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GI bleeds: what’s old, what’s new?

GI bleeds: what’s old, what’s new?. Grand Rounds, Department of Emergency Medicine April 15, 2004 Christine Hall MSc MD FRCPC. Outline. Upper GI bleeds overall summary PUD Drinkers and non drinkers Variance NSAIDs Upper GI bleeds specific physiology NSAIDs Upper GI bleed Rx issues

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GI bleeds: what’s old, what’s new?

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  1. GI bleeds: what’s old, what’s new? Grand Rounds, Department of Emergency Medicine April 15, 2004 Christine Hall MSc MD FRCPC

  2. Outline • Upper GI bleeds overall summary • PUD • Drinkers and non drinkers • Variance • NSAIDs • Upper GI bleeds specific physiology • NSAIDs • Upper GI bleed Rx issues • PPI’s • EGD • Discharge criteria • Variceal bleeds • Lower GI bleeds • Patient disposition

  3. Introduction • GI bleeding: • 2% of all US hospital admissions • 5% of admissions originating in the ED • Majority of bleeds are UGI

  4. UGI bleeding incidence • 103/100,00 adult per year in UK • incidence 23/100,00 in age under 30 to 485/100,00 in over 75 • men more than double women except in elderly • 14% occurred in inpatients already in hospital for some other reason • 27% of cases (37% female, 19% male) patients were aged over 80. Rockall TA, Logan RF, Devlin HB, Northfield TC. Gastrointest Endosc. 2002 Jan;55(1):1-5.

  5. UGI Bleeding mortality • Overall mortality 14% • 11% in emergency admissions • 33% in inpatients • In the emergency admissions: • 65% of deaths in pts under 80 associated with malignancy or organ failure at presentation • Mortality for patients under 60 in the absence of malignancy or organ failure at presentation was 0.8%. Rockall TA, Logan RF, Devlin HB, Northfield TC. Gastrointest Endosc. 2002 Jan;55(1):1-5.

  6. UGI bleeds in drinkers • From August 1, 1990 through September 9, 1994. Prospective. • Pts referred to GI (selection bias) • subnormal hematocrit on or within 12 h of admission or a fall of at least 5 points from previous • Upper GI endoscopy was performed in all patients within 48 h of admission • Alcohol use was quantitated as chronic (80 g or more per day for at least 1 month), binge, occasional, or none.

  7. UGI bleeds in drinkers • 727 pts: 212 (29%) chronic alcohol users • Peptic ulcer disease was most common cause of bleeding (60%). • Gastropathy etiological in only 32 patients (4%) • portal hypertension in 22 patients • NSAID induced gastropathy in 5 • Alcohol induced gastropathy in 5 pts • bleeding was mild and self-limited. Wilcox CM, Alexander LN, Straub RF, Clark WS Am J Gastroenterol. 1996 Jul;91(7):1343-7

  8. UGI bleeds in drinkers • Causes of bleeding were compared between drinkers and nondrinkers • drinkers were more likely to bleed from varices (p = 0.024) • portal hypertension-related causes (p < 0.01), • Peptic ulcer was more common in nondrinkers compared with chronic ETOH • (67 vs 53%; p < 0.01) • Esophagitis (p = 0.95) and Mallory-Weiss tear (p = 0.15) were NS between the two groups. Wilcox CM, Alexander LN, Straub RF, Clark WS Am J Gastroenterol. 1996 Jul;91(7):1343-7

  9. UGI bleed variance • Qiu, YJ. Zhonghua Hu Li Za Zhi. 1987 Jun;22(6):269-70. • Relation between hemorrhage and the waxing or waning of the moon • Unfortunately in Chinese so not available for today…

  10. Upper GI bleeds: pathophysiology • Esophagitis • Candidal • Non candidal • bisphosphonates • Esophageal tears • Gastritis • That’s all we’ll say about the benign causes

  11. UGI bleed diagnosis: to OG or not to OG? • Not great evidence for confirming UGI bleed by putting in NG or OG • Practice discouraged by most GI’s • Can confound UGI bleed re: trauma of insertion • Relative contraindication in variceal bleed although this is witchcraft…more about that later…

  12. PUD Causation

  13. H. Pylori • Serology never becomes negative once positive • Even if H. Pylori is eradicated • Complicates repeat breath tests or biopsies • PPIs are antimicrobial for h.pylori despite poor initial performance in development as an antibiotic

  14. Current Rx for H. Pylori Eradication

  15. NSAID induced ulcers

  16. NSAIDS: what’s the problem? • Toxic effects of NSAIDs thought to be due to Cox-1 inhibition • launch of the cyclooxygenase-2 (COX-2) selective NSAIDs was based on 2 hypotheses: • the major adverse effects limiting the usefulness of nonselective NSAIDs are gastrointestinal in nature • COX-2 selective NSAIDs are associated with fewer gastrointestinal adverse effects than nonselective NSAIDs.

  17. The CLASS Trial • To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs. • double-blind, randomized controlled trial conducted from September 1998 to March 2000 • Three hundred eighty-six clinical sites in the United States and Canada

  18. The CLASS trial • 8059 patients : >/=18 years old, OA or RA, 7968 received at least 1 dose of study drug. • 4573 patients (57%) received treatment for 6 months • Random assign: • celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively • n = 3987 • ibuprofen, 800 mg 3 times per day (n = 1985) • diclofenac, 75 mg twice per day (n = 1996). • ASA for CV prophylaxis (</=325 mg/d) was permitted.

  19. CLASS Trial • Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period. • Overall annual incidence rates of UGI ulcer complications alone: 0.76% vs 1.45% with NSAIDs (p=0.09) • Overall annual incidence rate of UGI ulcer complications plus symptomatic ulcers 2.08% vs 3.54% , p=0.02 • Pts not on ASA: • UGI complication alone 0.44% vs 1.27%, p=0.04 • UGI complication plus symptoms: 1.40% vs 2.91%, p =.02 • For patients onASA: • UGI complications alone 2.01% vs 2.12%,l p=0.92 • UGI complications plus symptomatic ulcers 4.70% vs 6.00% (P =.49).

  20. CLASS conclusions • Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. • No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use. • CONCLUSIONS: Celecoxib, at big doses, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as “other clinically important toxic effects”, compared with NSAIDs at standard dosages (800 mg tid). • The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly. JAMA. 2000 Sep 13;284(10):1247-55.

  21. The VIGOR trial • clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective NSAIDs • Is rofecoxib associated with a lower incidence of clinically important upper gastrointestinal events than Naproxen among patients with rheumatoid arthritis • randomly assigned 8076 RA patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) • received either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily • primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers)

  22. VIGOR Trial • Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. • median follow-up of 9 months • 2.1 per 100 pt years confirmed gastrointestinal events with refecoxib • 4.5 per 100 pt-years with naproxen • relative risk, 0.5; CI 0.3 to 0.6; P<0.001 • The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) • 0.6 per 100 patient-years refecoxib • 1.4 per 100 patient-years naproxen • relative risk, 0.4; CI 0.2 to 0.8; P=0.005

  23. VIGOR trial • The incidence of myocardial infarction • lower among patients in the naproxen group than among those in the rofecoxib group • 0.1 percent vs. 0.4 percent • relative risk, 0.2; CI 0.1 to 0.7 • the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ N Engl J Med. 2000 Nov 23;343(21):1520-8

  24. So…. • increased incidence of total and nongastrointestinal serious adverse events with the COX-2 selective NSAIDs remains a major concern • increased morbidity may be a manifestation of the COX-2 selectivity or the supramaximal doses of these drugs used in the trials • proof that the increased harm was not caused by the COX-2 selectivity of the drugs depends on a randomized controlled trial of COX-2 selective NSAIDs at usual doses vs. nonselective NSAIDs • Thus far, no such trial • What about Cox-2’s plus PPII’s?...no trial

  25. Rx of UGI bleed • Shots in the dark?

  26. Upper GI bleeds • Coagulation and fibrinolysis are dependent on intragastric pH • When pH is below 6, platelet aggregation is abolished • When pH is below 4, fibrin clots are digested by gastric pepsin • In UGI bleed, need to raise gastric pH and keep it there for 72 hours

  27. PUD H2 blockers • H2 receptor antagonists inhibit gastric acid production • Little if any evidence of improved outcome in active GI bleed • Insufficient acid suppression • Rapid drug tolerance

  28. Proton Pump Inhibitors • More profound and sustained acid suppression • Binds irreversibly to H+K+ATPase (proton pump) inhibiting actively secreting parietal cells • Predictable: t1/2 1 hr but effect 24 hrs • No tolerance developed • Excellent safety profile, no dose reduction in renal failure/cirrhosis • IV Omeprazole released in 1991

  29. PPI’s in PUD • IV Proton pump inhibitors • Lau et al NEJM 2000 Aug 3: 343 (5) 310-16 • After endoscopic Rx, bleed recurs in 15-20% • Assess whether use of high dose PPI decreased recurrence within 30 days • Dbl blind rand to Omeprazole bolus and infusion vs placebo • All got Omeprazole orally x 2 weeks post infusion

  30. PPI’s in PUD (Lau, ct’d) • 240 patients, recur in 6.7% of omeprazole vs 22.5% of placebo • Most recurrent bleed occurs in first three days • “Only evidence for IV infusion is in acute bleed with ulcer with high risk stigmata (i,.e visible vessel)” • But, EGD was done within 1 hour 24/7

  31. Waiting for EGD

  32. PPI’s while waiting for EGD • R. Enns & C. Andrews, UBC, Can J Gastro 2003 & Aliment Pharmacol Ther 2003. • To evaluate cost effectiveness of IV PPI while awaiting EGD compared with EGD alone • Probabilities of rebleeding and surgery taken into account • In a hypothetical cohort of 1000 patients, IV PPI utilization while awaiting EGD = mean savings of $20,700 Canadian • Using PPI pre EGD averted 37 rebleeds • Use of PPI while awaiting EGD is cost effective • Finidngs do not apply to low risk stigmata, variceal bleeds, lower GI bleeds

  33. PUD: RUGBE • Canadian Registry of patients with Upper GI Bleeding Undergoing Endoscopy • Pt char and Rx from 1999 on • J. Romagnolo is local PI • Protective effect of PPI use and EGD in specific patient subgroups • Meta-analysis supports high dose IV PPIs leads to improvement when coupled with EGD • Optimum dose, timing, and subgroup analysis needs further work

  34. PPI’s the local challenge • CHR: Pharmanews • Vol 28 Issue 3 Revised November 2003 • Kaplan Gf, Bates D, McDonald D, Romagnulo J. • “Inappropriate Prescribing Leading to Rapidly Escalating Costs of IV PPI in the Calgary Health Region”

  35. PPI’s the local cost

  36. PPI’s Local guidelines • Ideally withold PPI’s until EGD but case by case adaptation…i.e. night • IV Omeprasole 80 mg bolus and 8mg/hr infusion for max of 72 hours • Pts with HRS on EGD (arterial or venous active bleed, visible vessel, adherent clot) should have endo Rx and then 72 hr infusion • No HRS = stop infusion • Inpts who are NPO get bid dosing not infusion

  37. PPI’s Local guidelines ct’d • Clinical equivalence between IV PPI and oral PPI in GERD • Clinical equivalence between IV PPI and NG PPI • 40 mg PPI IV = $13.70 • 40 mg PPI po = $0.45

  38. Can UGI bleeds go home? • Selection of patients for early discharge or outpatient care after acute UGI haemorrhage. National Audit of Acute Upper GI Haemorrhage • Attempted to identify patients who had negligible risk of further bleeding or death and for whom early discharge or even outpatient management would be possible with no adverse effect on standards of care.

  39. UGI bleed and discharge • Used a validated risk scoring system based on: • age (score 0-2) • presence of shock (0-2) • comorbidity (0-3) • diagnosis (0-2) • endoscopic stigmata of recent haemorrhage (0-2) • maximum possible score was 11.

  40. Rockall’s Scoring System

  41. UGI bleed and discharge • 2531 patients who underwent endoscopy after an acute admission • 744 (29.4%) of the 2531 patients scored 2 or less on the risk score • Of these: • 32 or 4.3% rebled [95% Cl 3.0-6.0] • 1 or 0.1% died [95% CI 0.006-0.75] • Conclusions: the risk score identifies patients at low risk of rebleeding or death • Median hospital stay increased with risk score • Within low risk score categories of 5 or less: • trend of increasing hospital stay as the time between admission and endoscopy increased Lancet. 1996 Apr 27;347(9009):1138-40 Rockall TA, Logan RF, Devlin HB, Northfield TC.

  42. UGI bleed and discharge • Three year prospective validation of a PRE-EGD risk stratification in patients with acute UGI hemorrhage • To assess the accuracy of a risk stratification used at initial assessment (does not rely on EGD) • To identify groups with increased risk of mortality and requirement for urgent treatment intervention • Prospective assessment of risk stratification in consecutive patients with acute upper-gastrointestinal haemorrhage.

  43. UGI risk stratification • 3-year period, 1349 consecutive patients, risk stratified and followed up for 2 weeks • Two-week, all-cause mortality, re-bleeding, and need for urgent treatment intervention.

  44. UGI bleed and discharge without EGD? • Stratification within the high-risk group predicted a significant increased risk of 2-week, all-cause mortality (P < 0.001) • Hi risk 11.8% • Intermediate risk 3% • Low risk 0% • High risk strata significantly higher re-bleeding (P < 0.001) • Hi risk 44.1% • Intermediate 2.3% • Low risk 0% • High risk strata significantly higher need for urgent treatment intervention (P < 0.001) • Hi risk 71% • Intermediate risk 40.6% • Low risk 2.6% Cameron EA, Pratap JN, Sims TJ, Inman S, Boyd D, Ward M, Middleton SJ.Eur J Gastroenterol Hepatol. 2002 May;14(5):497-501.

  45. So, who admits? • Physician specialty and variations in the cost of treating patients with acute upper gastrointestinal bleeding. • Pts stratified into three groups based on a validated risk score • Length of stay and hospital costs compared • primarily cared for by internists, surgeons, and gastroenterologists • Median length of stay (2 days) if admitted to GI • Significantly shorter than admitted under other physicians (P < 0.05) • Median hospitalization cost ($2856) if admitted to GI • Significantly lower than other services (P < 0.01) • No differences in the time to endoscopy among services. Quirk DM, Barry MJ, Aserkoff B, Podolsky DK Gastroenterology. 1997 Nov;113(5):1443-8

  46. Now for some risky business…

  47. Variceal bleeding • Esophageal and/or gastric varices account for about 20% of all GI bleeds • Most dramatic and life threatening presentation of portal hypertension • 25-50% of bleeds in cirrhotic pts is non variceal • Dave P et al, Clin Gastroenterol 5:113, 1983 • After 1 bleeding episode, risk of a second is 70% • Accounts for 50% of all deaths from cirrhosis

  48. Variceal bleeding • Risk of mortality from each bleeding episode is 20-84% • Risk depends on etiology of portal hypertension, hepatic reserve of the pt., duration of hemorrhage prior to presentation

  49. IV Octreotide • Octreotide or Somatostatin is a potent nonselective vasoconstrictor • Should be routine in known or strongly suspected variceal bleed • Can be used alone or in conjunction with sclerotherapy/banding • No role in non variceal UGI bleeds

  50. Balloon tamponade • Originated in the 1930s, first filled with water not air • 1950 Sengstaken and Blakemore invented double lumen balloon • Modified by Linton, Nachlasm, Boyce and Edlich • Currently have: • Blakemore: 3 lumens – gastric, esoph and gastric suction • Linton: as above with esoph aspiration port as well

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