proton pump inhibitors
TRANSCRIPT
Proton Pump Proton Pump InhibitorsInhibitorsTom MillerTom Miller
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…
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
A few extra…A few extra… C-difficileC-difficile Hip FracturesHip Fractures PneumoniaPneumonia B12 deficiencyB12 deficiency
C-difficileC-difficile; The ; The EvidenceEvidence
Systematic reviewSystematic review Cohorts and case-controlsCohorts and case-controls Animal modelsAnimal models
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.
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
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
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
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
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
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)
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
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.
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
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
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.
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
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
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
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)
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)
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
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.
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??
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
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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