Adverse Events Associated with
Use of Proton Pump Inhibitors
Thomas B. Hargrave III, M.D.
Proton Pump Inhibitors
• The use of PPIs has increased progressively over the
last 25 years, with approx 5% of the developed
world now receiving such treatment
– 113.4 million prescriptions for PPIs are filled each year,
– $13.9 billion in sales
• Long-term PPI therapy is indicated primarily for
erosive reflux esophagitis and symptomatic NERD
• Treatment with PPIs is initiated primarily by
primary care physician for uninvestigated dyspepsia
• Up to 33% of pts started on PPIs continue long-term
therapy without an obvious indication for
maintenance therapy
Total Expenditure of OTC Antisecretory
Therapy, USA, 2003–2006
Total Expenditure of Brand Name PPIs:
USA 2003–2006
Adverse Consequences of PPIs
• Rebound Hypersecretion of Acid
– PPI-Induced Dyspepsia
• Increased risk of pathological fracture
• Interactions with clopidogrel
• Increased Risk of Enteric infections
– Food-borne bacterial infections
– C. Difficile
– Spontaneous Bacterial Peritonitis
• Pneumonia
– Community and Hospital-Acquired
Should PPI’s be First-Line
Treatment for Newly-Diagnosed
Dyspepsia or GERD?
No!!
PPI-Induced Rebound
Hypersecretion of Acid
• Since 1966, several studies have shown that
as little as 2 months on omeprazole 40
mg/day can result in marked rebound of
gastric acid secretion upon PPI withdrawal.
• The effect is most evident in Helicobacter
pylori-negative individuals.
• The degree of acid rebound is proportional
to the degree elevation of intragastric pH
during treatment, and fasting plasma gastrin
levels during PPI therapy.
Gastrin Exerts a Powerful Trophic Effect on
Enterochromaffin-like cells and Parietal cells
Rebound Hypersecretion of
Acid on PPI’s
• In HP-negative subjects on omeprazole 40
mg/day for 8 weeks there was a median increase
in the BAO of 82%, and a 28% increase in the
MAO 15 days after discontinuation
• The response in HP-positive patients is similar
but more highly variable
• Presumed due to gastrin-induced increase in
parietal cell mass and EC cells.
• The duration of the rebound acidity was not
determined
Gastroenterology 1999;116:239-47
Rebound Hypersecretion of Acid
on PPI’s:Basal Acid Output
6.8
3.0
3.0
1.9
Gastroenterology 1999;116:239-47
Rebound Hypersecretion of Acid
on PPI’s: Maximal Acid Output
41.7
32.4
3.0
40.4
6.8 29.8
3.0
1.9
Gastroenterology 1999;116:239-47
Rebound Hyper-Secretion on PPIs
Lasts Up To Eight Weeks
• 12 HP(-) and 20 HP(+) tested for basal, submaximal and maximal gastric acid secretion
before and on days 7,14,28,42,56, days after
stopping omeprazole 40 mg/day for 8 weeks
• HP eradication was completed on the last week
of omeprazole therapy.
• Rebound maximal (up 40%) and sub-maximal
acid ( up 43%) secretion was observed in HP(-)
subjects at 28 days, lasting at least 56 days
(16% and 31%)
Gastro 2004;126:980-87
37%
16%
43%
31%
Gastro 2004;126:980
PPI Therapy Induces AcidRelated Symptoms in Previously
Asymptomatic Healthy Volunteers
PPI Therapy Induces Acid-Related Symptoms
in Healthy Volunteers After Withdrawal of Rx
• 120 subjects, without any clinically significant
history of reflux symptoms, randomized in
double-blind fashion to 2 months treatment with
esomeprazole 40 mg/d or placebo, and then 4
weeks all received placebo
• During weeks 2, 3, and 4 post-treatment, clinically
significant symptoms of heartburn, acid reflux, or
dyspepsia were reported by 44% of those who
had received omeprazole versus only 15% of
those who had received placebo throughout
(P < .001).
Gastroenterology 2009 ;Vol. 137(1): 20-22)
Temporal Changes in the Proportion of Subjects with
Heartburn, Acid Regurgitation or Dyspepsia.
P <0 .001
Gastroenterology 2009 ;Vol. 137, Issue 1, Pages 20-22
PPI-Induced Dyspepsia: Statistically
Significant but Relatively Mild
P <0.001
1= No Bothersome Symptoms
7= Very Bothersome Symptoms
Gastroenterology 2009 ;Vol. 137, Issue 1, Pages 20-22
Implications of Rebound
Hypersecretion of Acid on PPI’s
• PPI should not be first-line therapy for
dyspepsia/GERD
• The greater the acid suppression, the
greater the rebound
– Acid rebound lasts for at least 2 months
• Once you start PPI’s for GERD be
prepared to use as long-term therapy
– Discontinuation of PPI or switching to H2RA
may be difficult
Meta-Analysis of 34 Trials of PPI vs
H2RA for Erosive GERD
7653 patients
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
PPI
H2RA
Healing 12
Weeks
Symptom-Free
Weekly-Healing
Rate
Gastro 1997;112:1798
Implications of Rebound
Hypersecretion of Acid on PPI’s
• When treating acid-like dyspepsia or
GERD, start with H2-receptor antagonist as
initial therapy
• If H2-RA’s fail, use the lowest does PPI
once a day.
• If nocturnal symptoms predominate, try
PPI before dinner, or add an evening H2RA
before bid dosing of PPI
• Never use Nexium 40 as initial therapy
Implications of Rebound
Hypersecretion of Acid on PPI’s
• Empiric PPI trials should be brief (2-4 wks)
– It is not necessary to test the efficacy of PPIs
over several months
– The maximal acid suppression occurs within 2-5
days
• Try different PPI’s before going to high-dose
PPI
• Once symptoms have been controlled for
several months, try to back down to lowest
effective PPI dose periodically
Range of Acid Suppresion in 103 Patients LA
Grade C or D GERD on Esomeprasole 40
Individual Variability of Acid Suppression on
B.I.D Omeprazole vs Lansoprazole
Alimentary Pharmacology Ther. 2000;14:709-14
Adverse Consequences of PPIs
• Rebound Hypersecretion of Acid
• Increased risk of pathological fracture
• Enteric infections
– C. Difficile
– Food-borne bacterial infections
• Pneumonia
• Interactions with Plavix??
PPI and Hip Fractures: Overview
• Since 2006, 4 published studies have shown an
association between chronic PPI use and
fractures of the hip
– 2 of the studies show greater risk with longer duration
or higher intensities of use or both
• One study was unable to detect an effect of PPI
use on the occurrence of hip fracture in the
absence of other risk factors for hip fracture
• PPI use does not affect bone density
– Association between PPIs and hip fracture may be due
to the presence of unmeasured confounders
PPI and Hip Fractures
• PPI therapy 1st linked to an increased risk for hip
fractures in 2006
• UK General Practice Research Database (1987 - 2003),
– Cases included all patients with an incident hip
fracture (n = 13,556), and 135,386 controls
• The strength of the association between hip fracture
and PPI therapy increased with increasing duration of
PPI therapy . AOR
– 1 year, 1.22 [95% C I, 1.15 - 1.30]
– 2 years, 1.41 [95% C I, 1.28 - 1.56]
– 3 years, 1.54 [95% C I, 1.37 - 1.73]
– 4 years, 1.59 [95% C I, 1.39 - 1.80] (P < .001).
JAMA. 2006;296:2947-2953.
PPI and Hip Fractures
• 2008 Canadian, retrospective, case–control study
matched 15,792 cases of osteoporosis-related
fractures with 47,289 controls
• Long-term exposure to PPI therapy, defined as 7
or more years, was significantly associated with
an increased risk of any osteoporosis-related
fractures (hip, vertebral, wrist) (OR 1.92 [1.16–
3.18], P = 0.011)
• Hip fracture risk was increased after only 5 years
of continuous use
Targownik et al CMAJ 2008;179(4):319
Association Between Continuous Exposure to PPI and
Osteoporosis-related Fractures (Hip, Vertebra or Wrist)
Targownik, L. E. et al. CMAJ 2008;179:319-326
Relation Between Continuous Exposure
to PPI and Risk of Hip Fractures
Targownik, L. E. et al. CMAJ 2008;179:319-326
PPI and Hip Fractures
• Northern California Kaiser database to identify patients
with a hip fracture (cases, n = 33,752) and matched these 4:1
to controls (n = 130,471)
• PPI use > 2 years
• Cases, men and women, were 30% more likely than controls
to have taken PPIs for at least 2 years (odds ratio [OR] 1.30
[95% CI 1.21–1.39]) and 18% more likely to have consumed
H2-blockers for 2 years (1.18 [1.08–1.28]).
• The greatest relative risk of hip fractures in patient 50-59 on
PPI>2 years (OR 2.31)
• Risk declines after discontinuation
Gastroenterology. 2009:136(suppl 1):A–70.
PPI and Hip Fractures
• Higher dosages for longer durations increased risk
in a linear fashion
• Effect was dose dependence
– 0.01-0.75 pills/day = OR 1.2
– 0.76-1.49 pills/day = OR 1.3
– >1.49 pills/day
= OR 1.42
• Minimal durational effect beyond 2 years (risk
approximately the same at 4 years as 2)
Gastroenterology. 2009:136(suppl 1):A–70.
PPI and Hip Fractures
• United Kingdom General Practice Database
• 4414 hip fractures 1995-2005 with at least 2
years of GERD therapy
• 3316 had at least one major risk factor for hip
fracture (ETOH, seizure, dementia, steroids)
• 1098 without risks factors compared to 10,923
controls
• In patients with no other risks for hip
fractures, PPI use did not increase the risk of
hip fracture
Pharmacology 2008; 28:951-959.
PPI and Fracture Risk
• 161,806 postmenopausal women aged 50 to 79 years,
without a history of hip fracture, who participated in
the Women's Health Initiative (WHI) Observational
Study and Clinical Trials.
• The investigators analyzed data from 130,487 women
with complete information during mean follow-up of
7.8 ± 1.6 years.
• Primary endpoints were self-reported hip (adjudicated)
fractures, clinical spine fractures, forearm or wrist
fractures, and total fractures.
• In addition, 3-year change in BMD was determined
Arch Intern Med. 2010;170:747-748
PPI and Fracture Risk
• During 1,005,126 person-years of follow-up, there were
1500 hip fractures, 4881 forearm or wrist fractures,
2315 clinical spine fractures, and 21,247 total fractures
identified
• Use of PPIs was associated with only a marginal effect
on 3-year BMD change at the hip (P=.05) but not at
other sites
• Multivariate-adjusted hazard ratios were 1.00 for hip
fracture, 1.47 for clinical spine fracture, 1.26 for
forearm or wrist fracture, and 1.25 for total fractures
• Use of PPIs was not associated with hip fractures but
was modestly associated with clinical spine, forearm or
wrist, and total fractures.
Arch Intern Med. 2010;170:747-748
Is There a Biologically Plausible
Mechanism for PPI-Induced
Fractures ?
PPI Use Is Not Associated With Osteoporosis or
Accelerated Bone Mineral Density Loss
• Manitoba Bone Mineral Density Database : 2000-2007
• 2193 subjects had evidence of osteoporosis at the hip
and were matched to 5527 controls with normal hip
measurements.
• A total of 3596 subjects had BMD measurements
consistent with osteoporosis at the lumbar spine and
were in turn matched to 10,257 normal controls.
• The researchers found PPI use was not associated with
having osteoporosis at either the hip or the lumbar
spine for proton-pump inhibitor use over 1500 doses
over the previous 5 years.
Targownik, L. E. et al. Gastroenterology 2010; 138:869
PPIs and Fractures
• A Japanese study 18 women with esophagitis
taking PPI therapy and 57 age-matched
controls without PPI.
• There was a greater risk of multiple
vertebral fractures assessed by X-ray in the
esophagitis group.
• There was no statistically significant
difference in bone mineral density between
the two groups
J Bone Miner Metab 2005;23:36–40.
Physiologic Mechanisms by Which use of
PPI Could Affect Bone Mineral Metabolism
• The dissociation of food calcium complexes and
the liberation of Ca2+ from calcium salts is
strongly dependent on pH
• Calcium carbonate, which is the most common
calcium salt found in dietary supplements, is
relatively insoluble at high pH levels, which
could potentially hinder its absorption
• PPI use may reduce absorption of inorganic
calcium by as much as 60%
Effects of PPI on Calcium Carbonate
Absorption in Elderly Women
• Randomized, double-blind,
placebo-controlled, crossover
clinical trial
• Mean age 76 (68-79)
• 500 mg 45Ca-carbonate
• Fractional calcium absorption
for each subject (N = 18) after
1 week of placebo and
omeprazole 20 mg. The 25th
to 75th percentile bars and
means are depicted for each
treatment period. * P = 0.003.
AJM 2005;118(7):778-83
Direct PPI Effect on Bone Fragility?
Direct PPI Effect on Bone Fragility?
• Approximately 50% of low-velocity fractures occur in
patients without osteoporotic BMD as determined by
DXA scanning
• PPIs are capable of blocking the osteoclast-based
vacuolar proton pump, leading to decreased bone
turnover.
• Inhibition of proton pump activity in osteoclasts has
direct inhibitory effects on bone resorption and release
of bone calcium
• Decreased bone turnover may promote slight increases
in BMD but may increase fracture risk by blocking the
repair of microfractures and microarchitectural defects
PPI’s and Osteoporosis: Conclusions
• 4 of 5 case-control studies do appear to confirm an
increased risk of pathological fractures with longterm PPI use as short as 2 years, and a lesser degree
with H2RA
• Risk appears related to dose and duration of acid
suppression; possibly reversible
• No measurable decrease in bone density
• Impaired absorption of calcium may be a
contributing factor
– Whether additional calcium/vitamin D supplementation
will offset this risk is unknown
Risk of Hip Fractures Based on Age and
Femoral Neck BMD during 5 years of Follow-up
Ther Adv Musculoskel Dis. 2010;2(2):63-77.
Adverse Consequences of PPIs
• Rebound Hypersecretion of Acid
– PPI-Induced Dyspepsia
• Increased risk of hip fracture
• Interactions with clopidogrel
• Increased Risk of Enteric infections
– Food-borne bacterial infections
– C. Difficile
– Spontaneous Bacterial Peritonitis
• Pneumonia
– Community and Hospital-Acquired
Clopidogrel plus PPI After Hospitalization for
ACS Increased Risk of Adverse Outcomes
• Retrospective cohort study published in the JAMA
demonstrated that concomitant use of clopidogrel and a
PPI after hospital discharge for acute coronary
syndrome (ACS) is associated with an increased risk of
all-cause mortality and rehospitalization for ACS.
• 8,205 patients with ACS were taking clopidogrel after
hospital discharge.
• 63.9% were prescribed a PPI at discharge, during
follow-up, or both, and 36.1% were not prescribed a
PPI.
• The median follow-up was 521 days.
JAMA. 2009;301:937–944.
Clopidogrel plus PPI After Hospitalization
for ACS Increased Risk of Adverse Outcomes
• Multivariable analysis demonstrated that the use of a
PPI during clopidogrel treatment was associated with
an increased risk of death or rehospitalization for ACS
(adjusted OR=1.25; 95% CI, 1.11–1.41).
• Patients taking a PPI with clopidogrel also
demonstrated
– Increased rates of recurrent hospitalization for ACS
(14.6% vs 6.9%; P<.001).
– Revascularization procedures (15.5% vs 11.9%;
P<.001), and
– Death (19.9% vs 16.6%; P<.001) compared with
patients taking clopidogrel without a PPI
.
JAMA. 2009;301:937–944
Clopidogrel plus PPI After Hospitalization for
ACS Increased Risk of Adverse Outcomes
• 820 patients with drug-eluting coronary stents
– 502 patients who were not prescribed a PPI at discharge
– 318 patients who were prescribed a PPI.
• All patients were taking clopidogrel.
• 1 year follow up
• Univariate survival analysis of the outcomes showed a
greater rate of MACE (13.8% vs 8.0%, p = 0.008) and
overall mortality (4.7% vs 1.8%, p = 0.02) in the PPI
group.
• After multivariate analysis, the adjusted MACE hazard
ratio for PPI at discharge was 1.8 (95% confidence
interval 1.1 to 2.7, p = 0.01).
Am. J Cardiology 2010:105:833
.
Clopidogrel -PPI Interaction
• Widely accepted explanation is the competitive
inhibition of cytochrome 450-2C19
– The isoenzyme responsible for conversion of
clopidogrel to it’s active form
• A PPI’s metabolized to some degree by
CYP2C19
• Omeprazole, esomeprazole, lansoprazole
showed the greatest CYP2C19 inhibition,
followed by pantoprazole and rabeprazole
PPIs and Anti-Platelet Agents
• In 2009, both the FDA and the European
Medicines Agency (EMEA)issued public
warnings about potential adverse
interactions between PPI’s and clopidgrel
• EMEC issues statement that PPI and
clopidogrel use not advisable unless
absolutely necessary
• FDA advised re-evaluation of the use of
omeprazole with clopidogrel
FDA Alert
• The concomitant use of omeprazole and clopidogrel should be avoided
because of the effect on clopidogrel's active metabolite levels and anticlotting activity. Patients at risk for heart attacks or strokes, who are
given clopidogrel to prevent blood clots, may not get the full protective
anti-clotting effect if they also take prescription omeprazole or the OTC
form (Prilosec OTC).
• Separating the dose of clopidogrel and omeprazole in time will not
reduce this drug interaction.
• Other drugs that should be avoided in combination with clopidogrel
because they may have a similar interaction include: esomeprazole
(Nexium), cimetidine (which is available by prescription Tagamet and
OTC as Tagamet HB), fluconazole (Diflucan), ketoconazole (Nizoral),
voriconazole (VFEND), etravirine (Intelence), felbamate (Felbatol),
fluoxetine (Prozac, Serafem, Symbyax), fluvoxamine (Luvox), and
ticlopidine (Ticlid
Clopidogrel-PPI Interactions Remain Only
Observational at This Time
• Three randomized databases that are not subject to
confounding, and all suggest that there is no significant
adverse interaction between clopidogrel and PPIs.
– CREDO trial, presented at the AHA 2008
– TRITON trial
– PRINCIPLE 44 trial
• Several studies have also shown no difference in in vitro
platelet aggregation between eomeprazole, pantoprazole,
and lasoprazole when given with either clopidogrel or
prasugrel
1) Am. Heart Journal 2009;51:258 (pantoprazole/eosmeprazole/clopidogrel)
2) J. Clinical Pharm 2008;48:475 (lansoprazole/prasugrel/clopidogrel)
Two Randomized Trials of
PPI/Clopidogrel
• Two double-blind trials of 202 (Principle) &
13,608 (Triton) PTCA patients comparing
clopidogrel vs prasurgrel
– Platelet functions measure day 1, 14, 28
• PPI use was at the discretion of the treating
physician
– 33% on PPI at start of study
• Mean inhibition of platelet aggregation was
modestly but significantly lower on PPIs for both
clopidorgrel and prasurgrel
• No association between use of PPI and adverse
cardiac events
Lancet Sept 19, 2009; 374:989
Adjusted Hazard Ratios of PPI
Use and Risk of CV Death: Triton
CV death: all
cause
MI
Plavix
11.8%
9.5%
Stent Occlusion 2.4%
Major Bleeding 2.4%
PPI
OR
12.2% 0.94
Prasugrel PPI
10.2%
9.7%
OR
1.00
9.8%
2.3%
1.6%
7.7%
1.1%
2.5%
1.02
1.03
0.97
0.98
1.08
1.20
7.3%
1.1%
2.4%
Lancet Sept 19, 2009; 374:989
Adjusted Hazard Ratios of PPI
Use and Risk of CV Death: Triton
Plavix
Prasugrel
CVdeath,MI,
CVA
MI
CVdeath,MI,C
VA
MI
Omeprazole
0.91
0.95
1.04
1.02
Pantoprazole
0.94
0.97
1.09
1.09
Esomeprazole
1.07
1.18
0.86
0.92
Lanzoprazole
1.00
0.86
0.98
1.08
H2-RA also not associated
with increased CV risk
Lancet Sept 19, 2009; 374:989
COGENT Trial
• COGENT trial of combination Clopidogrel75/omeprazole 20 vs Clopiodrel 75/placebo
in 3627 ASCHD patients +/- stents
End Point
Placebo PPI p
All CV events
67
69
ns
MI
37
Revascularization 67
36
69
ns
ns
GI Events
38
0.007
67
Mean followup 133 days: Trial halted due to company bankruptcy
Outcomes With Concurrent Use of
Clopidogrel and PPI
• 20 596 patients (including 7593 concurrent users of
clopidogrel and PPIs) hospitalized for MI, coronary
artery revascularization, or unstable angina pectoris.
(1999-2005) Tenn. Medicaid Database
• 65% pantoprazole 9% omeprazole
• Adjusted incidence of hospitalization for gastroduodenal
bleeding in concurrent PPI users was 50% lower than
that in nonusers [95% CI, 0.39 to 0.65]).
• The hazard ratio associated with concurrent PPI use for
risk for serious cardiovascular disease was 0.99 (CI, 0.82
to 1.19) for the entire cohort and 1.01 (CI, 0.76 to 1.34)
for the subgroup of patients who had PTCA with stenting
during the qualifying hospitalization.
Annals Int Med 2010; 152:337
Meta-analysis of Outcomes With
Concurrent Use of Clopidogrel and PPI
• Meta-analysis of 23 observational and randomized
controlled trials of CV and mortality risk in 93,278
patients on PPI and clopidogrel
• Considerable heterogeneity in findings
– Observational studies generally showed a significant
association of PPI and CV risk
– Randomized and propensity-matched trials showed no
association of PPI with CV risk
• Meta-analysis of 13 studies showed no
significant association between PPI use and
overall mortality (RR 1.09 95%CI 0.94-1.26, p=0.23)
APT 2010;31:810-23
Clopidogrel-PPI Interactions:
Conclusions/ Recommendations
• Three randomized, prospective databases all indicate that
there is no clinically important adverse interaction
between clopidogrel and PPIs.
• There had been a recommendation that PPIs be given as
blanket gastric protection to all patients at risk of gastric
problems taking dual anti-platelet therapy,
– No longer advisable, given the possibility of an
interaction
• PPIs should be prescribed to patients taking clopidogrel
only if they have increased risk of GI bleeding or dyspeptic
symptoms that are not controlled with H2 antagonists.
• Pantoprazole would appears to be default PPI
When in doubt?
Adverse Consequences of PPIs
•
•
•
•
Rebound Hypersecretion of Acid
Osteoporosis
Interactions with Plavix??
Enteric infections
– Food-borne bacterial infections
– C. Difficile Colitis
– Spontaneous Bacterial Peritonitis
• Pneumonia
Gastric Acid Influences Gut Flora
• Gastric acid < pH 4.0 is bactericidal within 15
minutes for most species of bacteria
• Loss of the normal stomach acidity has been
associated with colonization of the normally sterile
upper gastrointestinal tract
• Profound gastric acid suppression is associated
with significant increase in total colonic bacterial
count of all genera and significant changes in the
mix of dominant flora Gastroenterology 2009;136(suppl1): W2001
• Acid suppression increases the risk of enteric
infections
Chronic AST may Predispose Otherwise Healthy
Individuals to Clinically Significant SIBO
• Retrospectively analyzed data on 108 adults who
underwent lactulose breath test.
• 43 patients who reported daily acid suppression therapy
for at least two months and 65 patients who reported no
acid suppression.
• Among patients on chronic acid suppression, 49% had
positive breath tests compared with 26% to 27% of the
control group. (OR 2.311, P=0.019).
• About 10% of the acid-suppression group had mixed gas
production, which was significantly different from the
control group rate of about 1% (P=0.03).
Chan W et al. "Chronic use of acid suppression medication is associated with clinically
significant small intestinal bacterial overgrowth" ACG 2009; Abstract 944.
PPI and Bacterial Overgrowth
• Investigators used glucose hydrogen breath tests to
look for small intestinal bacterial overgrowth in 450
consecutive patients enrolled in three groups:
– 200 GERD patients treated with PPIs for a median of 36
months;
– 200 patients with irritable bowel syndrome (IBS) who had not
used PPIs for at least 3 years; and
– 50 healthy controls who had not used PPIs for at least 10
years.
• Small intestinal bacterial overgrowth in 50% of the PPI
users with GERD, 24.5% of the IBS patients, and 6%
of the healthy control
Clin Gastroenterol Hepatol 2010;8(6):504
PPI and Bacterial Overgrowth
Prevalence of SIBO
50%
25%
6%
Clin Gastroenterol Hepatol 2010;8(6):504
PPI and Bacterial Overgrowth
Prevalence of SIBO by Duration of Therapy
P<0.001
Clin Gastroenterol Hepatol 2010;8(6):504
Gastric Acidity Inhibitors Increases the Risk of
Acute Gastroenteritis and Community-Acquired
Pneumonia in Children
• The study was performed by expert pediatric
gastroenterologists from 4 pediatric gastroenterology
centers. Children (aged 4–36 months)
– 95 healthy controls and 91 GA-inhibitor users (47 on ranitidine
and 44 on omeprazole) for GERD.
• In the GA inhibitor-treated group, the rate of subjects
presenting with acute gastroenteritis (p<0.001) and
community-acquired pneumonia (p= 0.02) was increased
when comparing the 4 months before and after
enrollment
• No differences were observed between H2RA and PPI
users in acute gastroenteritis and pneumonia incidence in
the previous 4 months and during the follow-up period
PEDIATRICS Vol. 117 No. 5 May 2006, pp. e817-e820
TABLE 1 Baseline Clinical Data and Outcome Measures
Controls (n =
95)
GA Inhibitors (n
= 91)
10 (8–15)
10 (8–16)
50 (53)
48 (53)
Weight, median, kg (IQR)
9.3 (8–10)
9.1 (8–15)
Length, median, cm (IQR)
74 (70–78)
74 (70–80)
Acute gastroenteritis in the previous 4 mo,
n (%)
17 (18)
18 (20)
Acute gastroenteritis in the follow-up
period, n (%)
19 (20)
43 (47)a,b
Pneumonia in the previous 4 mo, n (%)
1 (1)
3 (3)
Pneumonia in the follow-up period, n (%)
2 (2)
11 (12)a,b
Characteristics
Age, median, mo (IQR)
Male, n (%)
Patients presenting with
a
P < .05, GA inhibitor users versus control children.
b P < .05, 4 months before versus 4 months after the enrollment.
Systematic Review of the Risk of Enteric
Infection in Patients Taking Acid Suppression
• Systematic review to evaluate any association
between acid suppression and enteric infections
• 12 papers evaluating 2,948 patients with
Clostridium difficile were included in the
review.
• A total of 6 studies evaluated Salmonella,
Campylobacter, and other enteric infections in
11,280 patients.
• Conclusion: Acid suppression increases risk of
enteric infections (OR 2.55, 95% CI 1.53–4.26).
Am . J Gastro. 2007 :102, 2047–2056
Meta-Analysis of Risk Association of Enteric
Infections with PPI and H2RA Therapy.
The association was greater for PPI use (OR 3.33, 95% CI 1.84–
6.02) compared with H2RA use (OR 2.03, 95% CI 1.05–3.92).
Am . J Gastro. 2007 :102, 2047–2056
Risk Association of C. difficile with
PPI and H2RA Therapy.
1.40, 95% CI 0.85–2.29
OR 1.96, 95% CI 1.28–3.00
Am . J Gastro. (2007) :102, 2047–2056
PPI and Community-Acquired CD
• UK case-control study of community-acquired CD
• 317 cases and 3167 controls
Prior 90 days Case
Control
Adjusted OR
PPI
Antibiotic
H2RA
IBD
CRF
5.0%
12.8%
3.5%
0.2
0.7
3.5
8.2
1.4
46.1
6.2
19.2%
54.9%
7.3%
5.7%
5.2%
CMAJ 2006;175(7):745
PPI Use: Risk for HospitalAcquired CDAD
• Case-control study 277 hospital CDAD
PPI
Yes
No
Yes
Yes
Yes
Antibiotic
No
Yes
Yes
No
Yes
ChemoRx
No
No
No
Yes
Yes
OR (95%)
2.4
5
17
20
43
J Hosp. Infection 2003;54:243
Risk for Nosocomial CD Infection Increased
with Increasing Level of Acid Suppression
• Secondary analysis of prospectively collected data from
101,796 patients who were discharged from a tertiary
care medical center during a 5-year period.
• Acid suppression treatment was the primary exposure
of interest, classified by intensity (no acid suppression,
histamine2-receptor antagonist [H2RA] treatment, daily
PPI use, and PPI use more often than daily)
• The risk for nosocomial C difficile infection increased
with increasing level of acid suppression.
• The association persisted after adjustment for comorbid
conditions, age, antibiotics, and propensity score–based
likelihood of receiving no acid suppression treatment
Arch Intern Med. 2010;170:747-748
Risk for Nosocomial CD Infection
Increased with Increasing Acid Suppression
Arch Intern Med. 2010;170:747-748
Role of PPI on Severity of CD
• Retrospectively review 295 pts diagnoses of C. difficileassociated diarrhea over a 12-month period at a tertiary
hospital.
• The records were examined to determine duration of
diarrhea, need for treatment escalation (such as ICU
care), immunoglobulin therapy, colectomy, death related
to C. difficile diarrhea, and recurrence.
• 164 of the 295 patients received PPIs
• In a multivariate analysis, PPI therapy doubled the
likelihood of severe diarrheal disease (OR 1.92, 95% CI
1.27 to 2.89, P=0.002).
• The only other independent predictor of severe illness
was male sex.
Sravinthan A, et al "Role of proton pump inhibitors on severity of outcome
of Clostridium difficile associated disease" DDW 2010; Abstract T1782.
PPI Use Increased Risk of
Recurrent CD Colitis by 42%
• 1166 inpatients and outpatients treated with
metronidazole or vancomycin hydrochloride for incident
C difficile infection.
• Investigators measured the hazard ratio (HR) for
recurrent C difficile infection, which was defined as a
positive toxin result in the 15- to 90-day period after
incident C difficile infection.
• Compared with patients not using PPIs, those using them
were more likely to have recurrent C difficile infection
(25.2% vs 18.5%),
• Adjusted HR of recurrent C difficile infection of 1.42
(95% CI, 1.11 - 1.82)
Arch Intern Med. 2010;170: 772-778
Role of PPI on Severity and Recurrence
of CD: 2010 DDW Abstracts
• Study of 155 patients with C. difficile-associated diarrhea, 66 of
whom met criteria for having severe illness
• In a multivariate analysis, use of a PPI prior to admission
doubled the risk of severe illness compared with patients who
did not receive a PPI before admission (RR 2.12, 95% CI 1.01
to 4.45, P=0.047).
Morgan M, et al "Proton pump inhibitors increase risk of severe disease among patients
hospitalized with Clostridiium difficile associated diarrhea" DDW 2010; Abstract S1225.
• A review of medical records for 198 patients with C. difficile
diagnoses showed that 28 patients had recurrent disease.
Investigators performed a propensity score comparison of 21
patients with recurrent disease and 21 without.
• Significantly more patients with recurrent disease had been
treated with PPIs (47.6% versus 4.8%, P=0.004).
Kim YG, et al "Association of proton pump inhibitors with recurrent Clostridium difficile associated
disease: a matched case-control analysis by using propensity score" DDW 2010; Abstract S1231.
Acid Suppression and CD
• The use of acid-suppressive therapy, particularly
proton pump inhibitors, is associated with an
increased risk of both hospital and communityacquired C. difficile
• The risk appears to be independent of antibiotic
use and potentially additive
• If a patient has been treated for C. difficile,
strongly consider stopping PPI, especially if there
has been a recurrence
• Frequently reassess the indications for PPI,
especially in elderly hospitalized or
institutionalized patients
Magnitude and Economic Impact of
Inappropriate Use of Stress Ulcer Prophylaxis
• The practice of SUP has become increasingly more
common in general medicine patients, with little to
no evidence to support it
• Several studies have demonstrated the
inappropriate use of acid- suppressive therapy
(AST) in general medicine (non-ICU) patients,
based on current recommendations.
• AST is commonly misused in hospitals, with as
many as 71% of patients in general medicine
wards receiving some sort of AST without an
appropriate indication.
American Journal of Health-System Pharmacy. 2007;64(13):1396-1400
Inappropriate PPI Use In Hospitals
• Prospective evaluation of IV PPI use in two
Midwest community-based teaching hospitals
• Identify all patients for whom an IV PPI was
ordered
• Fifty-six percent of patients who received IV
PPIs had no acceptable indication for their use
• Of the 126 patients who were started on PPIs
for the first time during their hospital stay, 102
(81%) were discharged on a PPI.
AJG 2004; 99:1233 - 1237
Beware of PPIs in Cirrhotics
with Ascites
Spontaneous Bacterial Peritonitis:
Risk Factors
• Ascitic fluid total protein
concentration less than 1 g/dl
• Prior episode of SBP
• Variceal hemorrhage
• Bilirubin above 2.5 mg/dl
• Malnutrition
• PPI use
PPIs and SBP
• Retrospective case controlled study of
culture proven SBP 2002-2007
• 70 SBP patients, age and Child’s class
matched, 1:1 with cirrhotics admitted for
non-SBP indications
• Pre-hospital PPI use in 69% of SBP vs
31% non-SBP admissions (p<0.0001)
• 47% of patients on PPI had no documented
indication for PPI use
Am. J. Gastro 2009;104(5):1130
PPI and SBP
• 2631 cirrhotics with ascites followed from
2002-2007
• PPI use strongly associated with SBP and
hepatorenal syndrome
– SBP on PPI 23.7%
– HSR on PPI 15.3%
No PPI
No PPI
5.7%
1.9%
• Number needed to treat for harm from PPI
use: 5.5 for 1 episode of SBP
Hepatology 2008;48:324A
MECHANISMS OF BACTERIAL TRANSLOCATION (BT)
Mechanisms of Bacterial
Translocation and SBP
Intestinal Bacterial Overgrowth
Dysmotility Delayed transit time
Nutrition?
Intestinal Permeability
Mucosal Hypoxia, Acidosis
ATP depletion, NO, LPS, TNF
Impaired Immunity
Impaired chemotaxis,
migration,
phagocytic function,
complement
deficiency, etc.
Aerobic
bacteria
Anaerobi
c
bacteria
Enterocytes
Lamina
propria
Adverse Consequences of PPIs
•
•
•
•
Rebound Hypersecretion of Acid
Osteoporosis
Interactions with Plavix??
Enteric infections
– Food-borne bacterial infections
– C. Difficile Colitis
– Spontaneous Bacterial Peritonitis
• Pneumonia
Use of PPI and the Risk of
Community-Acquired Pneumonia
• Population-based case-control study using data
from the County of Funen, Denmark
• Cases (n = 7642) first-discharge diagnosis of
community-acquired pneumonia from a hospital
during 2000 -2004: 34 176 control subjects
• Adjusted odds ratio (OR) associating current use
of PPIs with community-acquired pneumonia was
1.5 (95% confidence interval [CI], 1.3-1.7).
• No dose-response association demonstrated
Arch Intern Med. 2007;167(9):950-955.
Use of PPI and the Risk of
Community-Acquired Pneumonia
Arch Intern Med. 2007;167(9):950-955.
Use of PPI and the Risk of
Community-Acquired Pneumonia
• Nested case-control study of 88,066 communityacquired pnemonia and 799,886 controls
• PPI use >30 days NOT associated with increase
risk of CAP
• Short-term PPI use increased relative risk!!
• 1-2 days OR 6.5 (CI 3.9-10.8)
• 7 days OR 3.8 (CI 2.6-5.4)
• 14 days OR 3.2 (2.4-4.2)
Ann Intern Med. 2008;148:319
Use of PPI and the Risk of
Hospital-Acquired Pneumonia
• Cohort study of 63,878 adult patients admitted for
>72 hours BIMDC over a 3 year period
• Assess PPI and H2RA use and hospital-acquired
pneumonia
• 52% (32,922) of patients placed on acid suppressive
therapy
• Corrected for age , sex, race, other medications,
season, and co-morbidities
• Validated result via a propensity matched analysis
(whatever that is)
JAMA 2009;301(20):2120-8
Use of PPI and the Risk of
Hospital-Acquired Pneumonia
• PPI use associated with increased risk of
pneumonia (OR = 1.3)
• Trend towards similar effect with H2RA
(OR =1.2) but not stasticially significant
• The association was stronger for
aspiration than non-aspiration
pneumonia
JAMA 2009;301(20):2120-8
Use of PPI and the Risk of
Pneumonia??
• No biologically plausible explanation for
short-term PPI use and increased risk of
CAP.
• Likewise no clear explanation for PPI
use and non-aspiration pneumonia in
hospitalized patients
• The jury is still out.
PPI Use: Risk for Community
and Hospital Acquired CDAD
• Prospective study of PPI prescriptions in 138
hospitalized patients diagnosed with C. difficile
infection over a 4-month period.
• Sixty-four percent (88 of 138) of all patients who
developed C. difficile infections were on PPIs
• Ninety percent of the patients were on one of these
drugs for >4 weeks, 50% for >6 months and 35% for
>12 months.
• A valid indication for PPIs therapy was not apparent in
63% of the patients.
QJM 2008 101(6):445-448
Conclusions
• PPI are effective in management of GERD,
acute acid peptic bleeding and stress ulcer
prophylaxis but carry significant infectious
risks and possible risk of pathologic
fractures
• The PPI-Plavix interaction likely artifactual
• Up to 30-50% of acid suppression therapy
may be inappropriate in outpatients and
hospital inpatients
• Question the indication for and risks of
chronic PPI’s on a regular basis