Proton Pump Inhibitors vs

H2 Receptor Antagonists

for Stress-Related Mucosal BleedingProphylaxis in Critically ill patients

Problem of SRMB

In the intensive care admissionsOccult bleed- 15-50% Overt bleed- 5-25%Clinically significant UGIB- 1- 2.5%Endoscopic evidence – 74- 100%Morbidity increases – 4 times

Risk factors for SRMB

• Respiratory failure requiring mechanical ventilation for more than 48 hr• Acute renal insufficiency• Acute hepatic failure• Severe head or spinal cord injury• Burns involving more than 35% of the body surface area• Major surgery (lasting more than 4 h)• Anticoagulation• Coagulopathy (INR > 1.5, aPTT > 2 or platelet count > 50 000 mm3)*• Sepsis syndrome• Hypotension• Administration of high-dose corticosteroids (250 mg/d of steroids or

equivalent hydrocortisone)• Enteral feedings

Due to this multifactorial etiology, the SRMD lesions and their bleeding prevention,are thought to be less critically dependent on profound acid suppression than in the setting of rebleeding prevention of peptic ulcers.

Hence the target pH in the prevention of SRMD bleeding is a more modest intragastric pH of 4 (rather than the postulated 6 – 6.5 for prevention of ulcer rebleeding and clot stabilization in PUD)

What are the prevention options?Sucralfate Enteral FeedingH2RA andPPISucralfate- (1) forms a protective barrier on the surface of gastric mucosa;(2) stimulates mucus and bicarbonate secretion; (3) stimulates epidermal growth factor and renewal;(4) improves mucosal blood flow and enhances prostaglandin release

Though they have advantage of lesser risk of nosocomial pneumonia due to absence of gm –ve gastric colonisation as it does not alter gastric pH,

Issues associated with their use like-1) Clogging of NG tubes and bezoar formation2) Constipation 3) Reports of aluminium toxicity4) Effect on absorption of other oral drugs have eventually led to their disuse

H2RA – most widely used as prophylaxis(Year 2006 national survey of 2000 intensivists, H2RAs were chosen 64% time, followed by PPIs23.1%.) -Lam NP et al Crit Care Med. 2006(cimetidine,ranitidine, famotidine, and nizatidine)

They cause modest acid supression , are an effective option in SRMB prevention and rebleed prophylaxis.

But H2RA are not found to be effective in PUD rebleeding prophylaxis.Additionally problems like- 1) Early tolerance(72 hrs)2) Drug interaction with use of cimetidinehave allowed PPIs to get past them in recent years

PPIs - Cause most potent acid supression (lansoprazole,omeprazole, esomeprazole, pantoprazole,rabeprazole)They have an advantage of being useful in both settings of SRMB prophylaxis and PUD ulcer rebleeding prophylaxis.

But increased risk of 1) Nosocomial pneumonia 2) Clostridial difficile enterocolitis3) Rebound hyperacidity after discontinuationis a matter of concern in critical care setting.

Thus the superiority of PPI vs H2RA in SRMB prevention prophylaxis is a matter of debate with only few head to head trials or meta- analysis available comparing them.

PPI vs. H2RA forStress-Related MucosalBleeding Prophylaxis in Critically ill Patients: A Meta-Analysis

31st Jan 2012

Alan N. Barkun. MD, Marc Bardou. MD, Myriam Martel , BSc, C.Q.D. Pham , PharmD

Methodology Search strategy- Tailored literature searches from year 1980 to 2011 were conducted using OVID MEDLINE, EMBASE, CENTRAL & ISI Web of knowledge 5.3.Validity assessmentThe eligibility and quality of the studies were assessed independently by two investigators (M.B. and C.Q.D.P.). An independent third investigator A.N.B. arbitrated disagreementsConflict of interest- A. N Barkun is a consultant forAstraZeneca and Takeda Canada.

Inclusion criteria – RCTs of patients at risk for bleeding in an ICU setting comparing PPIs to H2RA were included.

Exclusion criteria – RCTs involving - pediatric population , - comparing only different dosing regimens of the same molecule and - whose only outcomes were gastric pH measurements were excluded.

Choice of outcomes Primary outcome- the rate of clinically significant upper gastro- intestinal bleeding (UGIB)Secondary outcome-1) the occurrence of nosocomial pneumonia,2) all-cause mortality, and 3) number of days in ICU.

Clinically significant UGIBOvert bleeding (ie, hematemesis, gross blood or “coffeegrounds” material in NG aspirate, hematochezia,or melena) complicated by one of the following within 24 hours after the onset of bleeding:1) Fall of > 20 mm Hg in systolic blood pressure;2) Rise of > 20 beats per minute in the heart rate, 3) Fall of >10 mm Hg in the systolic blood pressure measured on sitting up from supine position 4) Fall of more than 2 g/dL in the hemoglobin level and subsequent blood transfusion, after which the hemoglobin level did not increase by a value defined as the number of units of blood transfused minus 2 g/dl - Cook. MD et al N Engl J Med. 1994;330:

Statistical methodsFor each outcome , effect size was calculated asOdds ratio (OR) for the proportions Weighted mean differences (WMD) for continuous variables.

All statistical analyses were done using RevMan Version 5.0.18 and R version 2.4.0 (R Foundation for Statistical Computing,Vienna, Austria, 2008).

Included studies

From a total of 489 citations identified assessing the outcome of upper GI bleed (1993-2010)- only 13 studies( 8 fully published articles + 5 abstracts ) involving 1,587 patients met the inclusion criteria and hence included in meta- analysis

Primary outcome analysis• With UGIB regardless of the definition for

the primary outcome analysis (significant + non significant bleed)

A - 13(n = 1587)

• Applying the definition of clinically significant UGIB.

B - 6(n= 951)

• Definition of clinically significant UGIB not adhered with.

C - 7(n=636)

(Treated- PPI, Controls – H2RA)

• OR = 0.30; 95% CI: 0.17– 0.54A

• OR = 0.39; 95 % CI: 0.19 – 0.77B

• OR = 0.17; 95 % CI: 0.06 – 0.52C

Inference

Prophylactic PPI administration significantly decreased the incidence of 1) UGI bleeding overall2) Clinically significant UGIB3) Clinically non significant UGIB as compared to H2RA

Secondary outcomes A) Nosocomial pneumonia - Nosocomial pneumonia was assessed in seven studies ( n = 1,017 patients)

No significant associations were noted when comparing its occurrence in PPI vs. H2RA-treated patients

OR = 1.05; 95 % CI: 0.69 – 1.62

B) Mortality -

All-cause mortality was studied in eight trials( n=1,260 )

No statistical differences were noted in mortality

OR = 1.19; 95% CI: 0.84 – 1.68

C) Days in ICU -

The total mean ICU stay in days was noted inthree studies (n= 339 )

This outcome was not significantly reducedwith the use of PPIs as compared to H2RAs

WMD = − 0.12 days; 95 % CI − 1.90 to 1.66

Rationalisation of the outcomes by authors

A) PPIs are superior to H2RA in reducing SRMD related UGIB –

- PPI lead to more profound acid suppression and since many SRMD lesions have been recently found to be quite acid sensitive.

- PPI lead to pH dependent clot stabilisation and reduce risk of rebleeding- PPI exhibit some anti- inflammatory effect

B) PPIs do not appear to enhance the risk of nosocomial pneumoniaComparison was done with H2RA which itself can increase the risk of nosocomial pneumonia

C) PPI do not reduce the mortality significantlysince very few patients actually die directly from acute hemorrhagic complications but rather from their underlying illnesses

D) PPI does not shorten ICU stay significantlyAgain this outcome is dependent on multiple variables and not only on SRMD related bleeding

Limitations of the metaanalysis1) Impact on incidence of clostridium difficile enterocolitis unadressed2) Definition of clinically significant UGIB not applicable in all studies included.3) 2 trials were based on Asian populations whose slow metabolisers trait if considered, may affect the results. Author are not sure of significance of this confounding factor.

Take home messagea) Use of PPI to prevent SRMD-related bleeding is superior to prophylaxis with H2RA. b) There is no increased risk of nosocomial pneumonia with PPI.c) PPIs don’t decrease overall mortality d) Nor do they reduce the duration of ICU stay.e) Don’t forget to discontinue prophylaxis when patients begin an oral diet or are transferred from the ICU (INR 60 / day)