2. PPIsPPIs
Available since late 80’sAvailable since late 80’s
One of the most frequently prescribedOne 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…
4. A few extra…A few extra…
C-difficileC-difficile
Hip FracturesHip Fractures
PneumoniaPneumonia
B12 deficiencyB12 deficiency
5. C-difficileC-difficile; The Evidence; The Evidence
Systematic reviewSystematic review
Cohorts and case-controlsCohorts and case-controls
Animal modelsAnimal models
6.
7.
8. Systematic reviewSystematic review44
LeonardLeonard et alet al. J Am Gastroenterology 2007;102:2047-2056. J Am Gastroenterology 2007;102:2047-2056
Objective – Evaluate associations betweenObjective – Evaluate associations between
acid suppression and enteric infectionacid suppression and enteric infection
Data Sources – MEDLINE, EMBASE andData Sources – MEDLINE, EMBASE and
CINAHLCINAHL
Selection – Observational studies includingSelection – Observational studies including
cross-sectional, case control and cohort thatcross-sectional, case control and cohort that
evaluated risk of enteric infection associatedevaluated risk of enteric infection associated
with antisecretory therapy.with antisecretory therapy.
9. Data SynthesisData Synthesis
12 papers, 2948 patients with12 papers, 2948 patients with C-diffC-diff..
Increased risk of taking antisecretoryIncreased risk of taking antisecretory
therapytherapy
– 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 CompylobacterSalmonella and Compylobacter
– OR 2.55 (95% CI 1.53-4.26) again withOR 2.55 (95% CI 1.53-4.26) again with
heterogeneity and greater for PPIsheterogeneity and greater for PPIs
10. Cohort and Case ControlCohort and Case Control
Risk ofRisk of Clostridium difficileClostridium difficile diarrhoeadiarrhoea
among hospital inpatients prescribedamong hospital inpatients prescribed
proton pump inhibitorsproton pump inhibitors
DialDial et alet al. CMAJ 2004;171(1):33-8. CMAJ 2004;171(1):33-8
11. CohortCohort
1187 patients from pharmacy database1187 patients from pharmacy database
receiving abx in an 8 month periodreceiving abx in an 8 month period
2 Medical and one Cardiothoracic sugical2 Medical and one Cardiothoracic sugical
wardward
Analysis of meds, ward, number and type ofAnalysis of meds, ward, number and type of
abx and type of acid suppressive therapyabx and type of acid suppressive therapy
Positive toxin assay as recorded withPositive toxin assay as recorded with
infection controlinfection control
12. Case-controlCase-control
To control for ‘sicker patients’ with added riskTo control for ‘sicker patients’ with added risk
factors forfactors for C-diffC-diff
Separate hospital, same timeSeparate hospital, same time
Cases (94) were consecutive patients with historyCases (94) were consecutive patients with history
of diarrhoea and positiveof diarrhoea and positive C-diffC-diff toxin assay (newtoxin assay (new
patients).patients).
Controls (94) had abx but noControls (94) had abx but no C-diff,C-diff, type matchedtype matched
for age, type and number of abx, Charlston co-for age, type and number of abx, Charlston co-
morbidity indexmorbidity 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
13. ResultsResults
CohortCohort
– Those taking PPIs had RR of 2.1 (1.4-Those taking PPIs had RR of 2.1 (1.4-
3.4) of developing3.4) of developing C-diffC-diff diarrhoeadiarrhoea
– Remained significant after multivariateRemained significant after multivariate
analysis for ward type and abx numbersanalysis for ward type and abx numbers
14. Case-controlCase-control
– Unadjusted OR 3.1 (1.7-5.6), significantUnadjusted OR 3.1 (1.7-5.6), significant
after adjustment for other significantafter adjustment for other significant
factorsfactors
– 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 relapseOf 21 pts experiencing 1 or more relapse
19 (90%) were Rx PPI OR 5.2 (1.1-24.6)19 (90%) were Rx PPI OR 5.2 (1.1-24.6)
15. DiscussionDiscussion
Controlled for number of abx and co-Controlled for number of abx and co-
morbiditiesmorbidities
In cohort greater effect seen with low-In cohort greater effect seen with low-
risk abxrisk abx
Time and dose relevanceTime and dose relevance
Omeprazole and Pantoprazole = classOmeprazole and Pantoprazole = class
effecteffect
16. Case-control 2Case-control 2
Proton pump inhibitor therapy is a riskProton pump inhibitor therapy is a risk
factor offactor of Clostridium difficileClostridium difficile--
associated diarrhoeaassociated diarrhoea
YearsleyYearsley et alet al. Aliment Pharmacol. Aliment Pharmacol
Ther 2006;24:613-619.Ther 2006;24:613-619.
17. MethodsMethods
155 patients with CDAD, 153 controls.155 patients with CDAD, 153 controls.
Controls chosen as patients on sameControls chosen as patients on same
ward with closest DOBward with closest DOB
Mean age 79.1 and 78.7Mean age 79.1 and 78.7
18. 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 1.84Abx 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
19. AnimalsAnimals
Comparitive role of antibiotics andComparitive role of antibiotics and
proton pump inhibitor in experimentalproton pump inhibitor in experimental
Clostridium difficileClostridium difficile infection in miceinfection in mice
KaurKaur et alet al. Microbiol. Immunol.. Microbiol. Immunol.
2007;51(12):1209-1214.2007;51(12):1209-1214.
20. Human studies bedevilled by problems ofHuman studies bedevilled by problems of
sample size, uncertainties of how much andsample size, uncertainties of how much and
how often drugs taken, combinationhow often drugs taken, combination
therapies and ignorance of exposuretherapies and ignorance of exposure
Morphological findings in mice during c-diffMorphological findings in mice during c-diff
similar to human intestine and successfulsimilar to human intestine and successful
model of c-diff infection used formodel of c-diff infection used for
investigation of histological changesinvestigation of histological changes
21. MethodsMethods
4 groups4 groups
– 1. Control1. Control
– 2.2. C-difficileC-difficile
– 3. Ampicilln and3. Ampicilln and C-difficileC-difficile
– 4.4. Lansoprazole andLansoprazole and C-difficileC-difficile
Assesed for C-difficile activity, MPO activity andAssesed for C-difficile activity, MPO activity and
histology.histology.
BALB/c
22. ResultsResults
Groups 1, 2 and 3 colonisedGroups 1, 2 and 3 colonised
Caecal contents of group 1 and 2Caecal 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 BPPI (d) – 83.3% A, 100 B
23. Antibiotic and PPI groups significantlyAntibiotic and PPI groups significantly
higher colonisation thanhigher colonisation than C-difficileC-difficile
group (and control)group (and control)
MPO activity significantly higher inMPO activity significantly higher in
antibiotic and PPI group vs.antibiotic and PPI group vs. C-difficileC-difficile
(and control)(and control)
24. Antibiotic and PPI groups showed significantAntibiotic and PPI groups showed significant
differences for epithelial damage, oedemadifferences for epithelial damage, oedema
and neutrophil infiltrate in the colon againstand neutrophil infiltrate in the colon against
controls andcontrols and C-difficile groupC-difficile group
No significant difference between antibioticNo significant difference between antibiotic
and PPI group for colonisation or histologyand PPI group for colonisation or histology
(except for oedema)(except for oedema)
25. DiscussionDiscussion
C-difficleC-difficle group adequately colonisedgroup adequately colonised
but no production of toxin orbut no production of toxin or
histological change akin to adulthistological change akin to adult
carrierscarriers
PPIs act as an independent factor forPPIs act as an independent factor for
C-difficile infection in experimentalC-difficile infection in experimental
animalsanimals
26. SummarySummary
Cohort and case control human studiesCohort and case control human studies
show PPI use to have an increased risk ofshow PPI use to have an increased risk of
developingdeveloping C-difficileC-difficile diarrhoea in thosediarrhoea in those
taking antibiotics and as an independent risktaking antibiotics and as an independent risk
factor, compounded by animal modelfactor, compounded by animal model
evidence.evidence.
Evidence includes omeprazole,Evidence includes omeprazole,
pantoprazole and lansoprazolepantoprazole and lansoprazole classclass
effect.effect.
27. Food for thought…Food for thought…
Indication for PPIIndication for PPI
Consider reducing or stopping withConsider reducing or stopping with
antibioticsantibiotics
Acid suppressant guidelines??Acid suppressant guidelines??
28. Also in the newsAlso in the news
Use of acid suppressants increase the riskUse of acid suppressants increase the risk
of community acquiredof community acquired C-difficileC-difficile by 3 foldby 3 fold88
,,
but is not a risk for hospitalisation inbut is not a risk for hospitalisation in
community dwelling older patientscommunity dwelling older patients99
Recent PPI increases the risk of communityRecent PPI increases the risk of community
acquired pneumonia, especially in the underacquired pneumonia, especially in the under
40’s40’s1010
PPIs mayPPIs may1111
or may notor may not1212
cause a decline incause a decline in
B12 status with prolonged useB12 status with prolonged use
29. FinallyFinally
PPIs also to blame for broken hips…PPIs also to blame for broken hips…
In a nested case control study theIn a nested case control study the
adjusted odds ratio for hip fractureadjusted odds ratio for hip fracture
associated with PPI use over 1 yearassociated with PPI use over 1 year
was 1.44 (1.30-1.59), increased inwas 1.44 (1.30-1.59), increased in
long term high dosage to AOR 2.65long 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.
30. ReferencesReferences
1.1. 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 SciWalker NM, Mc Donald. An evolution of the use of proton pump inhibitors. Pharm World Sci
2001;23:116-7.2001;23:116-7.
3.3. Grube RR May DB. Stress Ulcer prophylaxis in hospitalised patients not in intensive care untis. AmGrube RR May DB. Stress Ulcer prophylaxis in hospitalised patients not in intensive care untis. Am
J Health Syst Pharm 2007;64:1396-400.J Health Syst Pharm 2007;64:1396-400.
4.4. LeonardLeonard et alet al. J Am Gastroenterology 2007;102:2047-2056. J Am Gastroenterology 2007;102:2047-2056
5.5. DialDial et alet al. CMAJ 2004;171(1):33-8. CMAJ 2004;171(1):33-8
6.6. YearsleyYearsley et alet al. Aliment Pharmacol Ther 2006;24:613-619. Aliment Pharmacol Ther 2006;24:613-619
7.7. KaurKaur et alet al. Microbiol. Immunol. 2007;51(12):1209-1214. Microbiol. Immunol. 2007;51(12):1209-1214
8.8. DialDial 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-diff-C-diff-
associated disease. JAMA 2005;294:2989-2995.associated disease. JAMA 2005;294:2989-2995.
9.9. PPI and hospitalisation forPPI and hospitalisation for C-diffC-diff-associated disease: A population based study. CID 2006;43:1272--associated disease: A population based study. CID 2006;43:1272-
1276.1276.
10.10. Use of PPIs and the risk of community acquired pneumonia. GulmezUse of PPIs and the risk of community acquired pneumonia. Gulmez et alet al. Arch Intern Med.. Arch Intern Med.
2007;167:950-955.2007;167:950-955.
11.11. Do acid lowering agents affect vitamin B12 status in older adults? DharmarajanDo acid lowering agents affect vitamin B12 status in older adults? Dharmarajan et alet al. J AM Med Dir. J AM Med Dir
Assoc. 2008;9(3):162-7.Assoc. 2008;9(3):162-7.
12.12. Long term use of proton pump inhibitors and vitamin B12 status in elderly individuals. ElzenLong term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Elzen et alet al..
Aliment Pharmacol Ther 2008;10. EPub.Aliment Pharmacol Ther 2008;10. EPub.
13.13. YangYang et alet al. Long term PPI therapy and risk of hip fracture. JAMA 2006;296(24):2947-2954.. Long term PPI therapy and risk of hip fracture. JAMA 2006;296(24):2947-2954.
