Francis K.L. Chan

Peptic-ulcer disease.

Peptic ulcer disease had a tremendous effect on morbidity and mortality until the last decades of the 20th century, when epidemiological trends started to point to an impressive fall in its incidence. Two important developments are associated with the decrease in rates of peptic ulcer disease: the discovery of effective and potent acid suppressants, and of Helicobacter pylori. With the discovery of H pylori infection, the causes, pathogenesis, and treatment of peptic ulcer disease have been rewritten. We focus on this revolution of understanding and management of peptic ulcer disease over the past 25 years. Despite substantial advances, this disease remains an important clinical problem, largely because of the increasingly widespread use of non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin. We discuss the role of these agents in the causes of ulcer disease and therapeutic and preventive strategies for drug-induced ulcers. The rare but increasingly problematic H pylori-negative NSAID-negative ulcer is also examined.

ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: A report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents

ACCF TASK FORCE MEMBERS Robert A. Harrington, MD, FACC, Chair; Eric R. Bates, MD, FACC; Charles R. Bridges, MD, MPH, FACC; Mark J. Eisenberg, MD, MPH, FACC; Victor A. Ferrari, MD, FACC; Mark A. Hlatky, MD, FACC; Sanjay Kaul, MBBS, FACC; Jonathan R. Lindner, MD, FACC‡; David J. Moliterno, MD, FACC; Debabrata Mukherjee, MD, FACC; Richard S. Schofield, MD, FACC‡; Robert S. Rosenson, MD, FACC; James H. Stein, MD, FACC; Howard H. Weitz, MD, FACC; Deborah J. Wesley, RN, BSN

Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers.

BACKGROUND After endoscopic treatment of bleeding peptic ulcers, bleeding recurs in 15 to 20 percent of patients. METHODS We assessed whether the use of a high dose of a proton-pump inhibitor would reduce the frequency of recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. Patients with actively bleeding ulcers or ulcers with nonbleeding visible vessels were treated with an epinephrine injection followed by thermocoagulation. After hemostasis had been achieved, they were randomly assigned in a double-blind fashion to receive omeprazole (given as a bolus intravenous injection of 80 mg followed by an infusion of 8 mg per hour for 72 hours) or placebo. After the infusion, all patients were given 20 mg of omeprazole orally per day for eight weeks. The primary end point was recurrent bleeding within 30 days after endoscopy. RESULTS We enrolled 240 patients, 120 in each group. Bleeding recurred within 30 days in 8 patients (6.7 percent) in the omeprazole group, as compared with 27 (22.5 percent) in the placebo group (hazard ratio, 3.9; 95 percent confidence interval, 1.7 to 9.0). Most episodes of recurrent bleeding occurred during the first three days, which made up the infusion period (5 in the omeprazole group and 24 in the placebo group, P<0.001). Three patients in the omeprazole group and nine in the placebo group underwent surgery (P=0.14). Five patients (4.2 percent) in the omeprazole group and 12 (10 percent) in the placebo group died within 30 days after endoscopy (P=0.13). CONCLUSIONS After endoscopic treatment of bleeding peptic ulcers, a high-dose infusion of omeprazole substantially reduces the risk of recurrent bleeding.

Guidelines for Prevention of NSAID-Related Ulcer Complications

Guidelines for clinical practice are intended to indicate preferred approaches to medical problems as established by scientifically valid research. Double-blind, placebo-controlled studies are preferable, but compassionate use reports and expert review articles are used in a thorough review of the literature conducted through Medline with the National Library of Medicine. Only when data that will not withstand objective scrutiny are available is a recommendation identified as a consensus of experts. Guidelines are applicable to all physicians who address the subject, without regard to specialty training or interests, and are intended to indicate the preferable, but not necessarily the only, acceptable approach to a specific problem. Guidelines are intended to be flexible and must be distinguished from standards of care, which are inflexible and rarely violated. Given the wide range of specifics in any health-care problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision. These guidelines were developed under the auspices of the American College of Gastroenterology by a committee of experts in the field, reviewed by its Practice Parameters Committee, and approved by the Board of Trustees. The recommendations of these guidelines are therefore considered valid at the time of production based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at an established time and indicated at publication to assure continued validity. Owing to the volume of new data on the subject of non-steroidal anti-inflammatory drug (NSAID)-related injury to the upper gastrointestinal tract, i.e., the advent of cyclooxygenase (COX)-2 inhibitors, new data on interactions between these agents, as well as traditional NSAIDs, with aspirin and H. pylori, it was elected by the Committee to confine these guidelines to upper gastrointestinal (GI) injury and to leave post-duodenal injury as the subject of a separate guideline.

Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers.

Background and Methods After endoscopic treatment to control bleeding of peptic ulcers, bleeding recurs in 15 to 20 percent of patients. In a prospective, randomized study, we compared endoscopic retreatment with surgery after initial endoscopy. Over a 40-month period, 1169 of 3473 adults who were admitted to our hospital with bleeding peptic ulcers underwent endoscopy to reestablish hemostasis. Of 100 patients with recurrent bleeding, 7 patients with cancer and 1 patient with cardiac arrest were excluded from the study; 48 patients were randomly assigned to undergo immediate endoscopic retreatment and 44 were assigned to undergo surgery. The type of operation used was left to the surgeon. Bleeding was considered to have recurred in the event of any one of the following: vomiting of fresh blood, hypotension and melena, or a requirement for more than four units of blood in the 72-hour period after endoscopic treatment. Results Of the 48 patients who were assigned to endoscopic retreatment, 35 had long-term...

Continuation of Low-Dose Aspirin Therapy in Peptic Ulcer Bleeding: A Randomized Trial

BACKGROUND It is uncertain whether aspirin therapy should be continued after endoscopic hemostatic therapy in patients who develop peptic ulcer bleeding while receiving low-dose aspirin. OBJECTIVE To test that continuing aspirin therapy with proton-pump inhibitors after endoscopic control of ulcer bleeding was not inferior to stopping aspirin therapy, in terms of recurrent ulcer bleeding in adults with cardiovascular or cerebrovascular diseases. DESIGN A parallel randomized, placebo-controlled noninferiority trial, in which both patients and clinicians were blinded to treatment assignment, was conducted from 2003 to 2006 by using computer-generated numbers in concealed envelopes. (ClinicalTrials.gov registration number: NCT00153725) SETTING A tertiary endoscopy center. PATIENTS Low-dose aspirin recipients with peptic ulcer bleeding. INTERVENTION 78 patients received aspirin, 80 mg/d, and 78 received placebo for 8 weeks immediately after endoscopic therapy. All patients received a 72-hour infusion of pantoprazole followed by oral pantoprazole. All patients completed follow-up. MEASUREMENTS The primary end point was recurrent ulcer bleeding within 30 days confirmed by endoscopy. Secondary end points were all-cause and specific-cause mortality in 8 weeks. RESULTS 156 patients were included in an intention-to-treat analysis. Three patients withdrew from the trial before finishing follow-up. Recurrent ulcer bleeding within 30 days was 10.3% in the aspirin group and 5.4% in the placebo group (difference, 4.9 percentage points [95% CI, -3.6 to 13.4 percentage points]). Patients who received aspirin had lower all-cause mortality rates than patients who received placebo (1.3% vs. 12.9%; difference, 11.6 percentage points [CI, 3.7 to 19.5 percentage points]). Patients in the aspirin group had lower mortality rates attributable to cardiovascular, cerebrovascular, or gastrointestinal complications than patients in the placebo group (1.3% vs. 10.3%; difference, 9 percentage points [CI, 1.7 to 16.3 percentage points]). LIMITATIONS The sample size is relatively small, and only low-dose aspirin, 80 mg, was used. Two patients with recurrent bleeding in the placebo group did not have further endoscopy. CONCLUSION Among low-dose aspirin recipients who had peptic ulcer bleeding, continuous aspirin therapy may increase the risk for recurrent bleeding but potentially reduces mortality rates. Larger trials are needed to confirm these findings.

ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use

This document has been developed by the American College of Cardiology Foundation (ACCF) Task Force on Clinical Expert Consensus Documents, the American College of Gastroenterology (ACG), and the American Heart Association (AHA). Expert consensus documents (ECDs) are intended to inform practitioners, payers, and other interested parties of the opinion of the ACCF and document cosponsors concerning evolving areas of clinical practice and/or technologies that are widely available or new to the practice community. Topics chosen for coverage by ECDs are so designed because the evidence base, the experience with technology, and/or the clinical practice are not considered sufficiently well developed to be evaluated by the formal American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines process. Often the topic is the subject of ongoing investigation. Thus, the reader should view ECDs as the best attempt of the ACCF and other cosponsors to inform and guide clinical practice in areas where rigorous evidence may not be available or the evidence to date is not widely accepted. When feasible, ECDs include indications or contraindications. Topics covered by ECDs may be addressed subsequently by the ACC/AHA Practice Guidelines Committee as new evidence evolves and is evaluated. The Task Force on ECDs makes every …

Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication

Background and aim: Gastric intestinal metaplasia (IM) is generally considered to be a precancerous lesion in the gastric carcinogenesis cascade. This study identified the risk factors associated with progression of IM in a randomised control study. Subjects and methods: A total of 587 Helicobacter pylori infected subjects were randomised to receive a one week course of anti-Helicobacter therapy (omeprazole, amoxicillin, and clarithromycin (OAC)) or placebo. Subjects underwent endoscopy with biopsy at baseline and at five years. Severity of IM was graded according to the updated Sydney classification and progression was defined as worsening of IM scores at five years in either the antrum or corpus, or development of neoplasia. Backward stepwise multiple logistic regression was used to identify independent risk factors associated with IM progression. Results: Of 435 subjects (220 in the OAC and 215 in the placebo group) available for analysis, 10 developed gastric cancer and three had dysplasia. Overall progression of IM was noted in 52.9% of subjects. Univariate analysis showed that persistent H pylori infection, age >45 years, male subjects, alcohol use, and drinking water from a well were significantly associated with IM progression. Duodenal ulcer and OAC treatment were associated with a reduced risk of histological progression. Progression of IM was more frequent in those with more extensive and more severe IM at baseline. With multiple logistic regression, duodenal ulcer (odds ratio (OR) 0.23 (95% confidence interval (CI) 0.09–0.58)) was found to be an independent protective factor against IM progression. Conversely, persistent H pylori infection (OR 2.13 (95% CI 1.41–3.24)), age >45 years (OR 1.92 (95% CI 1.18–3.11)), alcohol use (OR 1.67 (95% CI 1.07–2.62)), and drinking water from a well (OR 1.74 (95% CI 1.13–2.67)) were independent risk factors associated with IM progression. Conclusion: Eradication of H pylori is protective against progression of premalignant gastric lesions.

Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial.

BACKGROUND Whether Helicobacter pylori increases the risk of ulcers in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) is controversial. We hypothesised that eradication of H pylori infection would reduce the risk of ulcers for patients starting long-term NSAID treatment. METHODS Patients were enrolled if they were NSAID naïve, had a positive urea breath test, had dyspepsia or an ulcer history, and required long-term NSAID treatment. They were randomly assigned omeprazole triple therapy (eradication group) or omeprazole with placebo antibiotics (placebo group) for 1 week. All patients were given diclofenac slow release 100 mg daily for 6 months from randomisation. Endoscopy was done at 6 months or if severe dyspepsia or gastrointestinal bleeding occurred. The primary endpoint was the probability of ulcers within 6 months. Analyses were by intention to treat. FINDINGS Of 210 arthritis patients screened, 128 (61%) were positive for H pylori. 102 patients were enrolled, and 100 were included in the intention-to-treat analysis. H pylori was eradicated in 90% of the eradication group and 6% of the placebo group. Five of 51 eradication-group patients and 15 of 49 placebo-group patients had ulcers. The 6-month probability of ulcers was 12.1% (95% CI 3.1-21.1) in the eradication group and 34.4% (21.1-47.7) in the placebo group (p=0.0085). The corresponding 6-month probabilities of complicated ulcers were 4.2% (1.3-9.7) and 27.1% (14.7-39.5; p=0.0026). INTERPRETATION Screening and treatment for H pylori infection significantly reduces the risk of ulcers for patients starting long-term NSAID treatment.

Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial

BACKGROUND Cyclo-oxygenase (COX)-2-selective non-steroidal anti-inflammatory drugs (NSAIDs) and non-selective NSAIDs plus a proton-pump inhibitor (PPI) have similar upper gastrointestinal outcomes, but risk of clinical outcomes across the entire gastrointestinal tract might be lower with selective drugs than with non-selective drugs. We aimed to compare risk of gastrointestinal events associated with celecoxib versus diclofenac slow release plus omeprazole. METHODS We undertook a 6-month, double-blind, randomised trial in patients with osteoarthritis or rheumatoid arthritis at increased gastrointestinal risk at 196 centres in 32 countries or territories. Patients tested negative for Helicobacter pylori and were aged 60 years and older or 18 years and older with previous gastroduodenal ulceration. We used a computer-generated randomisation schedule to assign patients in a 1:1 ratio to receive celecoxib 200 mg twice a day or diclofenac slow release 75 mg twice a day plus omeprazole 20 mg once a day. Patients and investigators were masked to treatment allocation. The primary endpoint was a composite of clinically significant upper or lower gastrointestinal events adjudicated by an independent committee. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00141102. FINDINGS 4484 patients were randomly allocated to treatment (2238 celecoxib; 2246 diclofenac plus omeprazole) and were included in intention-to-treat analyses. 20 (0.9%) patients receiving celecoxib and 81 (3.8%) receiving diclofenac plus omeprazole met criteria for the primary endpoint (hazard ratio 4.3, 95% CI 2.6-7.0; p<0.0001). 114 (6%) patients taking celecoxib versus 167 (8%) taking diclofenac plus omeprazole withdrew early because of gastrointestinal adverse events (p=0.0006). INTERPRETATION Risk of clinical outcomes throughout the gastrointestinal tract was lower in patients treated with a COX-2-selective NSAID than in those receiving a non-selective NSAID plus a PPI. These findings should encourage review of approaches to reduce risk of NSAID treatment. FUNDING Pfizer Inc.