Proton Pump Inhibitors vs. Histamine 2 -Receptor Antagonists for Stress Ulcer Prophylaxis Battle of the Acid Suppressants

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1 Proton Pump Inhibitors vs. Histamine 2 -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 histamine 2 -receptor antagonists and proton pump inhibitors

2 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 Stress-Related Injury Involves superficial mucosal damage Primarily erosions Stress Ulcer Involve focal deep mucosal damage High risk for bleeding Figure 1. Stress-Related Mucosal Disease Progression 2 II. Definitions of gastrointestinal (GI) bleeding A. Occult bleeding 4 i. Not visible to naked eye ii. Detected via guaiac test B. Overt bleeding 4 i. Visible to naked eye ii. Examples include hematemesis, hematochezia, and coffee ground aspiration C. Clinically-significant bleeding 5 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 mortality 6 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 % of patients have endoscopically detectable mucosal damage within 24 hours 6,7 B. Up to 25% of patients develop overt gastric bleeding 6 D. Clinically-significant GI bleeding ranges from 0.6-5% 6 Burris AJ Page 2

3 IV. Pathophysiology of SRMD 1,3 Critical Illness Cardiac output Catecholamines vasoconstriction Proinflammatory cytokine release Splanchnic hypoperfusion GI motility Mucosal ischemia Acid back diffusion Reduced HCO 3 secretion Impaired mucous production Acute stress ulcer Figure 2. Pathophysiology of Stress Ulcers 3 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

4 Table 1. Risk Factors for SRMD 5 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 st reported case series of SRMD 1983 FDA approved ranitidine CSB ranged from % 2000 FDA approved omeprazole & pantoprazole 2010 s CSB reported incidence 5% 6% 1970 s CSB ranged from 5.3% - 33% 1977 FDA approved cimetidine 1986 FDA approved famotidine 1995 FDA approved lansoprazole Figure 3. Stress Ulcer Prophylaxis Timeline 10, FDA approved esomeprazole CSB: clinically significant bleeding; FDA: Food and Drug Administration Burris AJ Page 4

5 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. Histamine 2 -receptor antagonists (H 2 RAs) i. MOA (Figure 4) 1. Inhibit histamine-stimulated acid secretion by blocking H 2 -receptor 2. Highly selective with little or no effect on other histamine receptors ii. Efficacy 1. H 2 RAs are significantly better than placebo, antacids and sucralfate 9 2. Proton pump inhibitors vs. H 2 RAs 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

6 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. H 2 RAs 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 B 12 deficiency 4. Clostridium difficile-associated diarrhea v. Agents 1. Omeprazole (Prilosec ) 2. Pantoprazole (Protonix ) 3. Esomeprazole (Nexium ) 4. Lansoprazole (Prevacid ) 5. Rabeprazole (Aciphex ) ACh M 3 Gastrin Histamine CCK 2 + K H+/K+ ATPase H + Proton pump inhibitors H 2 receptorantagonists H 2 Parietal cell Gastric lumen ph 2 Figure 4. Mechanism of Action for H 2 RAs & PPIs 13 Burris AJ Page 6

7 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 organization ,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 H 2 RAs 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

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

9 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 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 clinicallysignificant bleeding B. Significant heterogeneity among studies with regard to risk difference C. Superior efficacy of PPIs compared to H 2 RAs is difficult to support with current available evidence What are the risks associated with PPIs and H 2 RAs? I. PPIs are one of the most commonly prescribed classes of drugs worldwide 21 A. Sales totaling US $26.9 billion dollars in 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

10 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 cells 23 Table 3. Studies Evaluating the Risk of CAP with PPIs & H 2 RAs 24,25 Laheij RJ et al Gulmez SE et al 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 No use of acid suppression before enrollment Cases defined by first admission with CAP Index date = first registered date of CAP diagnosis Exclusion Diagnosis of PNA in preenrollment period (1 year) Statistics Nested case-control analysis preformed to confounders o 10 controls from cohort matched with each case of PNA o Matched on sex, year of birth, & index date (date of first PNA) RR of PNA estimated with OR & adjusted for all covariates Results 19,459* received 1 st Rx for acid-suppression o H 2 RAs: n=10,177 o PPIs: n=2,337 Pneumonia risk o PPIs & H 2 RAs: adjusted OR, 1.27 (95% CI, ) o PPIs alone: adjusted OR, 2.2 (95% CI, ) Significant dose response observed o H 2 RAs alone: adjusted OR, 1.7 (95% CI, ) No dose response observed NNH PPIs = 226 H 2 RAs = 508 Critique Large case-control study o Appropriate for study on adverse effect Nested analysis conducted to confounders Higher risk when evaluating only laboratoryconfirmed PNA risk most pronounced with PPI use o Dose-response relationship NNH calculated for H 2 RAs with no statistical significance Diagnosis of malignancy, recent d/c in last 7 days Controls randomly extracted from population Matched by age & sex to the cases with a 4:1 ratio Logistic regression to estimate crude & adjusted ORs Stratified analyses were conducted by: o Age o Dose of PPI o Recency of PPI 7,642 cases met inclusion/exclusion criteria o H 2 RAs: n=161 o PPIs: n=817 Pneumonia risk o PPIs alone: adjusted OR, 1.5 (95% CI, ) Associating current use with CAP Highest risk in first 7 days (OR, 5.0; 95% CI, ) o H 2 RAs alone: adjusted OR, 1.1 (95% CI, ) No definite association found PPIs = 6 H 2 RAs = N/A Large case-control study o Appropriate for study on adverse effect risk of CAP with PPI use Highest risk seen in first seven days No association observed in H 2 RA users 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 H 2RAs plus PPIs Burris AJ Page 10

11 B. Take home points i. Increased risk of CAP observed with PPI use and no risk observed in H 2 RA users ii. Most pronounced risk seen in current users of PPIs and higher doses iii. Case-control study and meta-analysis report consistent results 26,27 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 2 RAs 22,28 Miano TA et al Eom CS et al Objective To determine whether SUP with PPI PNA risk compared with H 2 RA To examine the association between acid-suppressive medication and PNA Study Design Retrospective cohort analysis Meta-analysis 31 studies o 5 case-control o 3 cohort studies o 23 randomized controlled trials N 834 Observational studies: n=1,965,358 RCTs: n=4,168 Patient Population Inclusion Exclusion Statistics Critically ill patients Cardiothoracic surgery patients All patients receiving acid-suppressive therapy Age > 18 years Admitted to cardiothoracic surgery service Received either pantoprazole or ranitidine without crossover Documented aspiration during hospital admission Diagnosis of PNA within preceding 3 months History of immunosuppression Diagnosis of HIV infection Recent SOT Propensity score analysis to balance the distribution of covariates Multivariate logistic regression model to control for selection bias 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 H 2 RAs 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 H 2 RAs 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 Higgins I 2 used to assess heterogeneity Random-effects model for overall effect Burris AJ Page 11

12 Table 4. (Continued) Studies Evaluating the Risk of Nosocomial Pneumonia with PPIs & H 2 RAs Miano TA et al Eom CS et al Results 834 patients o PPIs: n=377 o H 2 RAs: n=457 Nosocomial PNA incidence o Pantoprazole: n=35 (9.3%) o Ranitidine: n=7 (1.5%) Unadjusted OR, 6.6 (95% CI, ) o Propensity adjusted, multivariable linear regression found pantoprazole to be independent risk factor Adjusted OR, 2.7 ( 95% CI, ; p=0.034) Observational studies o PPI use risk of PNA o Adjusted OR, 1.27 (95% CI, ) RCTs o H 2 RA use risk of HAP o RR 1.22 (95% CI, ) Subgroup analysis o Higher dose of PPIs more strongly associated with PNA o Highest risk seen in first seven days Adjusted OR, 3.95 (95% CI, ) o Among high-quality RCTs no risk of PNA seen with H 2 RAs RR 0.96 (95% CI, ) NNH PPIs = 13 Acid-suppression = 200 Critique Large comparison of PPIs & H 2 RAs in critical care population Propensity sore methodology was used to balance covariate distribution Results may not apply to other populations Large meta-analysis including RCTs & observational studies When looking at high quality RCTs no risk observed with H 2 RA use 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; H 2RA, histamine 2-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 H 2 RAs 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

13 Table 5. Studies Evaluating the Risk of Clostridium difficile Infection with PPIs & H 2 RAs 29,30 Objective Study Design Beaulieu M et al Kwok CS et al To determine if PPIs & H 2 RAs are risk factors for CDAD in hospitalized ICU patients Cohort study C. difficile (+) MICU patients To evaluate risk of CDI with PPI use To evaluate risk of CDI with PPI use + abx To evaluate risk of CDI with H 2 RAs Meta-analysis 42 observational studies o 30 case-control o 12 cohort N ,000 Inclusion MICU admission 24 hours CDAD (+) o Diarrhea 24 hours o Enzyme immunoassay (+) for C. difficile toxins A & B Studies that reported OR/RR for CDI with PPI use or Reported sufficient raw data to calculate OR/RR Exclusion CDAD diagnosed before study period Studies not evaluating PPI use and risk of CDI Statistics Results Kaplan-Meier curves constructed o Day 0 = day of MICU admission Multivariate logistic regression model 335 (40.5%) patients received PPI 470 (56.8%) patients received H 2 RA 182 (22%) patients received no acid suppression Kaplan-Meier analysis o Clindamycin HR, 2.06 (95% CI, ) p 0.05 o Macrolide HR, 1.85 (95% CI, ) p 0.05 Independent risk factors o Age 65 years HR, 2.33 (95% CI, ) p 0.01 o Female sex HR, 1.68 (95% CI, ) p 0.01 No significant difference in PPIs & H 2 RAs o PPIs HR, 0.90 (95% CI, ) o H 2 RAs HR, 0.78 (95% CI, ) NNH N/A PPIs = 67 H 2 RAs = 121 PPIs + abx = 22 NNT N/A PPIs H 2 RAs = 69 Critique Risk of CDAD assessed in the ICU setting o Limited data in this setting where SUP is mostly indicated No significant difference between no prophylaxis & PPI/H 2 RA use Identified risk factors for developing CDAD o Women o Older age ( 65 years) o Clindamycin/macrolide exposure Random effect model I 2 statistic to assess heterogeneity o 30-60% moderate Prespecified subgroup analysis Rothman synergy index o Assessing PPI + antibiotic risk Risk of CDI with PPI use o 39 studies o OR 1.74 (95% CI, ; p<0.001; I 2 = 85%) Risk of recurrent CDI with PPI use o 3 studies o OR 2.51 (95% CI, ; p = 0.02; I 2 = 78%) Risk of CDI with PPI use & abx o 6 studies o OR 1.96 (95% CI, ) o Rothman s synergy index 1.36 o Attributable proportion of risk 19% Risk of CDI with H 2 RAs* o 15 studies o OR 0.71 (95% CI, ) Large meta-analysis of observational studies o Appropriate for study on adverse effects PPI use associated with a 74% risk of CDI Pooled analysis showed risk of recurrent CDI Unexplained significant heterogeneity among studies 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; H 2RAs, histamine 2-receptor antagonists; OR, odds ratio; RR, risk ratio; CI, confidence interval; *In comparison to PPIs Burris AJ Page 13

14 B. Take home points i. Conflicting results ii. Significant unexplained heterogeneity also observed in Janarthanan et al 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 H 2 RAs C. PPIs have also been linked to potential long-term side effects or complications 21 i. Fracture risk ii. Iron deficiency iii. Hypomagnesaemia iv. Vitamin B 12 deficiency D. Many evaluations did not find a risk with H 2 RAs Table 6. Potential Adverse Effects with PPIs 21 Adverse effect Underlying mechanism Strength of association CAP Plausible Weak to moderate OR > 2 Nosocomial Plausible Weak to PNA moderate OR > 2 C. difficile Infection Plausible Weak to moderate OR > 2 Consistency of association Inconsistent results Inconsistent results Inconsistent results CAP, community-acquired pneumonia; PNA, pneumonia; CDI, Clostridium difficile infection; OR, odds ratio Summary and Recommendations Clinical implications PPI therapy should only be used for appropriate indications PPI therapy should only be used for appropriate indications Consider potential alternative therapy in patients with concurrent CDI risk factors 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. CAP 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

15 ii. Nosocomial pneumonia 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 infection % 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 N=6 Attributable Mortality NNH N=13 Attributable Mortality NNH N=22 Attributable 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, histamine 2 -receptor antagonists are the preferred agent of choice Burris AJ Page 15

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18 Appendix Appendix A. Summary of Individual Studies Included in Meta-Analyse Study N Intervention Definition of Bleeding Outcomes Powell et al Omeprazole 80 mg IV bolus, then 40 mg IV bolus TID (n=10); omeprazole 80 mg IV bolus then 40 mg IV infusion TID (n=10); ranitidine 50 mg IV TID (n=11); placebo (n=10) Bloody nasogastric tube aspirate Clinically important bleeding; mortality Levy et al Kantorova et al Conrad et al Somberg et al Hata et al Solouki et al Azevedo et al Omeprazole 40 mg NG daily (n=32); ranitidine 50 mg IV bolus, then 150 mg IV daily (n=35) 287 Omeprazole 40 mg IV daily (n=72); famotidine 40 mg IV BID (n=71); sucralfate 1 g NG QID (n=69); placebo (n=75) 359 Omeprazole suspension 40 mg NG BID loading, then 40 mg NG daily (n=178); cimetidine 300 mg IV bolus, then infusion at 50 mg/hr (n=181) 202 Pantoprazole 40 mg IV daily (n=32); pantoprazole 40 mg IV BID (n=38); pantoprazole 80 mg IV daily (n=23); pantoprazole 80 mg IV BID (n=39); pantoprazole 80 mg IV TID (n=35); cimetidine 300 mg IV bolus, then 50 mg/hr infusion (n=35) 210 Rabeprazole PO 10 mg daily (n=70); ranitidine PO 30 mg daily (n=70); teprenone 150 mg NG daily (n=70) 129 Omeprazole 20 mg NG BID (n=61); ranitidine 50 mg IV BID (n=68) 108 Omeprazole 40 mg IV BID (n=38); ranitidine 150 mg/day infusion (n=38); sucralfate 1 g NG QID (n=32) Gross bleeding as manifest by hematemesis, aspiration of coffee ground material from the NG tube, or melena, or a Hgb of > 2 g/dl complicated by either the need for transfusion or hemodynamic instability Overt bleeding with one of the following: a) Drop in SBP >20 mm Hg or rise in HR >20 beats/min within 24 hrs of the onset of bleeding not explained by other causes; or b) Drop in Hgb by 2 g/dl or more not explained by other causes a) Bright right blood not clearing after tube adjustment and lavage with saline for 5-10 mins; b) 8 hrs of persistent gastro-occult positive coffee ground material with aspirates every 2 hrs not clearing with lavage; or c) Persistent gastro-occult positive coffee ground material over 2-4 hrs on d 3-14 in three consecutive aspirates not clearing with lavage a) Hematemesis or bright red blood in gastric aspirate that did not clear after adjustment of NG or OG tube and a 5- to 10-min lavage with iced water or saline; b) Persistent coffee ground material for 8 consecutive hrs that did not clear with a 100 ml lavage, or was accompanied by a 5% in Hct; c) A in Hct requring one or more transfusions that occurred in the absence of any obvious source and required further diagnostic studies; or d) Melena or frank bloody stools from an upper GI source Upper GI bleeding (hematemesis, coffe ground emesis, or melena) confirmed with gastrodudenoscopy Overt bleeding associated with one of the following: a) A 20 mm Hg in SBP or DBP during the first 24 hrs after bleeding; b) A 20 beat/min HR or 10 mm Hg in SBP in a standing position; c) A 2 g/dl of Hgb or 6% decrease in Hct during the first 24 hrs after bleeding; d) Lack of in Hgb after infusing two units of packed cells Upper GI bleeding including hematemesis, bright red blood, coffee ground emesis or melena Clinically important bleeding; nosocomial PNA; mortality; ICU LOS Clinically important bleeding; nosocomial PNA; mortality; ICU LOS; adverse events Clinically important bleeding; overt bleeding; PNA; mortality Clinically important bleeding; PNA; mortality; adverse events Overt bleeding; adverse events Clinically important bleeding; nosocomial PNA; mortality; ICU LOS Overt bleeding; nosocomial PNA; mortality; ICU LOS

19 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 No clear definition Phillips et al Fink et al Morris et al Kotlyanskaya et al Brophy et al Omeprazole 40 mg daily IV, then 20 mg PO daily (n=14); ranitidine 150 mg IV daily, then 300 mg PO daily (n=14) 58 Omeprazole 40 mg NG loading, then 20 mg NG daily (n=33); ranitidine 50 mg IV loading, then mg/day infusion (n=25) 189 (4:1) Randomization as follows: IV pantoprazole 40 mg daily, 40 mg BID, 80 mg daily, or 80 mg BID (n=158); IV cimetidine 300 mg bolus, then 50 mg/hr infusion (n=31) 202 (5:1) Randomization as follows: IV pantoprazole 40 mg daily, 40 mg BID, 80 mg daily, 80 mg BID, or 80 mg TID (n=169); IV cimetidine 300 mg IV loading, then 50 mg/hr (n=33) 66 Lansoprazole (suspension) NG (n=22); lansoprazole (tablet) NG (n=23); ranitidine (n=21) (dose and frequency not reported) 51 Lansoprazole (suspension) 30 mg NG daily (n=23); famotidine 20 mg IV BID (n=23) No clear definition No clear definition No clear definition Overt bleeding associated with change in hemodynamics or drop in the Hgb Endoscopic evidence of stress-related mucosal bleeding, bright red blood per NG tube that did not clear after lavage, or overt bleeding (hematemesis, bloody gastric aspirate, melana, or hematochezia) plus either a in BP of 20 mm Hg, or a of 2 g/dl in Hg and two units of blood transfused within 24 hrs Clinically important bleeding; overt bleeding; adverse events Clinically important bleeding; PNA; adverse events UGI bleeding; mortality UGI bleeding; nosocomial PNA Clinically important bleeding; overt bleeding; nosocomial PNA; drug adverse events Time ph 4; percentage of time gastric residuals < 28 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