Proton Pump Inhibitors vs.

Histamine2-Receptor
Antagonists for Stress Ulcer Prophylaxis
Battle of the Acid Suppressants

Andrew J. Burris, Pharm.D.

PGY1 Pharmacy Resident
University Health System, San Antonio, Texas
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center,
University of Texas Health Science Center at San Antonio

February 7, 2014

Learning Objectives:
1. Describe the pathophysiology associated with stress-related mucosal disease
2. Identify appropriate indications for stress ulcer prophylaxis
3. Identify when stress ulcer prophylaxis should be discontinued
4. Evaluate the safety and efficacy associated with histamine2-receptor antagonists and proton
pump inhibitors
 Stress-Related Mucosal Disease

I. What is stress-related mucosal disease (SRMD)?1-3

A. Acute superficial inflammatory lesions of the gastric mucosa
B. Occurs during critical illness
C. Continuum of manifestations

• Involves superficial mucosal damage

Stress-Related • Primarily erosions
Injury

• Involve focal deep mucosal damage

• High risk for bleeding
Stress Ulcer

2
Figure 1. Stress-Related Mucosal Disease Progression

II. Definitions of gastrointestinal (GI) bleeding

A. Occult bleeding4
i. Not visible to naked eye
ii. Detected via guaiac test
B. Overt bleeding4
i. Visible to naked eye
ii. Examples include hematemesis, hematochezia, and coffee ground aspiration
C. Clinically-significant bleeding5
i. Overt bleeding complicated by:
1. Hemodynamic instability
2. Decreased hemoglobin requiring blood transfusion
ii. Should be used as outcome measure for all trials
iii. Increased morbidity and mortality6
1. Increase intensive care unit (ICU) length of stay by 11 days
2. Mortality increased seven-fold

III. What is the incidence of SRMD in the ICU?1

A. 75-100% of patients have endoscopically detectable mucosal damage within 24 hours6,7
B. Up to 25% of patients develop overt gastric bleeding6
D. Clinically-significant GI bleeding ranges from 0.6-5%6

Burris AJ Page 2
 IV. Pathophysiology of SRMD1,3

Critical Illness
↓Cardiac output
↑Catecholamines → ↑vasoconstriction
Proinflammatory cytokine release

Splanchnic hypoperfusion

↓GI motility
Mucosal ischemia
Acid back diffusion
Reduced HCO3 secretion
Impaired mucous production

Acute stress ulcer

3
Figure 2. Pathophysiology of Stress Ulcers

V. What are the risk factors associated with SRMD?1-4,7

A. Cook et al.5 – prospective, multicenter cohort study
i. 2,252 ICU patients evaluated for potential risk factors for stress ulceration
ii. Two independent risk factors
1. Respiratory failure
2. Coagulopathy
iii. Low incidence of clinically-significant bleeding
1. Patients with one or both independent risk factor(s)  3.7%
2. Patients with neither risk factor  0.1%
B. Hastings et al.8 randomized 100 patients at risk for stress ulcers to prophylaxis vs. no
prophylaxis
i. Increased risk of bleeding with increasing number of risk factors

Burris AJ Page 3
Table 1. Risk Factors for SRMD5
Mechanical ventilation >48 hours*
Coagulopathy*
INR >1.5
PTT >2 times control value
Platelet count <50,000
Hypotension
Severe sepsis
Hepatic failure
Spinal cord injury
Hepatic or renal transplantation
Thermal injury (>35% body surface area)
Multiple trauma with Injury Severity Score ≥16
General (medical, surgical, respiratory) ICU populations
Head injury (GCS ≤10) or inability to obey simple commands
History of gastric ulceration or bleeding during the year before admission
Presence of at least 2 of the following:
Sepsis
ICU stay >1 week
Occult bleeding for ≥ 6 days
Corticosteroid therapy (>250 mg of hydrocortisone or equivalent daily)
*Independent risk factors; INR, International Normalized Ratio; PTT, Partial Thromboplastin Time; GCS, Glasgow Coma Scale

Stress Ulcer Prophylaxis

I. What are the indications for stress ulcer prophylaxis (SUP) in ICU patients?1
A. Prophylaxis only recommended for subset of ICU patients (Table 1)
B. Discontinue when risk factors have resolved

II. What is the role for SUP in the non-ICU setting?1

A. Qadeer et al.9 (n=17,707 patients admitted to general medicine service)
i. Incidence of hospital-acquired GI bleeding  0.4%
ii. No protective benefit seen with prophylactic use
iii. Rates of bleeding and all-cause mortality similar between two groups
B. SUP not routinely indicated in this population

1971 1984-1994 2000 2010’s

st
1 reported case 1983 CSB ranged FDA approved CSB reported
series of SRMD FDA approved from 0.1-39% omeprazole & incidence ≤ 5%
ranitidine pantoprazole 6%

1986
1970’s 2001
1977 FDA approved
CSB ranged from FDA approved
FDA approved famotidine 1995
5.3% - 33% esomeprazole
cimetidine FDA approved
lansoprazole
CSB: clinically significant bleeding;
10,11
Figure 3. Stress Ulcer Prophylaxis Timeline FDA: Food and Drug Administration

Burris AJ Page 4
 III. Why did the incidence of bleeding change over time?1,4
A. Enteral feeding
B. Low tidal volume ventilation
C. Prompt and adequate fluid resuscitation

IV. What are the options for SUP?1-4

A. Antacids
i. Mechanism of action (MOA)
1. Directly buffer or neutralize acid contents of stomach
ii. Efficacy
1. Hastings et al.8 randomized 100 patients at risk for stress ulcers
a. Prophylaxis with antacids vs. no prophylaxis
b. Decreased bleeding rate when antacid therapy titrated to pH
>3.5 (p<0.005)
iii. Limitations
1. Administered every 1-2 hours for adequate acid neutralization
2. High dose antacids increase risk of aspiration pneumonia and toxicity
a. Highest risk in patients with renal dysfunction
B. Sucralfate
i. MOA
1. Adheres to epithelial cells and forms protective barrier
2. No acid-neutralizing activity
ii. Efficacy
1. Cook et al.12 randomized 1,200 ICU patients to intravenous (IV)
ranitidine vs. sucralfate
a. Clinically significant GI bleeding higher in the sucralfate group
(3.8%) vs. ranitidine (1.7%) group (p=0.02)
b. No significant difference in the incidence of pneumonia
iii. Limitations
1. Constipation
2. Hypophosphatemia
3. Nasogastric tube occlusion
4. Aluminum toxicity (chronic renal insufficiency)
5. Decreased absorption of concomitantly administered oral medications
C. Histamine2-receptor antagonists (H2RAs)
i. MOA (Figure 4)
1. Inhibit histamine-stimulated acid secretion by blocking H2-receptor
2. Highly selective with little or no effect on other histamine receptors
ii. Efficacy
1. H2RAs are significantly better than placebo, antacids and sucralfate9
2. Proton pump inhibitors vs. H2RAs  to be determined (TBD)
iii. Adverse effects
1. Tolerance
2. Drug Interactions
a. Cimetidine = primary offender
b. Inhibition of cytochrome P450s
3. Thrombocytopenia
4. Renal dysfunction requires dose adjustment

Burris AJ Page 5
 iv. Agents
1. Ranitidine (Zantac®)
2. Famotidine (Pepcid®)
3. Cimetidine (Tagamet®)
D. Proton pump inhibitors (PPIs)
i. MOA (Figure 4)
1. Inhibit gastric acid secretion by inhibition of H+/K+ ATPase pump
ii. Efficacy
1. PPIs vs. H2RAs  TBD
iii. Adverse effects
1. Drug interactions
2. Hypomagnesemia
3. Increased risk of infection
4. Acute interstitial nephritis
iv. Warnings/Precautions
1. Bone fracture
2. Hypomagnesemia
3. Vitamin B12 deficiency
4. Clostridium difficile-associated diarrhea
v. Agents
1. Omeprazole (Prilosec®)
2. Pantoprazole (Protonix®)
3. Esomeprazole (Nexium®)
4. Lansoprazole (Prevacid®)
5. Rabeprazole (Aciphex®)

ACh

M3
Gastrin
K+

CCK2 + H+/K+ Proton pump

+ ATPase inhibitors
+
Histamine H+

H2 receptor-
antagonists H2
Gastric lumen
Parietal cell pH 2

13
Figure 4. Mechanism of Action for H2RAs & PPIs

Burris AJ Page 6
 Discontinuation of Stress Ulcer Prophylaxis

I. Is SUP used appropriately in the inpatient setting?1

A. Patients who are critically-ill with zero risk factors  70% receive SUP
B. Original risk factors resolve  SUP is continued after ICU downgrade
C. SUP often used in medicine patients and continued on hospital discharge

II. What is the economic impact of the inappropriate use of SUP?1

A. Substantial economic impact on the overuse of SUP
i. Heidelbaugh et al.14 (n=1,769 general medicine patients)
1. Inappropriate SUP use increased annual inpatient and outpatient costs
$111,791
ii. Managed care organization15
1. 20,000 patients prescribed PPI inappropriately at hospital discharge
2. Inappropriate continuation for 30 days associated with cost of US $3
million over four years
iii. Neither study accounted for costs incurred from complications of SUP

III. What strategies can reduce the overuse of SUP?1

A. Few studies have explored potential solutions
B. Interventions that improve prescribing patterns
i. Educational materials
ii. Daily medication reconciliation
iii. Pharmacist participation on rounds
C. Additional strategies
i. Reevaluate use of H2RAs and PPIs on standardized order sets
ii. Integrate decision-making prompts into the electronic medical record
D. Quality improvement studies are needed

Burris AJ Page 7
 What is the efficacy associated with PPIs and H2RAs?
16-18
Table 2. Meta-Analyses Evaluating Safety and Efficacy of PPIs vs. H2RAs for SUP
Lin PC et al. 2010 Barkun AN et al. 2012 Alhazzani W et al. 2013
Objective To examine the efficacy and safety of PPIs vs. H2RAs for stress-related upper GI bleeding
Study Selection Published Articles - 5 Published Articles – 8 Published Articles - 10
Powell 1993 Powell 1993 Powell 1993
Levy 1997 Levy 1997 Levy 1997
Kantorova 2004 Kantorova 2004 Kantorova 2004
Conrad 2005 Conrad 2005 Conrad 2005
Somberg 2008 Somberg 2008 Somberg 2008
Abstracts - 2 Hata 2005 Hata 2005
Phillips 1998 Solouki 2009 Solouki 2009
Azevedo 1999 Brophy 2010 Azevedo 2000
Abstracts - 5 Pan 2004
Phillips 1998 Risaliti 1993
De Azevedo 2000 Abstracts – 4
Morris 2001 Phillips 1998
Fink 2003 Morris 2001
Pan 2004 Fink 2003
Kotlyanskaya 2007
N 936 1,587 1,720
Inclusion Studies directly comparing any PPIs vs. any H2RAs (any drug, dose, or route of administration)
Exclusion Studies using placebo, antacids or Trials comparing different dosing Other interventions
sucralfate rather than H2RAs for regimens of the same molecule Pediatric population
comparator Observational studies
Primary Outcome Incidence of stress-related upper GI Rate of clinically significant upper Clinically important GI bleeding
bleeding GI bleeding Overt upper GI bleeding
Secondary Outcome Pneumonia Nosocomial Pneumonia Nosocomial pneumonia
ICU mortality All-cause mortality All-cause mortality
ICU LOS ICU LOS
Clostridium difficile infection
Statistics Random effect model Fixed effect model Random effect model
2 2 2
I statistic to assess heterogeneity I statistic to assess heterogeneity I statistic to assess
Pre-planned sensitivity & subgroup Pre-planned sensitivity analysis heterogeneity
analysis Funnel plot to assess publication Pre-planned sensitivity &
Funnel plot to assess publication bias bias subgroup analysis
Funnel plot to assess publication
bias
o o o o
Results No difference in 1 or 2 outcomes PPIs>H2RAs for 1 outcome PPIs>H2RAs for 1 outcome
(Pooled risk difference 0.04; 95% CI, (OR 0.30; 95% CI, 0.17-0.54) (RR 0.36; 95% CI, 0.19-0.68;
2 o 2
-0.09 to 0.01; p=0.08; I =66%) No difference in 2 outcomes p=0.002; I =0%)
o
No difference in 2 outcomes
No trials reported on C. difficile
NNT N/A 39 78

I. Critique of meta-analyses
A. Low quality studies
i. Levy et al.19 compared omeprazole to ranitidine
1. Included in all three meta-analyse
2. Clinically-significant bleeding appropriately defined
3. Differing number of risk factors between groups
a. Ranitidine (2.7) vs. omeprazole (1.9) (p<0.05)

Burris AJ Page 8
 4. High incidence of bleeding
a. Ranitidine (31%) vs. omeprazole (6%) (p<0.05)
b. Higher than reported rate (0-16%) from other studies
c. Barkun et al. reported overall incidence of 1.3%
5. Study accounted for 20% of weight
ii. Brophy et al.20 compared lansoprazole to famotidine
1. Only included in meta-analysis by Barkun et al.
2. Clinically-significant bleeding appropriately defined
a. Only overt bleeding reported
3. Clinically-significant bleeding is secondary outcome
a. Study not powered for outcome
B. Definitions of bleeding
i. Variable from study to study
ii. Few studies appropriately define clinically-significant bleeding
iii. In Barkun et al.17  7 studies have no definition
C. Data quality
i. Positives
1. Funnel plot performed
2. All assessed heterogeneity
3. Sensitivity and subgroup analysis preformed
4. Trial quality assessed
a. Higher quality studies showed smaller treatment effect
ii. Negatives
1. Heterogeneity seen in Lin et al.
a. No heterogeneity seen in Barkun et al.17 and Alhazzani et al.18
b. Five studies and one abstract included in all three meta-analysis
2. 40% of patients included  low risk of clinically significant bleeding
3. Publication/language bias seen via funnel plots

II. Take home points

A. Majority of studies included in meta-analyses did not appropriately define clinically-
significant bleeding
B. Significant heterogeneity among studies with regard to risk difference
C. Superior efficacy of PPIs compared to H2RAs is difficult to support with current available
evidence

What are the risks associated with PPIs and H2RAs?

I. PPIs are one of the most commonly prescribed classes of drugs worldwide21
A. Sales totaling US $26.9 billion dollars in 200522
B. Experts generally view PPIs as safe
C. Potential complications (↑ risk of infection) have caused concern

II. Community-acquired pneumonia (CAP)22

A. Proposed mechanisms
i. Increase in gastric pH  bacterial overgrowth and colonization
1. Subsequent translocation to lungs by aspiration

Burris AJ Page 9
 ii. H+/K+ ATPase also present in the respiratory tract
1. PPIs may alter pH of seromucinous secretions  bacterial growth
iii. Acid-suppressive drugs may impair function of neutrophils and natural killer
cells23

24,25
Table 3. Studies Evaluating the Risk of CAP with PPIs & H2RAs
Laheij RJ et al. 2004 Gulmez SE et al. 2007
Objective To examine the association between the use of acid-suppressive drugs and the risk of PNA
Study Design Nested case-control Case-control
N 364,683 34,176
Patient Population Primary care setting, data collected via IPCI Inpatient setting, data collected via County of
Funen
Inclusion One year history of valid database history Cases defined by first admission with CAP
No use of acid suppression before enrollment Index date = first registered date of CAP diagnosis
Exclusion Diagnosis of PNA in preenrollment period (1 Diagnosis of malignancy, recent d/c in last 7 days
year)
Statistics Nested case-control analysis preformed to ↓ Controls randomly extracted from population
confounders Matched by age & sex to the cases with a 4:1
o 10 controls from cohort matched with ratio
each case of PNA Logistic regression to estimate crude & adjusted
o Matched on sex, year of birth, & index ORs
date (date of first PNA) Stratified analyses were conducted by:
RR of PNA estimated with OR & adjusted for o Age
all covariates o Dose of PPI
o Recency of PPI
st
Results 19,459* received 1 Rx for acid-suppression 7,642 cases met inclusion/exclusion criteria
o H2RAs: n=10,177 o H2RAs: n=161
o PPIs: n=2,337 o PPIs: n=817
Pneumonia risk Pneumonia risk
o PPIs & H2RAs: adjusted OR, 1.27 o PPIs alone: adjusted OR, 1.5
(95% CI, 1.06-1.54) (95% CI, 1.3-1.7)
o PPIs alone: adjusted OR, 2.2  Associating current use with CAP
(95% CI, 1.4-3.5)  Highest risk in first 7 days
 Significant dose response (OR, 5.0; 95% CI, 2.1-11.7)
observed o H2RAs alone: adjusted OR, 1.1
o H2RAs alone: adjusted OR, 1.7 (95% CI, 0.8-1.3)
(95% CI, 0.8-2.9)  No definite association found
 No dose response observed
NNH PPIs = 226 PPIs = 6
H2RAs = 508 H2RAs = N/A
Critique Large case-control study Large case-control study
o Appropriate for study on adverse effect o Appropriate for study on adverse effect
Nested analysis conducted to ↓ confounders ↑ risk of CAP with PPI use
Higher risk when evaluating only laboratory- Highest risk seen in first seven days
confirmed PNA No association observed in H2RA users
↑ risk most pronounced with PPI use
o Dose-response relationship
NNH calculated for H2RAs with no statistical
significance
PNA, pneumonia; IPCI, Integrated Primary Care Information; RR, relative risk; OR, odds ratio; Rx, prescription; CI, confidence interval; d/c,
discharge; N/A, not applicable; *Some patients used both H2RAs plus PPIs

Burris AJ Page 10
 B. Take home points
i. Increased risk of CAP observed with PPI use and no risk observed in H2RA users
ii. Most pronounced risk seen in current users of PPIs and higher doses
iii. Case-control study and meta-analysis report consistent results26,27
III. Nosocomial pneumonia (PNA)
A. Proposed mechanisms
i. Same proposed mechanisms as CAP
Table 4. Studies Evaluating the Risk of Nosocomial Pneumonia with PPIs & H 2RAs
Miano TA et al. 2009
Objective To determine whether SUP with PPI ↑
PNA risk compared with H2RA
Study Design Retrospective cohort analysis
N 834
Patient Critically ill patients
Population Cardiothoracic surgery patients
All patients receiving acid-suppressive
therapy
Inclusion Age > 18 years
Admitted to cardiothoracic surgery
service
Received either pantoprazole or
ranitidine without crossover
Exclusion Documented aspiration during
hospital admission
Diagnosis of PNA within preceding 3
months
History of immunosuppression
Diagnosis of HIV infection
Recent SOT
Statistics Propensity score analysis to balance
the distribution of covariates
Multivariate logistic regression model
to control for selection bias
Burris AJ
22,28
Eom CS et al. 2011
To examine the association between acid-suppressive
medication and PNA
Meta-analysis
31 studies
o 5 case-control
o 3 cohort studies
o 23 randomized controlled trials
Observational studies: n=1,965,358
RCTs: n=4,168
Mixed
Eight observational studies
o Five evaluating risk of CAP
o Three evaluating risk of HAP
o Evaluating risk of PNA with PPIs
RCTs
o ICU setting
o Evaluating risk of HAP with H2RAs
Case-control study, cohort study or RCT; investigating the
association between acid- suppressive drugs and risk of PNA
Study did not include data about risk of PNA
Results for PPIs and H2RAs not reported separately
Observational studies
o Pooled OR & 95% CI from the adjusted ORs & 95% CIs
reported in studies
RCTs
o Summary relative risk from the relative risks of
individual trials
2
Higgins I used to assess heterogeneity
Random-effects model for overall effect
Page 11
Table 4. (Continued) Studies Evaluating the Risk of Nosocomial Pneumonia with PPIs & H2RAs
Miano TA et al. 2009 Eom CS et al. 2011
Results 834 patients Observational studies
o PPIs: n=377 o PPI use ↑ risk of PNA
o H2RAs: n=457 o Adjusted OR, 1.27 (95% CI, 1.11-1.46)
Nosocomial PNA incidence RCTs
o Pantoprazole: n=35 (9.3%) o H2RA use ↑ risk of HAP
o Ranitidine: n=7 (1.5%) o RR 1.22 (95% CI, 1.01-1.48)
 Unadjusted OR, 6.6 (95% CI, 2.9- Subgroup analysis
14.9) o Higher dose of PPIs more strongly
o Propensity adjusted, multivariable linear associated with PNA
regression found pantoprazole to be o Highest risk seen in first seven days
independent risk factor Adjusted OR, 3.95 (95% CI, 2.86-5.45)
 Adjusted OR, 2.7 ( 95% CI, 1.1-6.7; o Among high-quality RCTs no risk of PNA
p=0.034) seen with H2RAs
RR 0.96 (95% CI, 0.65-1.43)
NNH PPIs = 13 Acid-suppression = 200
Critique Large comparison of PPIs & H2RAs in critical care Large meta-analysis including RCTs &
population observational studies
Propensity sore methodology was used to balance When looking at high quality RCTs no risk
covariate distribution observed with H2RA use
Results may not apply to other populations Risk of PNA still seen in high quality observational
studies
Use of acid-suppressive drugs associated with ↑
risk of PNA
SUP, stress ulcer prophylaxis; PPI, proton pump inhibitor; PNA, pneumonia; H2RA, histamine2-receptor antagonist; CAP, community-acquired
pneumonia; HAP, hospital-acquired pneumonia; RCTs, randomized controlled trials; HIV, human immunodeficiency virus; SOT, solid organ
transplant; OR, odds ratio; CI, confidence interval; RR, relative risk

B. Take home points

i. PPI use associated with increased risk of nosocomial PNA in ICU setting
ii. Results echo CAP studies with highest risk in recent users and higher doses
iii. Results of high-quality RCTs did not find an increased risk of PNA with H2RAs

IV. Clostridium difficile infection (CDI)21

A. Proposed mechanism
i. ↑ gastric pH > 4 allows ≥50% of ingested bacteria to escape acid barrier
ii. Disruption in natural gut bacteria
1. Lack of destruction of ingested microorganism
2. ↑ ascending bacterial colonization from the intestine

Burris AJ Page 12
 29,30
Table 5. Studies Evaluating the Risk of Clostridium difficile Infection with PPIs & H2RAs
Beaulieu M et al. 2007 Kwok CS et al. 2012
Objective To determine if PPIs & H2RAs are risk factors for CDAD in To evaluate risk of CDI with PPI use
hospitalized ICU patients To evaluate risk of CDI with PPI use + abx
To evaluate risk of CDI with H2RAs
Study Cohort study Meta-analysis
Design C. difficile (+) MICU patients 42 observational studies
o 30 case-control
o 12 cohort
N 827 313,000
Inclusion MICU admission ≥ 24 hours Studies that reported OR/RR for CDI with PPI
CDAD (+) use or
o Diarrhea ≥ 24 hours Reported sufficient raw data to calculate
o Enzyme immunoassay (+) for C. difficile toxins A & B OR/RR
Exclusion CDAD diagnosed before study period Studies not evaluating PPI use and risk of CDI
Statistics Kaplan-Meier curves constructed Random effect model
2
o Day 0 = day of MICU admission I statistic to assess heterogeneity
Multivariate logistic regression model o 30-60% moderate
Prespecified subgroup analysis
Rothman synergy index
o Assessing PPI + antibiotic risk
Results 335 (40.5%) patients received PPI Risk of CDI with PPI use
470 (56.8%) patients received H2RA o 39 studies
2
182 (22%) patients received no acid suppression o OR 1.74 (95% CI, 1.47-2.05; p<0.001; I
Kaplan-Meier analysis = 85%)
o Clindamycin HR, 2.06 (95% CI, 1.06-4.00) Risk of recurrent CDI with PPI use
 p≤0.05 o 3 studies
2
o Macrolide HR, 1.85 (95% CI, 1.07-3.17) o OR 2.51 (95% CI, 1.16-5.44; p = 0.02; I
 p≤0.05 = 78%)
Independent risk factors Risk of CDI with PPI use & abx
o Age ≥ 65 years HR, 2.33 (95% CI, 1.23-4.40) o 6 studies
 p≤0.01 o OR 1.96 (95% CI, 1.03-3.70)
o Female sex HR, 1.68 (95% CI, 1.14-2.48) o Rothman’s synergy index 1.36
 p ≤ 0.01 o Attributable proportion of risk 19%
No significant difference in PPIs & H2RAs Risk of CDI with H2RAs*
o PPIs HR, 0.90 (95% CI, 0.59-1.38) o 15 studies
o H2RAs HR, 0.78 (95% CI, 0.50-1.23) o OR 0.71 (95% CI, 0.53-0.97)
NNH N/A PPIs = 67
H2RAs = 121
PPIs + abx = 22
NNT N/A PPIs  H2RAs = 69
Critique Risk of CDAD assessed in the ICU setting Large meta-analysis of observational studies
o Limited data in this setting where SUP is mostly o Appropriate for study on adverse
indicated effects
No significant difference between no prophylaxis & PPI use associated with a 74% ↑ risk of CDI
PPI/H2RA use Pooled analysis showed ↑ risk of recurrent
Identified risk factors for developing CDAD CDI
o Women Unexplained significant heterogeneity among
o Older age (≥65 years) studies
o Clindamycin/macrolide exposure No asymmetry testing performed to assess
publication bias

CDAD, Clostridium difficile-associated disease; MICU, medical ICU; CDI, Clostridium difficile infection; PPI, proton pump inhibitor; abx, antibiotic;
H2RAs, histamine2-receptor antagonists; OR, odds ratio; RR, risk ratio; CI, confidence interval; *In comparison to PPIs

Burris AJ Page 13
 B. Take home points
i. Conflicting results
ii. Significant unexplained heterogeneity also observed in Janarthanan et al.31
1. Janarthanan et al.31 conducted a meta-analysis (n=288,620) to
summarize the association between CDAD and PPIs
2. Included similar studies as Kwok et al.30 and heterogeneity unexplained
by subgroup analysis
3. Results showed a 65% increase in incidence of CDAD among PPI users
iii. PPI use may be associated with an increase risk of CDI and recurrent CDI
1. Quality of evidence is low  interpret cautiously

V. Summary of risks
A. Studies have demonstrated association but not causality
B. All associated risks were greater with PPIs as compared to H2RAs
C. PPIs have also been linked to potential long-term side effects or complications21
i. Fracture risk
ii. Iron deficiency
iii. Hypomagnesaemia
iv. Vitamin B12 deficiency
D. Many evaluations did not find a risk with H2RAs

21
Table 6. Potential Adverse Effects with PPIs
Adverse effect Underlying Strength of Consistency of Clinical implications
mechanism association association
CAP Plausible Weak to Inconsistent PPI therapy should only be used for
moderate results appropriate indications
OR > 2
Nosocomial Plausible Weak to Inconsistent PPI therapy should only be used for
PNA moderate results appropriate indications
OR > 2
C. difficile Plausible Weak to Inconsistent Consider potential alternative therapy in
Infection moderate results patients with concurrent CDI risk factors
OR > 2
CAP, community-acquired pneumonia; PNA, pneumonia; CDI, Clostridium difficile infection; OR, odds ratio

Summary and Recommendations

I. Summary
A. SUP is important in preventing clinically significant bleeding
B. Acid suppressive therapy is not indicated in everyone
C. Discontinuation of SUP is warranted when original risk factors resolve
D. Limitations of current available evidence make it difficult to claim PPIs as the superior
agent
E. Increases in gastric pH are associated with an increase risk of infection
i. CAP32
1. Management of an uncomplicated case of PNA costs approximately US
$7,000 dollars
2. 40% attributable mortality in patients requiring admission to an ICU

Burris AJ Page 14
 33
ii. Nosocomial pneumonia
1. Hospital-acquired pneumonia (HAP) has an associated cost of more than
US $40,000 dollars
2. Overall mortality attributed to HAP may be as high as 50%
iii. Clostridium difficile infection34
1. 6% attributable mortality in critically ill patients

Table 7. Comparison of Number Needed to Harm with PPIs and Attributable Mortality in ICU Patients
CAP Nosocomial PNA Clostridium difficile Infection
NNH Attributable NNH Attributable NNH Attributable
N=6 Mortality N=13 Mortality N=22 Mortality

II. Recommendations
A. With advancements in medicine SUP may no longer be required
B. Healthcare professionals should weigh the risks and benefits when choosing an agent
for SUP
C. If SUP is indicated, histamine2-receptor antagonists are the preferred agent of choice

Burris AJ Page 15
 References

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 Appendix

Appendix A. Summary of Individual Studies Included in Meta-Analyse

Study N Intervention Definition of Bleeding Outcomes
Powell et al. 41 Omeprazole 80 mg IV bolus, then 40 mg IV Bloody nasogastric tube aspirate Clinically important
1993 bolus TID (n=10); omeprazole 80 mg IV bolus bleeding; mortality
then 40 mg IV infusion TID (n=10); ranitidine
50 mg IV TID (n=11); placebo (n=10)
Levy et al. 67 Omeprazole 40 mg NG daily (n=32); ranitidine Gross bleeding as manifest by hematemesis, aspiration of coffee ground Clinically important
1997 50 mg IV bolus, then 150 mg IV daily (n=35) material from the NG tube, or melena, or a ↓ Hgb of > 2 g/dL complicated by bleeding; nosocomial
either the need for transfusion or hemodynamic instability PNA; mortality; ICU
LOS
Kantorova et 287 Omeprazole 40 mg IV daily (n=72); famotidine Overt bleeding with one of the following: a) Drop in SBP >20 mm Hg or rise in Clinically important
al. 2004 40 mg IV BID (n=71); sucralfate 1 g NG QID HR >20 beats/min within 24 hrs of the onset of bleeding not explained by bleeding; nosocomial
(n=69); placebo (n=75) other causes; or b) Drop in Hgb by 2 g/dL or more not explained by other PNA; mortality; ICU
causes LOS; adverse events
Conrad et al. 359 Omeprazole suspension 40 mg NG BID a) Bright right blood not clearing after tube adjustment and lavage with saline Clinically important
2005 loading, then 40 mg NG daily (n=178); for 5-10 mins; b) 8 hrs of persistent gastro-occult positive coffee ground bleeding; overt
cimetidine 300 mg IV bolus, then infusion at material with aspirates every 2 hrs not clearing with lavage; or c) Persistent bleeding; PNA;
50 mg/hr (n=181) gastro-occult positive coffee ground material over 2-4 hrs on d 3-14 in three mortality
consecutive aspirates not clearing with lavage
Somberg et al. 202 Pantoprazole 40 mg IV daily (n=32); a) Hematemesis or bright red blood in gastric aspirate that did not clear after Clinically important
2008 pantoprazole 40 mg IV BID (n=38); adjustment of NG or OG tube and a 5- to 10-min lavage with iced water or bleeding; PNA;
pantoprazole 80 mg IV daily (n=23); saline; b) Persistent coffee ground material for 8 consecutive hrs that did not mortality; adverse
pantoprazole 80 mg IV BID (n=39); clear with a 100 mL lavage, or was accompanied by a 5% ↓ in Hct; c) A ↓ in events
pantoprazole 80 mg IV TID (n=35); cimetidine Hct requring one or more transfusions that occurred in the absence of any
300 mg IV bolus, then 50 mg/hr infusion obvious source and required further diagnostic studies; or d) Melena or frank
(n=35) bloody stools from an upper GI source
Hata et al. 210 Rabeprazole PO 10 mg daily (n=70); ranitidine Upper GI bleeding (hematemesis, coffe ground emesis, or melena) confirmed Overt bleeding;
2005 PO 30 mg daily (n=70); teprenone 150 mg NG with gastrodudenoscopy adverse events
daily (n=70)
Solouki et al. 129 Omeprazole 20 mg NG BID (n=61); ranitidine Overt bleeding associated with one of the following: a) A 20 mm Hg ↓ in SBP Clinically important
2009 50 mg IV BID (n=68) or DBP during the first 24 hrs after bleeding; b) A 20 beat/min ↑ HR or 10 mm bleeding; nosocomial
Hg in SBP in a standing position; c) A 2 g/dL ↓ of Hgb or 6% decrease in Hct PNA; mortality; ICU
during the first 24 hrs after bleeding; d) Lack of ↑ in Hgb after infusing two LOS
units of packed cells
Azevedo et al. 108 Omeprazole 40 mg IV BID (n=38); ranitidine Upper GI bleeding including hematemesis, bright red blood, coffee ground Overt bleeding;
2000 150 mg/day infusion (n=38); sucralfate 1 g NG emesis or melena nosocomial PNA;
QID (n=32) mortality; ICU LOS
Appendix A. (Continued) Summary of Individual Studies Included in Meta-Analyse
Study N Intervention Definition of Bleeding Outcomes
Pan et al. 30 Rabeprazole PO 20 mg once daily (n=20); Melena or hematemesis Overt bleeding
2004 famotidine IV 40 mg BID (n=10)
Risaliti et al. 28 Omeprazole 40 mg daily IV, then 20 mg PO No clear definition Clinically important
1993 daily (n=14); ranitidine 150 mg IV daily, then bleeding; overt
300 mg PO daily (n=14) bleeding; adverse
events
Phillips et al. 58 Omeprazole 40 mg NG loading, then 20 mg No clear definition Clinically important
1998 NG daily (n=33); ranitidine 50 mg IV loading, bleeding; PNA;
then 150-200 mg/day infusion (n=25) adverse events
Fink et al. 189 (4:1) Randomization as follows: IV No clear definition UGI bleeding;
2003 pantoprazole 40 mg daily, 40 mg BID, 80 mg mortality
daily, or 80 mg BID (n=158); IV cimetidine 300
mg bolus, then 50 mg/hr infusion (n=31)
Morris et al. 202 (5:1) Randomization as follows: IV No clear definition UGI bleeding;
2001 pantoprazole 40 mg daily, 40 mg BID, 80 mg nosocomial PNA
daily, 80 mg BID, or 80 mg TID (n=169); IV
cimetidine 300 mg IV loading, then 50 mg/hr
(n=33)
Kotlyanskaya 66 Lansoprazole (suspension) NG (n=22); Overt bleeding associated with change in hemodynamics or drop in the Hgb Clinically important
et al. 2007 lansoprazole (tablet) NG (n=23); ranitidine bleeding; overt
(n=21) (dose and frequency not reported) bleeding; nosocomial
PNA; drug adverse
events
Brophy et al. 51 Lansoprazole (suspension) 30 mg NG daily Endoscopic evidence of stress-related mucosal bleeding, bright red blood per Time pH ≥ 4;
2010 (n=23); famotidine 20 mg IV BID (n=23) NG tube that did not clear after lavage, or overt bleeding (hematemesis, percentage of time
bloody gastric aspirate, melana, or hematochezia) plus either a ↓ in BP of 20 gastric residuals < 28
mm Hg, or a ↓ of 2 g/dL in Hg and two units of blood transfused within 24 hrs mL; clinically
significant bleeding
IV, intravenous; BID, twice daily; TID, three times daily; QID, four times daily; NG, nasogastric; OG, orogastric; Hgb, hemoglobin; Hct, hematocrit; PNA, pneumonia; LOS, length of stay; BP, blood
pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; GI, gastrointestinal; hrs, hours; d, day