Upper Gastrointestinal Bleeding Peptic Ulcer Disease Pharmacotherapy Issues in Acute Management and Secondary Prevention Peter J. Zed, B.Sc., B.Sc.(Pharm), Pharm.D. Pharmacotherapeutic Specialist - Emergency Medicine CSU Pharmaceutical Sciences, Vancouver General Hospital Clinical Assistant Professor, Faculty of Pharmaceutical Sciences, UBC Associate Member, Department of, Faculty of Medicine, UBC Objectives To discuss the acute management of upper GI bleeding peptic ulcers with a focus on antisecretory therapy. To discuss secondary prevention strategies following acute stabilization of acute GI bleeding peptic ulcers. Epidemiology Economic Implications Marshall et al. (Am J Gastroenterol 1999;94:1841-6) ~15, admissions annually in Canada Age (yrs) Total Cost LOS (days) 55% caused by peptic ulcer disease Helicobacter pylori ASA/NSAIDS/COX-2 Inhibitors 18-39 4-59 $183 $2435 2.96 3.82 8% will stop spontaneously 6-74 $2713 4.73 6-7% mortality rate.6% if <6 years of age and no co-morbidity 15% if >6 years of age and/or co-morbidity 75-85 Mean (n=116) $5364 $269 7.62 4.26 Helicobacter pylori NSAID-Induced Peptic Ulcer Disease 15-3% of all PUD is NSAID-induced NSAID use increases risk of PUD 3-5X 6% of NSAID users experience heartburn, pain, dyspepsia symptoms >4 weeks have increased risk of gastric ulceration 66% of all NSAID users will have endoscopic evidence of gastric lesions but clinical ulcers is 2-4% annually
Risk Factors for NSAID-Induced Gastropathy Wolfe et al. (NEJM 1999;32:1888-98) Definite: Age Prior history of ulcer Duration of NSAID therapy Concomitant corticosteroid therapy Concomitant warfarin therapy Concomitant ASA/NSAID NSAID dose Serious systemic illness (CHF, RA, CAD, others) Possible: Concomitant H. pylori infection? Smoking Alcohol Acute Gastrointestinal Bleeding Peptic Ulcer Prognostic Factors: Clinical Barkun et al. (Aliment Pharmacol Ther 1999;13:1565-84) hemodynamic instability hematochezia from upper GI source >6 years of age units of transfused blood concurrent illness onset of bleeding while hospitalized coagulopathy Prognostic Factors: Endoscopic Barkun et al. (Aliment Pharmacol Ther 1999;13:1565-84) High Risk Bleeds 6 55% 5 4 3 22% 43% Spurting Vessel 2 1 5% 1% Clean Base Flat Spot Clot NBVV Active Bleed Non-Bleeding Visible Vessel Overlying Clot Prevalence
Time to Goals of Therapy 6 5 4 3 2 1 Hemodynamic Stabilization and Resuscitation (ABC) Determine Cause Stop Bleeding Prevent Recurrence <24h 24-48h 48-72h 72-96h 96-168h >168h Management Endoscopic Therapy: Meta-Analysis Cook et al. Gastroenterol 1992;12:139-48 Oxygen Fluid Blood Transfusion Endoscopic Therapy Pharmacotherapy Endpoint Death OR (95% CI).38 (.32-.45).36 (.28-.45).55 (.4-.76) Endoscopy Better 1 ODDS RATIO No Endoscopy Better Pharmacological Therapy Role of Gastric Acid on Hemostasis Splanchnic blood pressure modifiers vasopressin, octreotide, somatostatin Antifibrinolytic Agents tranexamic acid Antisecretory Agents H2-receptor antagonists (H2RA) proton-pump inhibitors (PPI) Impairs clot formation impairs platelet aggregation and causes disaggregation Accelerates clot lysis acid-stimulated pepsin Impairs mucous/bicarbonate barrier Aliment Pharmacol Ther 1999;16:1565-84
H2RA in Acute GI Bleeding: Meta-Analysis Collins et al. (NEJM 1985;313:66-6) Famotidine in Acute GI Bleeding Walt et al. (Lancet 1992;34:158-62) 27 trials, N=25 randomized, placebocontrolled trials H2RA vs. -5-1 -15 11% Acute Endoscopically-proven GI Bleeding Peptic Ulcer P, MC, R, DB, PC n=15 RRR -2 ENDPOINTS -25 rebleeding -3 surgery -35 mortality -4 22% 3%* *p=.2 Mortality Famotidine 1 mg IV bolus followed by 3.2 mg/h x 72h Primary: Death during hospitalization Secondary: Famotidine in Acute GI Bleeding Walt et al. (Lancet 1992;34:158-62) Tolerance: Intragastric ph>4 Merki and Wilder-Smith (Gastroenterol 1994;16:6-4) 3 25 25.6% 23.9% p=ns for all endpoints 1 9 8 93%* 67% 96%* 2 15 1 5 6.2% 5.% 15.5% 17.1% 7 6 5 4 3 2 43% Death Famotidine 1 Day 1 Day 3 *p<.1 Tolerance: Daily Dose Merki and Wilder-Smith (Gastroenterol 1994;16:6-4) Proton-Pump Inhibitors Mechanism of Action 25 235 mg 55 541 mg Histamine Receptor 2 15 134 mg 54 53 52 camp Protein Kinase Ca 2+ Calmodulin Muscarinic Receptor Ca 2+ 1 51 52 mg K + K + Cl - Gastrin Receptor 5 5 49 ATPase Day 1 Day 3 48 Day 1 Day 3 H + Cl - K +
PPI is Acute GI Bleeding Peptic Ulcers 12 randomized, controlled trials since 199 omeprazole only PPI evaluated in these trials 5 placebo-controlled, 7 H2RA-controlled Issues Efficacy? Safety? Cost? PPI Alone vs. Adjuvant to Endoscopy? PPI Alone vs. Endoscopy Alone? Intermittent Dosing vs. Continuous Infusion? IV vs. PO? : Intermittent Bolus Daneshmend et al. (BMJ 1992;34:143-7) Clinically-Diagnosed Acute GI Bleeding P, MC, R, DB, PC n=1147 8 mg IV bolus followed by 4 mg IV Q8h x 24h followed by 4 mg PO BID x 3 days Primary: Death Transfusion : Intermittent Bolus Daneshmend et al. (BMJ 1992;34:143-7) 18 16 14 12 1 8 6 4 2 18%* 15% 11%* 11% *p=ns 6.9% 5.3%* Mortality 8 mg IV bolus then 4 mg IV Q8h x 24h then 4 mg PO BID x 3 days Proven Gastric/Duodenal Ulcer Daneshmend et al. (BMJ 1992;34:143-7) 3 25 2 15 1 5 27.2% 23.6% N=53 19.5% 18.3% 5.1% 9.3% Mortality 8 mg IV bolus then 4 mg IV Q8h x 24h then 4 mg PO BID x 3 days : Intermittent Bolus/Endoscopy Villanueva et al. (Endoscopy 1995;27:38-12) : Intermittent Bolus/Endoscopy Villanueva et al. (Endoscopy 1995;27:38-12) Acute Endoscopically-proven Actively Bleeding Peptic Ulcer P, R, OL n=86 8 mg IV bolus followed by 4 mg IV Q8h x 4 days followed by 2 mg PO daily 5 mg IV Q6h x 24h followed by 15 mg PO BID 3 25 2 15 1 26% 24% 2% 22% p=ns for all endpoints 7% All patients received endoscopic therapy within 4h 5 2% Primary: Death Death 8 mg IV bolus then 4 mg IV Q8h x 4 days then 2 mg/day 5 mg IV Q6h x 24h then 15 mg PO BID
Summary: Intermittent Bolus Study PPI Control Result Brunner (199) Daneshmend (1992) Lanas (1995) Villanueva (1995) Grosso (1995) TOTAL (n=19) (n=578) (n=23) (n=45) (n=21) N=686 (n=2) (n=569) (n=23) (n=41) Endo/Ran (n=21) Control N=674 Bleeding No Difference No Difference No Difference : Continuous Infusion/Endoscopy Schaffalitzky et al. (Scand J Gastroenterol 1997;32:32-7) Acute Endoscopically-proven Actively Bleeding Peptic Ulcer P, MC, R, DB, PC n=265 8 mg IV bolus followed by 8 mg/h x 3 days Overall Outcome (ordinal scale) Primary Variables: Death (5) (4) Endoscopic Treatment (3) Transfusion > 3 units (2) Transfusion 1-3 units (1) All patients received endoscopic therapy within 12h : Continuous Infusion/Endoscopy Schaffalitzky et al. (Scand J Gastroenterol 1997;32:32-7) : Continuous Infusion/Endoscopy Schaffalitzky et al. (Scand J Gastroenterol 1997;32:32-7) Overall Outcome of Treatment after 72 hours Category Outcome * (n=13) (n=135) 5 Death 2 4 6 15 3 Endoscopy 3 1 2 > 3 units 16 25 1-3 units 13 85 *p=.4 p=nr 1 91% 9 79.7% 8 7 6 p=.3 5 4 31.4% p=.4 3 18.% 2 5.4% 11.1% 1 Bleeding Treatment Success 8 mg IV bolus then 8 mg/h x 72 hours : Continuous Infusion Hasselgren et al. (Scand J Gastroenterol 1997;32:328-33) Acute Endoscopically-proven Actively Bleeding Peptic Ulcer P, MC, R, DB, PC n=322 8 mg IV bolus followed by 8 mg/h x 3 days Overall Outcome (ordinal scale) Primary Variables: Death (5) (4) Endoscopic Treatment (3) Transfusion > 3 units (2) Transfusion -3 units (1) Secondary Variables: Degree of bleeding Duration of bleeding Endoscopic Treatment Mortality Treatment Failure : Continuous Infusion Hasselgren et al. (Scand J Gastroenterol 1997;32:328-33) p=.4 p=.3 p=.9 2 17.4% 18.1% 18 16 14 12 9.8% 1 8.2% 8 6.2% 6 4 2.5% 2.6%.6% Death Treatment Failure 8 mg IV bolus then 8 mg/h x 72 hours
: Continuous Infusion/Endoscopy Lau et al. (NEJM 2;343:31-6) Acute Endoscopically-proven Actively Bleeding Peptic Ulcer P, R, DB, PC n=24 8 mg IV bolus followed by 8 mg/h x 3 days followed by 2 mg PO daily x 8 wks x 3 days followed by omeprazole 2 mg PO daily x 8 wks All patients received endoscopic therapy within 24h Primary: Secondary: at 3 days at 3 days Death at 3 days : Continuous Infusion/Endoscopy Lau et al. (NEJM 2;343:31-6) Summary: Continuous Infusion % 3 2 1 2.% 4.2% Day 3 Day 7 Day 3 22.5% ARR = 15.8% NNT = 7 p<.1 6.7% Study PPI Control Result Hasselgren (1997) Schaffalitzky (1997) Lin (1998) Lau (2) TOTAL (n=159) (n=13) (n=5) (n=12) N=459 (n=163) (n=135) (n=5) (n=12) Control N=468 Overall Outcome Overall Outcome Meta-Analysis Zed PJ et al. (Ann Pharmacother 21;35:1528-34) Meta-Analysis Zed PJ et al. (Ann Pharmacother 21;35:1528-34) Daneshmend Lanas Villanueva Grosso Hasselgren Schaffalitsky Lin Khuroo Lau TOTAL Rebleed OR.5, (95% CI.33-.77) p=.2; NNT = 9 Daneshmend Lanas Villanueva Grosso Hasselgren Schaffalitsky Lin Khuroo Lau TOTAL OR.47, (95% CI.29-.77) p=.3; NNT = 17 PPI Better 1 H2RA/ Better PPI Better 1 H2RA/ Better ODDS RATIO ODDS RATIO
vs. /Endoscopy Sung et al. (Ann Intern Med 23;139:237-43) vs. /Endoscopy Sung et al. (Ann Intern Med 23;139:237-43) Acute Endoscopically-proven High Risk Peptic Ulcer NBVV/Adherent Clot P, R, SB, PC n=156 12 1 11.6% p=.9 Endoscopy Sham Endoscopy 8 6 All patients omeprazole 8 IV bolus then 8 mg/h x 72h 4 2 1.1% Primary: at 3 days at 3 days Secondary: at 3 days Death at 3 days /Endoscopy : Oral Dosing Khuroo et al. (NEJM 1997;336:154-8) : Oral Dosing Khuroo et al. (N Engl J Med 1997;336:154-8) Acute Endoscopically-proven GI Bleeding Peptic Ulcer P, R, DB, PC n=22 4 mg PO BID x 5 days Primary: Death Transfusion 8 7 6 5 4 3 2 1 p<.1 7.9% p<.1 36.4% p<.1 29.1% 23.6% p=ns 1.9% 7.3% 1.8% 5.5% Death Transfusion 4 mg PO BID x 5 days : Oral Dosing Javid et al. (Am J Med 21;111:28-4.) : Oral Dosing Javid et al. (Am J Med 21;111:28-4.) Acute Endoscopically-proven GI Bleeding Peptic Ulcer P, R, DB, PC n=166 4 mg PO BID x 5 days Primary: Transfusion All patients received endoscopic therapy within 24h 8 7 6 5 4 3 2 1 p<.1 73% p<.2 p=ns p=ns 35% 21% 7% 9% 2% 1% 2% Death Transfusion 4 mg PO BID x 5 days
Conclusions H2RA have no role in the management of AGIB cannot provide necessary ph increase tolerance develops quickly no benefit in clinical trials PPI beneficial in select patient populations maintains desired intragastric ph tolerance has not been reported Conclusions Helicobacter pylori Intermittent Dosing of PPI minimal benefit Continuous Infusion PPI offers most promising results endoscopically-proven high-risk bleeding peptic ulcer reduced rebleeding and need for surgery no reduction in mortality pantoprazole 8 mg IV bolus followed by 8 mg/h x 72 hours Future Research IV vs. PO? Role of pre-endoscopy PPI H.pylori & Duodenal Ulcer Recurrence O Brien et al. (Arch Intern Med 1995;155:1958-64) Prevention of Recurrence: H.pylori Eradication 1 8 6 4 2 Endoscopic recurrence at 6 months (%) Eradicate Study Cure Rate Control H. pylori Tx Graham (1993) 76% 29% % Labenz (1994) 1% 38% % Rokkas (1995) 81% 33% % Jaspersen (1995) 83% 27% % Santander (1995) 79% 12% 2% Maier (1995) 9% 12% % Mekel & DenBoer Gough Becker Hansky & Korman Lauritsen Paoluzi Fitzpatrick Korman Dronfield Bardhand Blackwood Gray
H.pylori Eradication Can J Gastroenterol 1998;12:31-41 Prevention: Misoprostol (MUCOSA) Silverstein et al. (Ann Intern Med 1995;123:241-9) FIRST LINE PPI PO BID* Metronidazole 5 mg PO BID Clarithromycin 25 mg PO BID PPI-MC 25 PPI PO BID* Metronidazole 5 mg PO BID Clarithromycin 5 mg PO BID PPI-MC 5 PPI PO BID* Amoxicillin 1 mg PO BID Clarithromycin 5 mg PO BID PPI-AC SECOND LINE PPI PO BID* Bismuth ii tabs PO QID Metronidazole 25 mg PO QID Tetracycline 5 mg PO QID PPI-BMT 3 mg PO BID Bismuth 12 mg PO QID Metronidazole 25 mg PO QID Tetracycline 5 mg PO QID R-BMT (14 day regimen) * 2 mg or Lansoprazole 3 mg or Pantoprazole 4 mg P, MC, R, DB, PC N=8843 RA, >52 yrs, NSAID-users Misoprostol 2 mcg PO QID vs. ENDPOINT Serious GI Complications at 6 months 1.8.6.4.2 ARR=.38% NNT=264 p=.49.57% Complications Misoprostol.95% Prevention: H2RA NSAID-Induced Peptic Ulcer Disease Treatment and Prevention of Recurrence NSAID-Induced Peptic Ulcer Disease 4 3 2 1 16% 11% p<.5 28% PUD Famotidine 4 mg/d Famotidine 8 mg/d Taha, NEJM 1996;334:1435-9 1 8 6 4 2.6% 5.7% Gastric Ulcer p=.9 Misoprostol 2 mcg PO QID Rantidine 15 mg PO BID Raskin, Am J Gastroenterol 1996;91:223-7 ASTRONAUT (N Engl J Med 1998;338:719-26) P, MC, R, DB, N=541 NSAID-induced PUD vs. ENDPOINTS Healing at 8 weeks Maintenance at 6 months 1 8 6 4 2 63% p<.1 NNT = 6 8% 79% Healing p<.1 NNT = 8 72% 59% Maintenance 2 mg/day 4 mg/day Treatment and Prevention of Recurrence NSAID-Induced Peptic Ulcer Disease OMNIUM 1 (N Engl J Med 1998;338:727-34) 8 P, MC, R, DB, N=935 6 NSAID-induced PUD 4 Misoprostol vs. 2 p=ns 76% 75% 71% p=.1 NNT = 8 61% 48% 27% ENDPOINTS Healing at 8 weeks Maintenance at 6 months Healing Maintenance Misoprostol 2 mg/day 4 mg/day
Celecoxib vs. Diclofenac/ Chan et al. (NEJM 22;347:214-1) OA/RA, H. pylori-negative endoscopically-proven healed peptic ulcer P, R, DB, PC n=287 Celecoxib 2 mg PO BID po daily x 6 months Diclofenac 75 mg PO BID 2 mg PO daily x 6 months All patients received endoscopic evaluation every 2 months x 3 Celecoxib vs. Diclofenac/ Chan et al. (NEJM 22;347:214-1) Probability of Recurrent Ulcer Bleeding 16 recurrent ulcers at 6 months Difference: -1.5% (95% CI 6.8% to 3.8%, p=ns) 6.4% 4.9% PRIMARY ENDPOINT: within 6 months clinical features/hg drop + endoscopic confirmation Celecoxib vs. Diclofenac/ Chan et al. (NEJM 22;347:214-1) Post Acute Therapy for AGIB YES Is patient Hp+? YES Treat with Hp eradication therapy NO Is patient taking NSAIDS? NO PPI X 4-8 weeks YES Reduce to lowest dose possible + PPI NO Can NSAID be discontinued? YES www.vhpharmsci.com zed@interchange.ubc.ca