PEPTIC ULCER DISEASE
From GI-Liver Wrap Up, sponsored by the Division of Internal Medicine, Department of Gastroenterology, University of
Michigan Medical School, Ann Arbor
Educational Objectives
| The goal of this program is to manage and minimize risk factors associated with peptic ulcer disease (PUD). After
hearing and assimilating this program, the clinician will be better able to:
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 | Assess risk factors and clinical predictors of upper gastrointestinal (GI) bleeding.
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| Describe costs of health care utilization for patients admitted for GI bleeding.
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| Summarize rebleeding occurrences and other outcomes of various proton pump inhibitor therapies.
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| Provide gastroprotection in patients taking antiplatelet agents and nonsteroidal anti-inflammatory drugs.
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| Compare sequential therapy to standard triple therapies for treatment of Helicobacter pylori.
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Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this program, the
following has been disclosed: Dr. Saad received research support from SmartPill Corp. Dr. Chey has served on the
Speakers’ Bureaus of Axcan, Novartis, Santarus, Salix, and Takeda, and as a consultant to AGI, Axcan, Novartis, Procter
& Gamble, Santarus, Salix, and Takeda. The planning committee reported nothing to disclose.
Acknowledgments
Drs. Saad and Chey were recorded at GI-Liver Wrap Up, sponsored by the Division of Internal Medicine, Department
of Gastroenterology, University of Michigan Medical School, and held February 22-24, 2008, in Ann Arbor, MI. The
Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in the production of this program.
Peptic Ulcer Abstract Review
Richard J. Saad, MD, Lecturer, Department of Medicine, University of Michigan Medical School, Ann Arbor
Peptic Ulcer Disease (PUD) and Upper Gastrointestinal (UGI) Bleeding
| Patients with bleeding peptic ulcers (PUs) (American Journal of Gastroenterology [Am J Gastroenterol],
2008; American College of Gastroenterology [ACG] Meeting, #109): retrospective community-based case
control study; 230 patients (128 with bleeding ulcers and 102 nonbleeding ulcers [control group]); higher rate of nonsteroidal
anti-inflammatory drug (NSAID) use (69%) in those with bleeding PUs, compared to those without (48%); odds
ratio (OR) ≈2.5; no difference in age, sex, or ulcer location; lower rate of Helicobacter pylori infection in bleeding group
(27%), compared to nonbleeding (40%); concluded that NSAID use most important factor associated with increased risk
for bleeding PU
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| Stomal ulcers after Roux-en-Y gastric bypass (RYGB) (Gastroenterology, 2007; Digestive Disease
Week [DDW], #T1371): single-center retrospective chart review; 1052 consecutive RYGB patients (273 underwent
upper endoscopy [1-3 yr from RYGB]); 57 with stomal ulcers (21% of endoscopies and 6% of total group);
≈50% of ulcers 1 cm; multiple ulcers in 25% of patients; rebleeding in 50% of ulcers; nearly 20% refractory; 13% associated
with perforation; 60% of endoscopy patients needed repeat endoscopy, and 10% required surgery;
conclusion—stomal ulcers after RYGB common and complicated
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| Changing epidemiology of PU bleeding (Gastroenterology, 2007; DDW, #144): prospective 10-yr community
study; 1978 admissions to single GI bleeding unit; compared bleeding PUs from 1991 to 1992 with PUs from 2000 to
2001; in latter group, mean age increased by 3 yr, and aspirin and warfarin use increased 2-fold; NSAID use, acid suppression,
and percentage of NSAID users unchanged; no difference in percentage having significant bleeding, rebleeding, and
30-day all cause mortality); increase (≈4-fold) in endoscopic therapy and decrease (≈6-fold) in referrals for surgery;
conclusions—older age, comorbid illness, and increased use of aspirin and anticoagulants account for lack of change in
outcome measures
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| Economics of GI bleeding in managed care setting (Am J Gastroenterol, 2007; ACG Meeting, #906):
case-control study of patients with GI bleeding and controls (7600 matched pairs); in year after GI bleeding— health
care cost increased (5-fold); increases in inpatient (main cost), outpatient, pharmaceutical, and other medical costs; ≈25%
of patients rehospitalized; patients presented to emergency department (ED) and outpatient clinics more often;
conclusion—health resource utilization significantly greater in year after GI bleeding
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Proton Pump Inhibitors (PPIs) in Treatment of PUD
| Bolus vs continuous intravenous (IV) PPI therapy for acute bleeding PU (Gastrointestinal Endoscopy,
2007; DDW, #715): prospective, Italian multicenter study; 369 patients received endotherapy for ulcers due to high-risk
finding (ie, active bleeding or visible vessel); patients received omeprazole therapy, either 80-mg IV bolus followed by 8 mg/
hr for 72 hr, or 40 mg IV dose twice daily for 72 hr; after 72 hr, both groups converted to oral PPI therapy (twice daily for 4
wk); result—no difference in recurrence of bleeding, transfusion needs (units of blood), length of hospital stay (days), need
for surgery, or all-cause death; conclusion—continuous and bolus omeprazole IV comparable after endotherapy in high-risk
PUD
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| Continuous vs intermittent IV PPI infusion in PU bleeding (Gastroenterology, 2007; DDW, #T1242):
retrospective study of 97 patients with acute GI bleeding requiring endoscopic therapy for high-risk stigmata and hospitalization
for minimum of 72 hr; continuous group—received 24 hr of continuous IV PPI therapy after endotherapy; intermittent
group—received IV PPI therapy in any other manner; result—no difference in recurrence of bleeding in 7 days,
transfusion needs, surgery, and deaths; conclusion—comparable outcomes with continuous or intermittent IV PPI therapy
after endotherapy
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Antiplatelets, Anticoagulants, NSAIDs, and Cyclooxygenase [COX]-2 Inhibitors (COXIBs)
| Physician perspectives and practices (Gastroenterology, 2007; DDW, #921): 34-question Internet-based survey
of primary care physicians in 2003 and 2006; 52% increase in physicians willing to use gastroprotection with
NSAIDs; drop in COXIB use from 43% to 25% of all NSAID prescriptions; in certain scenarios, physician responses did
not correlate with practices (eg, PPI use in patients taking NSAIDs and/or aspirin long-term); conclusion—awareness of
need for GI protection not translated into practice
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| Incidence of UGI bleeding and impact of changing COX-2-specific NSAID prescription practices
(Gastroenterology, 2007; DDW, #917): incidence of UGI bleeding in 300000 Scottish patients; incidence of GI
bleeding in 2 time periods (1 yr before and after rofecoxib withdrawal); result—in year after withdrawal, increased incidence
of UGI bleeding (linked to rise in use of low-dose aspirin, other antithrombotic, or both, but not NSAID use)
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| Warfarin’s (Coumadin’s) role in Bleeding PUs (Gastrointestinal Endoscopy, 2007; DDW, #S1397): 1978
admissions (102 [5%] on warfarin); results—warfarin use associated with significant bleeding, transfusion requirements,
endoscopic stigmata, and requirement for endoscopic therapy; trend toward higher 30-day mortality in those taking warfarin;
conclusion—warfarin associated with increased bleeding complications in PUD
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| Aspirin use in setting of acute myocardial infarction (AMI) (American Journal of Gastroenterology,
2007; ACG Meeting, #141): retrospective study; 102 patients with AMI and subsequent bleeding PU; 79 patients
previously on aspirin; remaining on clopidogrel; 34 patients continued on aspirin after bleeding PU (in 68 patients, aspirin
stopped or temporarily held); all placed on appropriate therapy to treat PUD; result—no difference in rebleeding in
high- or low-risk ulcers; trend toward increase in mortality in patients who stopped aspirin; conclusion—aspirin does
not appear to increase risk for rebleeding in patients with AMI and concurrent bleeding PU
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| Prevalence of GI bleeding in patients receiving dual antiplatelet therapy (Gastroenterology, 2007;
DDW, #916): 664 patients on dual antiplatelet therapy (aspirin and clopidogrel); 3 treatments—dual therapy alone,
dual therapy plus H2 receptor antagonist, and dual therapy plus PPI; history of previous GI bleeding highest in group receiving
PPI prophylaxis; H2 receptor antagonist prophylaxis lowers risk for symptomatic ulcer or bleeding; same for PPI
(even greater benefit, compared to controls; PPI vs H2 receptor antagonist—trend in favor of PPI; conclusion—
antisecretory therapy reduces risk for symptomatic PUD associated with dual antiplatelet therapy
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H pylori Infection
| Efficacy of novel sequential therapy (Gastroenterology, 2007; DDW, #775): 10-day multicenter observational
study from Spain; 139 patients confirmed to have H pylori; indications—PUD (two-thirds) and dyspepsia (one-third);
all patients received PPI and amoxicillin (twice daily for 5 days); followed by PPI, clarithromycin, and metronidazole
twice daily for remaining 5 days; eradication rate—84% by intention to treat and 91% by per protocol analysis;
conclusion—sequential therapy highly effective as first-line therapy
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| Sequential therapy vs triple therapy for eradication (Gastroenterology, 2007; DDW, #775): randomized,
controlled trial (RCT); 300 patients evaluated for H pylori because of dyspepsia or PUD; treatments—10 days of sequential
therapy (40 mg pantoprazole and 1 g amoxicillin twice daily for 5 days, followed by pantoprazole, clarithromycin,
and tinidazole twice daily for 5 days) or standard clarithromycin-based triple therapy (pantoprazole, clarithromycin, and
amoxicillin twice daily); results—sequential therapy more effective, with eradication rate of 91% vs 78% with standard
triple therapy; for patients with clarithromycin-resistant strains, eradication rate 89% with sequential therapy vs 29%
with triple therapy
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| Effects of eradication on prevention of rebleeding PU (Gastroenterology, 2007; DDW, #T2065): prospective
study from Spain of 422 patients who presented with bleeding PU for 12 mo; all received eradication therapy; recurrence
of bleeding in only 2 patients in 1 yr (0.22% incidence; both patients using NSAIDs); conclusion—maintenance of antisecretory
therapy may be necessary only if patient continues NSAIDs after eradication
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| Comparisons of second-line levofloxacin-based triple schemes for treatment of persistent H pylori
(Gastroenterology, 2007; DDW, #774): randomized prospective trial, patients failed standard triple therapy; 4 treatment
arms, all containing esomeprazole, amoxicillin, and varying doses of levofloxacin; results—low eradication rate
(67%) in those treated 7 days (regardless of levofloxacin dose); of those receiving 10-day course, eradication rate approached
90% (did not differ with levofloxacin doses); conclusion— duration of therapy (10-day minimum) more important
than levofloxacin dose for salvage therapy
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Putting the Abstracts into Perspective
William D. Chey, MD, Professor of Internal Medicine, University of Michigan Medical School, Ann Arbor
PPIs and UGI bleeding
| Recent meta-analysis: PPI vs placebo—significant reduction (50%; OR, 5) in likelihood of recurrent GI bleeding in
individuals who receive PPI therapy; number needed to treat (NNT) 7, ie, must treat 7 patients with PPI to prevent one episode
of bleeding; PPI vs H2 receptor antagonist—clear reduction in rebleeding rate (OR 0.31); number needed to bleed
(NNB) 5; PPI and endoscopic therapy vs PPI alone—better outcomes with PPI plus endoscopy; NNB, 6; PPI plus endoscopy
vs endoscopic therapy alone—better outcomes with combination; statistically significant OR; NNB, 8
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| Take-home messages: PPI with endotherapy reduces risk for recurrent ulcer bleeding; combination more effective than
either alone; PPI useful as adjunctive therapy (not stand-alone) in patients with high-risk GI bleeding; intermittent IV and
continuous IV PPI yield similar outcomes
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| Risks associated with antiplatelet agents: low-dose aspirin (also indobufen, ticlopidine, clopidogrel, and dipyridamole)
associated with higher risk for UGI bleeding; for dipyridamole, no increase in risk; all PPIs associated with reduced
risk for bleeding; antiplatelet drugs associated with 14.5% of UGI bleeding; low-dose aspirin—balance of benefits
and harms most favorable in patients at high risk for coronary heart disease (5-yr risk >3%); American Heart Association
and others advocating use of risk calculators to determine patients for whom low-dose aspirin appropriate; use not common
in clinical practice, although quantifiable risks known; in 2003, 66% of physicians recommending 81 mg aspirin for cardioprotection
(in 2006, ≈82% recommended 81 mg); 20% recommend standard doses (325 mg); aspirin and
cardioprotection—for individuals using 100 mg of aspirin every other day, increased risk for UGI bleeding (no safe dose
of aspirin); Hong Kong study—15% of those with aspirin-associated ulcers who did not receive gastroprotection rebled
within 1 yr; risk for rebleeding reduced (<2%) in those who received gastroprotection; low-dose aspirin generally safe, except
in certain individuals with history of ulcer, ulcer bleeding, steroid therapy, use of anticoagulants, or concurrent use of
NSAIDs; Hong Kong study found 4.2% of GI bleeding or symptomatic ulcers associated with dual therapy (aspirin and
clopidogrel); aspirin with PPI after endoscopic hemostasis (study)—interim analysis of patients requiring aspirin for CV
accidents or CV disease who sustained acute UGI and ulcer bleeding; after endoscopic hemostasis, all received IV pantoprazole
80-mg bolus, then 8 mg/hr for 72 hr and oral pantoprazole 40 mg/day for an additional 8 wk; half of patients resumed
aspirin immediately after endoscopic therapy and half did not; low mortality rates from GI bleeding; higher 60-day
mortality for those who did not resume aspirin therapy (nearly all CV deaths); consider long-term CV risks; take-home
messages—in appropriately selected patients, benefits of aspirin clearly outweigh risks; 81 mg aspirin offers cardioprotection
while minimizing GI toxicity; patients with history of ulcer (with or without bleeding) should receive gastroprotection;
dual antiplatelet therapy increases risk for ulcer bleeding; CV disease and bleeding ulcer—treat with IV PPI; restart on aspirin
after endotherapy (except for high-risk lesions)
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| COX-2 selective NSAIDs: between 2003 and 2006, significant reduction in use; evidence to support use—Cochrane
review comparing COX-2-selective agents with NSAIDs, relative risk (RR) reduction 0.26%; COX-2-selective agents reduce
ulcer risk by 70%; absolute risk reduction 16%; COX-2-selective agents associated with reduced perforation,
obstruction, and bleeding, compared to NSAIDs; small absolute risk reduction (0.4%); adding aspirin to COXIB reduces
GI safety benefits of COXIB; reduction in lower GI events associated with COX-2-selective agents (majority of NSAID-
related events occur in UGI, not lower GI [LGI]); in study of LGI bleeding—no significant decrease in events (including
perforation, obstruction, bleeding, diverticulitis, or ulcer formation) in patients taking etoricoxib vs diclofenac (relatively
COX-2-specific nonselective NSAID)
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| CV risk and COXIBs: celecoxib—mixed data from trials; 2006 meta-analysis—no increased risk for CV toxicity; RR,
1.06; no data to show aspirin decreases CV risk; COX-2-selective agent vs traditional NSAID—no difference in risk for
serious CV events among COX-2-selective agents and non-naproxen NSAIDs; for many traditional NSAIDs, risk for
CV toxicity also increased, except for naproxen; use of multiple COX-2-selective inhibitors associated with increased
CV risk; mechanisms unclear; use COX-2-selective inhibitors with caution in patients at risk for CV disease; dose response
probable
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H pylori Infection
| PPI triple therapy: clarithromycin, amoxicillin, or metronidazole; tetracycline, oral bismuth subsalicylate, and metronidazole
(used less often, but works well); eradication <80%; recent trials (using pantoprazole or esomeprazole [Nexium])
show eradication rates 75%; possibly related to resistance, eradication rate has dropped 10% over 10 to 15 yr
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| Resistance: clarithromycin—12% to 13%; ask patients whether they previously used clarithromycin or macrolide antibiotic
in general (factors that dramatically increase risk for clarithromycin-resistant strain of H pylori); metronidazole
resistance—higher than clarithromycin; possibly overcome with PPI or increasing dose
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Suggested Reading
Aabakken L: Current endoscopic and pharmacological therapy of peptic ulcer bleeding. Best Pract Res Clin Gastroenterol
22:243, 2008; Andriulli A et al: High- versus low-dose proton pump inhibitors after endoscopic hemostasis
in patients with peptic ulcer bleeding: a multicentre, randomized study. Am J Gastroenterol 103:3011, 2008; Barkun
AN et al: Endoscopic hemostasis in peptic ulcer bleeding for patients with high-risk lesions: a series of meta-analyses.
Gastrointest Endosc. Jan 17, 2009 [Epub ahead of print]; Chan FK: Management of high-risk patients on non-steroidal
anti-inflammatory drugs or aspirin. Drugs 66 Suppl 1:23, 2006; Dahlberg LE et al: A randomized,
multicentre, double-blind, parallel-group study to assess the adverse event-related discontinuation rate with celecoxib
and diclofenac in elderly patients with osteoarthritis. Scand J Rheumatol Jan 22, 2009 [Epub ahead of print]; Elnachef
N et al: Changing perceptions and practices regarding aspirin, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2
selective nonsteroidal anti-inflammatory drugs among US primary care providers. Aliment Pharmacol Ther
28:1249, 2008; Laine L, McQuaid KR: Endoscopic therapy for bleeding ulcers: an evidence-based approach based
on meta-analyses of randomized controlled trials. Clin Gastroenterol Hepatol 7:33, 2009; Nguyen TV et al: Evaluation
of two triple-therapy regimens with metronidazole or clarithromycin for the eradication of H. pylori infection in
Vietnamese children: a randomized, double-blind clinical trial. Helicobacter 13:550, 2008; Uppalapati SS et al:
Risk Factors Involved in Patients with Bleeding Peptic Ulcers: A Case-Control Study. Dig Dis Sci Jul 22, 2008 [Epub
ahead of print]; Vakil N, Vaira D: Sequential therapy for Helicobacter pylori: time to consider making the switch?
JAMA 300:1346, 2008.
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