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The Cochrane Database of Systematic... Apr 2007Indomethacin is a prostaglandin inhibitor used to treat patent ductus arteriosus (PDA) in preterm infants. Although indomethacin produces ductal closure in the majority... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Indomethacin is a prostaglandin inhibitor used to treat patent ductus arteriosus (PDA) in preterm infants. Although indomethacin produces ductal closure in the majority of cases, it is ineffective in up to 40% of patients. Furthermore, the ductus will re-open in up to 35% of infants who initially respond to the drug. Prolonging the course of indomethacin has the potential to achieve higher rates of ductal closure.
OBJECTIVES
To determine the effect of a prolonged course of indomethacin (compared to a short course) on the rate of treatment failure without unwanted side-effects in preterm infants with PDA.
SEARCH STRATEGY
The search included review of personal files, abstracts of conferences, and the following electronic databases: MEDLINE (1966 to December 2006), EMBASE (1974 to December 2006), and Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2006). No language restrictions were applied.
SELECTION CRITERIA
Randomized or quasi-randomized controlled trials including preterm infants with PDA, diagnosed on clinical and/or echocardiographic examination that evaluated indomethacin treatment by any route given as a long course (four or more doses) vs. a short course (three or fewer doses) were included in the review. Trials needed to report on at least one of the following outcomes: failure of PDA to close, need for re-treatment, PDA re-opening, PDA ligation, mortality, duration of assisted ventilation, chronic lung disease (CLD), duration of supplemental oxygen dependence, intraventricular hemorrhage (IVH) (all and severe), diminished urine output, increased serum creatinine, necrotizing enterocolitis (NEC), bleeding diathesis, retinopathy of prematurity (ROP), and duration of hospital stay.
DATA COLLECTION AND ANALYSIS
The three review authors independently abstracted data from each study. Relative risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using the fixed effect model for meta-analysis are reported. When a statistically significant RD was found, the number needed to treat (NNT) or number needed to harm (NNH) was also calculated with 95% CIs. The I squared statistic was used to test for heterogeneity of results among included trials.
MAIN RESULTS
Five trials met inclusion criteria and included 431 infants. Prolonged indomethacin treatment when compared to the short course did not result in a statistically significant difference in PDA closure, re-treatment, re-opening, or ligation rates. The prolonged course was associated with an increased risk of NEC [typical RR 1.87 (95% CI 1.07, 3.27); typical RD 0.08 (95% CI 0.01, 0.15); NNH 13 (7, 100)] and a decreased incidence of renal function impairment, as evidenced by a lower proportion of infants having diminished urine output [typical RR 0.27 (95% CI 0.13, 0.6); typical RD -0.19 (95% CI -0.28, -0.09); NNT 5 (4, 11)] and increased serum creatinine level [typical RR 0.51 (95% CI 0.33, 0.77); typical RD -0.14 (95% CI -0.23, -0.06); NNT 7 (4, 16)].
AUTHORS' CONCLUSIONS
Implications for practiceProlonged indomethacin course does not appear to have a significant effect on improving important outcomes, such as PDA treatment failure, CLD, IVH, or mortality. The reduction of transient renal impairment does not outweigh the increased risk of NEC associated with the prolonged course. Based on these results, a prolonged course of indomethacin cannot be recommended for the routine treatment of PDA in preterm infants. Implications for researchThere is a paucity of data on optimal dosing and duration of indomethacin therapy for the treatment of PDA, in particular for extremely low birth weight infants (ELBW) premature infants. It is likely that a single standard indomethacin regime is not the ideal for every premature infant. Therefore, individual patient response should be considered and evaluated, in particular in ELBW infants. Future randomized clinical trials should include this high risk population and investigate the effect of tailoring dose and duration of therapy to individual response in terms of echocardiographic findings and/or prostaglandin levels, focusing on clinically significant outcomes, including long-term neurodevelopmental outcomes. In addition, factors that may influence treatment effect, such as birth weight, gestational age, age at the time of randomization, total fluid intake, feeding practice, and severity of PDA, need to be taken into account when designing such studies.
Topics: Ductus Arteriosus, Patent; Humans; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Prostaglandin Antagonists; Randomized Controlled Trials as Topic
PubMed: 17443527
DOI: 10.1002/14651858.CD003480.pub3 -
Health Technology Assessment... Oct 2006To assess the relative effectiveness, patient acceptability, costs and cost-effectiveness of four strategies for the prevention of non-steroidal anti-inflammatory drugs... (Meta-Analysis)
Meta-Analysis Review
A comparison of the cost-effectiveness of five strategies for the prevention of non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling.
OBJECTIVES
To assess the relative effectiveness, patient acceptability, costs and cost-effectiveness of four strategies for the prevention of non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrointestinal (GI) toxicity: (1) Cox-1 NSAIDs plus histamine-2 receptor antagonist (H2RA), (2) Cox-1 NSAIDs plus proton pump inhibitors (PPIs), (3) Cox-1 NSAIDs plus misoprostol, and (4) Cox-2 NSAIDs (later expanded to 4a Cox-2 coxibNSAIDs and 4b Cox-2 preferential NSAIDs).
DATA SOURCES
Electronic databases up to May 2002.
REVIEW METHODS
Relevant studies were selected, assessed and analysed. Pooled relative risk ratios (RR) from the systematic review were combined with up-to-date UK resource use and unit costs data in an incremental economic analysis. A probabilistic decision-analytic model was designed and populated with data to carry out incremental economic analysis. Incremental cost-effectiveness ratios (ICERs) were generated for the outcome measure, endoscopic ulcer or serious GI event averted, against total cost, and non-parametric bootstrapping was used to simulate variance of these ICERs.
RESULTS
Of 118 selected trials, including 125 relevant comparisons (which included 76,322 participants) only 138 deaths and 248 serious GI events were reported. Seven comparisons were judged to be at low risk of bias. Comparing the gastroprotective strategies against placebo, there was no evidence of effectiveness of H2RAs against any primary outcomes (few events reported), PPIs may reduce the risk of symptomatic ulcers [RR 0.09, 95% confidence interval (CI) 0.02 to 0.47], misoprostol reduces the risk of serious GI complications (RR 0.57, 95% CI 0.36 to 0.91) and symptomatic ulcers (RR 0.36, 95% CI 0.20 to 0.67), Cox-2 'preferentials' reduce the risk of symptomatic ulcers (RR 0.41, 95% CI 0.26 to 0.65) and Cox-2 'coxibs' reduce the risk of symptomatic ulcers (RR 0.49, 95% CI 0.38 to 0.62) and possibly serious GI events (RR 0.55, 95% CI 0.38 to 0.80). All strategies except Cox-2 'preferentials' reduce the risk of endoscopic ulcers. There were only 12 direct comparisons between gastroprotective strategies. All they suggest is that Cox-2 preferentials are better than misoprostol for preventing GI complications. Indirect comparisons suggested that PPIs may prevent symptomatic ulcers better than Cox-2 coxibs, but this is very weak evidence. For prevention of endoscopic ulcers PPIs and misoprostol appear more successful than H2RAs and misoprostol is better than Cox-2 preferentials. There were no UK head-to-head published economic analyses with regard to the main gastroprotective strategies. There were generally insufficient data with regards to cardiac or renal outcomes, serious GI outcomes or life-years gained to populate the mode. Mean (2.5th and 97.5th percentile) costs per endoscopic ulcer averted compared with Cox-1 NSAIDs alone were as follows: Cox-1 plus H2RAs, -186 pounds (-555 to 804); Cox-1 plus PPIs, 454 pounds (251 to 877); Cox-1 plus misoprostol, 54 pounds (-112 to 238); Cox-2 selective NSAIDs, 263 pounds (-570 to 1280), or Cox-2 specific NSAIDs, 301 pounds (189 to 418). With regard to the prevention of endoscopic ulcers, Cox-1 NSAID plus H2RA is a dominant option. Cost-effectiveness acceptability analysis showed a 95% probability that this combination was less costly and more effective. Cost-effectiveness acceptability frontiers showed that if the decision-maker is willing to pay up to 750 pounds to avoid an endoscopic ulcer, then Cox-1 plus H2RA is the optimal strategy. If the decision-maker is willing to pay over 750 pounds, the optimal strategy is NSAID plus misoprostol. Between 1900 pounds and 3750 pounds, Cox-2 selective inhibitors are optimal, and over 3750 pounds, Cox-2 specific inhibitors become optimal. NSAID plus PPI is never the optimal strategy. Sensitivity and subgroup analyses suggest that Cox-1 NSAID plus H2RA and Cox-1 NSAID plus misoprostol become more cost-effective in the older age group. Some conclusions were associated with high levels of uncertainty.
CONCLUSIONS
Although there is a very large body of evidence comparing Cox-2 NSAIDs with Cox-1 NSAIDs, this is not matched by studies of the other types of gastroprotectors or by studies directly comparing active gastroprotective strategies. This lack of direct comparisons led to the use of indirect comparisons to help understand the relative efficacy of these strategies. Indirect evidence in itself is weak and was also hampered by lack of evidence in the underlying studies (where the gastroprotectors were compared with placebo). Economic modelling suggests that Cox-1 NSAID plus H2RA or Cox-1 NSAID plus PPI are the most cost-effective strategies for avoiding endoscopic ulcers in patients requiring long-term NSAID therapy. All strategies other than Cox-2 selective inhibitors reduce the rate of endoscopic ulcer compared with Cox-1 alone. The economic analysis suggests that there may be a case for prescribing H2RAs in all patients requiring NSAIDs. Misoprostol is more effective, but is associated with a greater cost and GI side-effects which may be unacceptable for patients. However, when assessing serious GI events, the economic analysis is sufficiently weakened by the data available as to render clear practice recommendations impossible. Further large, independent RCTs directly comparing various gastroprotective strategies are needed. These should report items such as major outcomes, primary data, adverse events, assessment of practice and patient preference.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Cost-Benefit Analysis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Gastrointestinal Diseases; Humans; Isoenzymes; Membrane Proteins; Models, Econometric; Patient Satisfaction; Prostaglandin-Endoperoxide Synthases; Proton Pump Inhibitors; Risk Factors; United Kingdom
PubMed: 17018227
DOI: 10.3310/hta10380 -
Singapore Medical Journal May 2006Spontaneous preterm labour and delivery accounts for approximately one-third of preterm births, which is the predominant cause of perinatal mortality and morbidity. This... (Review)
Review
Spontaneous preterm labour and delivery accounts for approximately one-third of preterm births, which is the predominant cause of perinatal mortality and morbidity. This review aims to evaluate the evidence on the benefits and harms of five classes of tocolytic therapy, namely: betamimetics, calcium channel blockers, magnesium, non-steroidal anti-inflammatory agents, and atosiban. We performed a systematic review of the effectiveness of tocolytics to stop uterine contractions (first-line therapy). Reports of randomised controlled trials from searches of MEDLINE, bibliographies of review articles, Cochrane Collaboration and its Pregnancy and Childbirth Review Group between 1966 and 2003 were identified, using the search terms "randomised controlled trial" (RCT), "preterm labor", "tocolysis", "betamimetics", "ritodrine", "prostaglandin synthetase inhibitors", "indomethacin", "calcium channel blockers", "nifedipine", "oxytocin receptor blockers", "atosiban", and "magnesium sulphate". Studies on women with preterm labour comparing the effects of a tocolytic with a placebo or no treatment that met our inclusion criteria, were included. To our knowledge, the trials were conducted mainly before 1999 and there were no placebo-controlled trials after that. Of the 86 articles identified and evaluated, 14 first-line studies met more stringent requirements for meta-analyses. Tocolytics were associated with significant decreases in the odds of delivery within 24 hours (odds-ratio [OR] 0.54, 95 percent confidence interval [CI] 0.32-0.91) and 48 hours (OR 0.47, 95 percent CI 0.30-0.75). These effects were significant for beta-agonists, atosiban and indomethacin, but not magnesium sulphate. Maternal side-effects significantly associated with betamimetics were pulmonary oedema, cardiac arrhthymias and hypokalaemia. Although calcium antagonists have not been evaluated against placebo, comparative trials with beta-agonists have shown more favourable neonatal outcomes and better prolongation of gestation. In conclusion, the management of threatened preterm labour with first-line tocolytic therapy can prolong gestation. However, the time gained in-utero need to be optimised. There is no clear first-line tocolytic agent. The use of tocolytic agents should be individualised and based on maternal condition, potential side-effects and gestational age.
Topics: Female; Humans; Obstetric Labor, Premature; Pregnancy; Pregnancy Outcome; Time Factors; Tocolysis; Tocolytic Agents
PubMed: 16645683
DOI: No ID Found -
BMJ (Clinical Research Ed.) Dec 2004To estimate the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 inhibitors (coxibs), in patients with... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To estimate the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 inhibitors (coxibs), in patients with osteoarthritis of the knee.
DESIGN
Systematic review and meta-analysis of randomised placebo controlled trials.
STUDIES REVIEWED
23 trials including 10 845 patients, median age of 62.5 years. 7807 patients received adequate doses of NSAIDs and 3038 received placebo. The mean weighted baseline pain score was 64.2 mm on 100 mm visual analogue scale (VAS), and average duration of symptoms was 8.2 years.
MAIN OUTCOME MEASURE
Change in overall intensity of pain.
RESULTS
Methodological quality of trials was acceptable, but 13 trials excluded patients before randomisation if they did not respond to NSAIDs. One trial provided long term data for pain that showed no significant effect of NSAIDs compared with placebo at one to four years. The pooled difference for pain on visual analogue scale in all included trials was 10.1 mm (95% confidence interval 7.4 to 12.8) or 15.6% better than placebo after 2-13 weeks. The results were heterogeneous, and the effect size for pain reduction was 0.32 (0.24 to 0.39) in a random effects model. In 10 trials that did not exclude non-responders to NSAID treatment the results were homogeneous, with an effect size for pain reduction of 0.23 (0.15 to 0.31).
CONCLUSION
NSAIDs can reduce short term pain in osteoarthritis of the knee slightly better than placebo, but the current analysis does not support long term use of NSAIDs for this condition. As serious adverse effects are associated with oral NSAIDs, only limited use can be recommended.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disabled Persons; Humans; Isoenzymes; Membrane Proteins; Middle Aged; Osteoarthritis, Knee; Pain; Prostaglandin-Endoperoxide Synthases; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 15561731
DOI: 10.1136/bmj.38273.626655.63 -
BMJ (Clinical Research Ed.) Oct 2004To assess the effectiveness of five gastroprotective strategies for people taking non-steroidal anti-inflammatory drugs (NSAIDs)--H2 receptor antagonists plus... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To assess the effectiveness of five gastroprotective strategies for people taking non-steroidal anti-inflammatory drugs (NSAIDs)--H2 receptor antagonists plus non-selective (or cyclo-oxygenase-1) NSAIDs; proton pump inhibitors plus non-selective NSAIDs; misoprostol plus non-selective NSAIDs; COX-2 selective NSAIDs; or COX-2 specific NSAIDs--in reducing serious gastrointestinal complications, symptomatic ulcers, serious cardiovascular or renal disease, and deaths, and improving quality of life.
DATA SOURCES
The Cochrane Library, Medline, Embase, Current Controlled Trials, and System for Information on Grey Literature in Europe (SIGLE) were searched to May 2002. Bibliographies and author contacts were used to identify further studies; non-English articles were included.
REVIEW METHODS
Trial selection, data extraction, and quality assessment were performed independently, in duplicate. Articles were rejected only if the study was not a randomised controlled trial; did not assess a gastroprotective strategy versus placebo; included exclusively children or healthy volunteers; lasted less than 21 days; or no review outcomes were measured. Quality assessment included allocation concealment and baseline similarity. Random effects meta-analysis, meta-regression and subgrouping were used to pool effects and analyse associations with length of follow up, mean age, and baseline gastrointestinal status. Heterogeneity was examined and sensitivity analyses performed.
RESULTS
Of 112 included randomised controlled trials (74 666 participants), five were judged to be at low risk of bias, and 138 deaths and 248 serious gastrointestinal events were reported overall. On comparing gastroprotective strategies versus placebo we found no evidence of effectiveness of H2 receptor antagonists for any primary outcomes (few events reported); proton pump inhibitors may reduce the risk of symptomatic ulcers (relative risk 0.09, 95% confidence interval 0.02 to 0.47); misoprostol reduces the risk of serious gastrointestinal complications (0.57, 0.36 to 0.91) and symptomatic ulcers (0.36, 0.20 to 0.67); COX-2 selectives reduce the risk of symptomatic ulcers (0.41, 0.26 to 0.65) and COX-2 specifics reduce the risk of symptomatic ulcers (0.49, 0.38 to 0.62) and possibly serious gastrointestinal complications (0.55, 0.38 to 0.80). All strategies except COX-2 selectives reduce the risk of endoscopic ulcers (at least 3 mm in diameter).
CONCLUSIONS
Misoprostol, COX-2 specific and selective NSAIDs, and probably proton pump inhibitors significantly reduce the risk of symptomatic ulcers, and misoprostol and probably COX-2 specifics significantly reduce the risk of serious gastrointestinal complications, but data quality is low. More data on H2 receptor antagonists and proton pump inhibitors are needed, as is better reporting of rare but important outcomes.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Gastrointestinal Diseases; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Risk Factors
PubMed: 15475342
DOI: 10.1136/bmj.38232.680567.EB -
Annals of Internal Medicine May 2003Rofecoxib and celecoxib (coxibs) effectively treat chronic arthritis pain and reduce ulcer complications by 50% compared with nonselective nonsteroidal anti-inflammatory... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rofecoxib and celecoxib (coxibs) effectively treat chronic arthritis pain and reduce ulcer complications by 50% compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). However, their absolute risk reduction is small and the cost-effectiveness of treatment is uncertain.
OBJECTIVE
To determine whether the degree of risk reduction in gastrointestinal complications by coxibs offsets their increased cost compared with a generic nonselective NSAID.
DESIGN
Cost-utility analysis.
DATA SOURCES
Systematic review of MEDLINE and published abstracts.
TARGET POPULATION
Patients with osteoarthritis or rheumatoid arthritis who are not taking aspirin and who require long-term NSAID therapy for moderate to severe arthritis pain.
PERSPECTIVE
Third-party payer.
INTERVENTIONS
Naproxen, 500 mg twice daily, and coxib, once daily. Patients intolerant of naproxen were switched to a coxib.
TIME HORIZON
Lifetime.
OUTCOME MEASURES
Incremental cost per quality-adjusted life-year (QALY) gained.
RESULTS OF BASE-CASE ANALYSIS
Using a coxib instead of a nonselective NSAID in average-risk patients cost an incremental 275 809 dollars per year to gain 1 additional QALY.
RESULTS OF SENSITIVITY ANALYSIS
The incremental cost per QALY gained decreased to 55 803 dollars when the analysis was limited to the subset of patients with a history of bleeding ulcers. The coxib strategy became dominant when the cost of coxibs was reduced by 90% of the current average wholesale price. In probabilistic sensitivity analysis, if a third-party payer was willing to pay 150 000 dollars per QALY gained, then 4.3% of average-risk patients would fall within the budget.
CONCLUSIONS
The risk reduction seen with coxibs does not offset their increased costs compared with nonselective NSAIDs in the management of average-risk patients with chronic arthritis. However, coxibs may provide an acceptable incremental cost-effectiveness ratio in the subgroup of patients with a history of bleeding ulcers.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cardiovascular Diseases; Celecoxib; Chronic Disease; Cost-Benefit Analysis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Decision Support Techniques; Humans; Isoenzymes; Lactones; Membrane Proteins; Osteoarthritis; Peptic Ulcer; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Quality-Adjusted Life Years; Recurrence; Risk Factors; Sensitivity and Specificity; Sulfonamides; Sulfones
PubMed: 12755551
DOI: 10.7326/0003-4819-138-10-200305200-00007 -
The Cochrane Database of Systematic... 2000Non-steroidal anti-inflammatory drugs (NSAIDs) are important agents in the management of arthritic and inflammatory conditions, and are among the most frequently... (Review)
Review
BACKGROUND
Non-steroidal anti-inflammatory drugs (NSAIDs) are important agents in the management of arthritic and inflammatory conditions, and are among the most frequently prescribed medications in North America and Europe. However, there is overwhelming evidence linking these agents to a variety of gastrointestinal (GI) toxicities.
OBJECTIVES
To review the effectiveness of common interventions for the prevention of NSAID induced upper GI toxicity.
SEARCH STRATEGY
A literature search was conducted, according to the Cochrane methodology for identification of randomized controlled trials in electronic databases, including MEDLINE from 1966 to January 2000, Current Contents for 6 months prior to January 2000, Embase to Febuary 1999, and a search of the Cochrane Controlled Trials Register from 1973 to 1999. Recent conference proceedings were reviewed and content experts and companies were contacted.
SELECTION CRITERIA
Randomized controlled clinical trials (RCTs) of prostaglandin analogues (PA), H2-receptor antagonists (H2RA) or proton pump inhibitors (PPI) for the prevention of chronic NSAID induced upper GI toxicity were included.
DATA COLLECTION AND ANALYSIS
Two independent reviewers extracted data regarding population characteristics, study design, methodological quality and number of patients with endoscopic ulcers, ulcer complications, symptoms, overall drop-outs, drop outs due to symptoms. Dichotomous data was pooled using Revman V3.1. Heterogeneity was evaluated using a chi square test.
MAIN RESULTS
Thirty-three RCTs met the inclusion criteria. All doses of misoprostol significantly reduced the risk of endoscopic ulcers. Misoprostol 800 ug/day was superior to 400 ug/day for the prevention of endoscopic gastric ulcers (RR=0.18, and RR=0. 38 respectively, p=0.0055). A dose response relationship was not seen with duodenal ulcers. Misoprostol caused diarrhea at all doses, although significantly more at 800ug/day than 400ug/day (p=0.0012). Misoprostol was the only prophylactic agent documented to reduce ulcer complications. Standard doses of H2RAs were effective at reducing the risk of endoscopic duodenal (RR=0.24; 95% CI: 0.10-0. 57) but not gastric ulcers(RR=0.73; 95% CI:0.50-1.09). Both double dose H2RAs and PPIs were effective at reducing the risk of endoscopic duodenal and gastric ulcers (RR=0.44; 95% CI:0.26-0.74 and RR=0.37;95% CI;0.27-0.51 respectively for gastric ulcer), and were better tolerated than misoprostol.
REVIEWER'S CONCLUSIONS
Misoprostol, PPIs, and double dose H2RAs are effective at preventing chronic NSAID related endoscopic gastric and duodenal ulcers. Lower doses of misoprostol are less effective and are still associated with diarrhea. Only Misoprostol 800ug/day has been directly shown to reduce the risk of ulcer complications.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Chronic Disease; Duodenal Ulcer; Histamine H2 Antagonists; Humans; Misoprostol; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Stomach Ulcer
PubMed: 10908548
DOI: 10.1002/14651858.CD002296