12 status in elderly individuals.

Elzen Elzen et alet al. Aliment Pharmacol Ther 2008;10. EPub.. Aliment Pharmacol Ther 2008;10. EPub.13.13. Yang Yang et alet al. Long term PPI therapy and risk of hip fracture. JAMA 2006;296(24):2947-. Long term PPI therapy and risk of hip fracture. JAMA 2006;296(24):2947-

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