Omeprazole plus antibiotics in the eradication of Helicobacter pylori infection: a meta-regression analysis of randomized, controlled trials.

This article presents a meta-regression analysis of published studies of omeprazole plus antibiotics (amoxicillin, clarithromycin, or an imidazole derivative) in the treatment of Helicobacter pylori. Eligible studies were all randomized, controlled trials published through April 1996 with 10 or more patients receiving omeprazole plus antibiotics for 5 or more days and testing for H. pylori eradication 4 weeks or more after treatment. Probability of eradication was calculated for each treatment arm, and logistic regression was performed using study characteristics as covariates. Seventy-four studies involving 117 treatment arms with 4,769 patients were identified. The eradication rate was 76% for omeprazole plus clarithromycin and 65% for omeprazole plus amoxicillin dual regimens (P <.0001). Eradication rates for triple regimens were 82%, omeprazole plus amoxicillin plus clarithromycin; 83%, omeprazole plus amoxicillin plus imidazole; and 89%, omeprazole plus clarithromycin plus imidazole. In a multiple logistic regression analysis, significant factors were antibiotic, disease, omeprazole dose, and whether treatment was followed by maintenance omeprazole. A systematic overview of the best available evidence suggests that dual therapy with omeprazole plus clarithromycin is superior to omeprazole plus amoxicillin. Triple therapy is better than dual therapy. Treatment works better on ulcers than on nonulcer dyspepsia. Higher doses of omeprazole give better results. Additional trials exploring higher omeprazole doses for varying durations as well as cost, side effects, and compliance trade-offs with efficacy are recommended.

Are randomized control trial outcomes influenced by the inclusion of a placebo group?: a systematic review of nonsteroidal antiinflammatory drug trials for arthritis treatment.

Placebo groups are often included in randomized control trials evaluating drug therapy, yet we know little about the placebo effect. The purpose of our study was to evaluate how the presence of a placebo group in a randomized control trial (RCT) influences the patients' ratings of the efficacy of an active drug therapy and their reporting of its adverse effects. We identified studies published between 1966 and 1994 using MEDLINE. Randomized control trials evaluating acetylsalicylic acid, diclofenac, or indomethacin for the treatment of osteo or rheumatoid arthritis were included in our sample. Two investigators independently extracted data. Fifty-eight treatment arms met our inclusion criteria and were available for analysis. Twenty-five treatment arms evaluated a nonsteroidal antiinflammatory drug (NSAID) in placebo control trials and 33 in comparative trials. Using a logistic regression model to adjust for the differences between the evaluated drugs and between the types of arthritis, we found that patients receiving an NSAID in a placebo control trial were more likely to withdraw due to inefficacy (OR=1.3; 95% CI, 1.0 to 1.6; P=0.04). Using a similar model, withdrawals due to adverse effects were found to be more common when the NSAID was given in trials that did not include a placebo group (OR=1.5; 95% CI, 1.1 to 1.9; P=0.002) as were reports of cutaneous (OR=4.2; 95% CI, 1.7 to 9.9), gastrointestinal (OR=1.6; 95% CI, 1.3 to 2.0), and other types (OR=5.3; 95% CI, 3.8 to 7.4) of adverse effects. Although reports of central nervous system adverse effects were more frequent in the comparative trials, this difference was not significant. Including a placebo group in a RCT changes how patients rate the efficacy and adverse effects of their therapy. Our results highlight the need to consider the placebo effect in the design and analyses of clinical trials.

Safety of nifedipine in angina pectoris: a meta-analysis.

-Our objective was to compare cardiovascular event rates in patients with stable angina receiving nifedipine as monotherapy or combination therapy and in active drug controls. A MEDLARS search of published articles from 1966 to 1995 in English, French, German, Italian, or Spanish, supplemented by a manual search of bibliographies, identified 60 randomized controlled trials that met protocol criteria. Blinded articles were extracted by 2 physicians. The pooled risks of death, withdrawal, and cardiovascular event were computed and expressed as odds ratios (ORs) for all nifedipine formulations and relative to same study control drug regimens. Thirty cardiovascular events were reported in 2635 nifedipine exposures (1.14%) and 19 events in 2655 other active drug exposures (0.72%). Unadjusted ORs for nifedipine versus controls were 1.40 (95% CI, 0.56 to 3.49) for major events (death, nonfatal myocardial infarction, stroke, revascularization procedure), 1.75 (95% CI, 0.83 to 3.67) for increased angina, and 1.61 (95% CI, 0.91 to 2.87) for all events (major events plus increased angina). Episodes of increased angina were more frequent on immediate-release nifedipine (OR, 4.19 [95% CI, 1.41 to 12.49]) and on nifedipine monotherapy (OR, 2.61 [95% CI, 1.30 to 5.26]). The OR for immediate-release nifedipine was significantly higher than that for sustained-release/extended-release nifedipine (P=0.001), and the OR for nifedipine monotherapy was higher than that for nifedipine combination therapy (P=0.03). Increased risks of cardiovascular events in patients with stable angina on nifedipine were due primarily to more episodes of increased angina, confined to the immediate-release formulation and to nifedipine monotherapy.

The effectiveness of glucocorticoids in treating croup: meta-analysis.

OBJECTIVE: To determine the effectiveness of glucocorticoid treatment in children with croup. DESIGN: Meta-analysis of randomized controlled trials that examine the effectiveness of glucocorticoid treatment in children with croup. MAIN OUTCOME MEASURES: Score on scale measuring severity of croup,use of co-interventions (epinephrine, antibiotics, or supplemental glucocorticoids), length of stay in the emergency department or the hospital, and rate of hospitalization. RESULTS: Twenty-four studies met the inclusion criteria. Glucocorticoid treatment was associated with an improvement in the croup severity score at 6 hours with an effect size of -1.0 (95% confidence interval [CI] -1.5 to -0.6) and at 12 hours -1.0 (-1.6 to -0.4); at 24 hours, this improvement was no longer significant (-1.0, -2.0 to -0.1). There was a decrease in the number of epinephrine treatments needed in children treated with glucocorticoids: a decrease of 9% (95% CI 2% to 16%) among those treated with budesonide and of 12% (4% to 20%) among those treated with dexamethasone. There was also a decrease in the length of time spent in the emergency department (-11 hours, 95% CI -18 to 4 hours) and, for inpatients, hospital stay was reduced by 16 hours (-31 to 1 hour). Publication bias seems to play a part in these results. CONCLUSIONS: Dexamethasone and budesonide are effective in relieving the symptoms of croup as early as 6 hours after treatment. Fewer co-interventions are used, and the length of time spent in the hospital is decreased in patients treated withglucocorticoids.

The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials.

UNLABELLED: We performed meta-analyses of randomized, control trials to assess the effects of seven analgesic therapies on postoperative pulmonary function after a variety of procedures: epidural opioid, epidural local anesthetic, epidural opioid with local anesthetic, thoracic versus lumbar epidural opioid, intercostal nerve block, wound infiltration with local anesthetic, and intrapleural local anesthetic. Measures of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), vital capacity (VC), peak expiratory flow rate (PEFR), PaO2, and incidence of atelectasis, pulmonary infection, and pulmonary complications overall were analyzed. Compared with systemic opioids, epidural opioids decreased the incidence of atelectasis (risk ratio [RR] 0.53, 95% confidence interval [CI] 0.33-0.85) and had a weak tendency to reduce the incidence of pulmonary infections (RR 0.53, 95% CI 0.18-1.53) and pulmonary complications overall (RR 0.51, 95% CI 0.20-1.33). Epidural local anesthetics increased PaO2 (difference 4.56 mm Hg, 95% CI 0.058-9.075) and decreased the incidence of pulmonary infections (RR 0.36, 95% CI 0.21-0.65) and pulmonary complications overall (RR 0.58, 95% CI 0.42-0.80) compared with systemic opioids. Intercostal nerve blockade tends to improve pulmonary outcome measures (incidence of atelectasis: RR 0.65, 95% CI 0.27-1.57, incidence of pulmonary complications overall: RR 0.47, 95% CI 0.18-1.22), but these differences did not achieve statistical significance. There were no clinically or statistically significant differences in the surrogate measures of pulmonary function (FEV1, FVC, and PEFR). These analyses support the utility of epidural analgesia for reducing postoperative pulmonary morbidity but do not support the use of surrogate measures of pulmonary outcome as predictors or determinants of pulmonary morbidity in postoperative patients. IMPLICATIONS: When individual trials are unable to produce significant results, it is often because of insufficient patient numbers. It may be impossible for a single institution to study enough patients. Meta-analysis is a useful tool for combining the data from multiple trials to increase the patient numbers. These meta-analyses confirm that postoperative epidural pain control can significantly decrease the incidence of pulmonary morbidity.

Methadone vs. L-alpha-acetylmethadol (LAAM) in the treatment of opiate addiction. A meta-analysis of the randomized, controlled trials.

The authors conducted a meta-analysis of the reported randomized, controlled trials comparing methadone to L-alpha-acetylmethadol (LAAM) to assess the efficacy of LAAM relative to methadone in the treatment of opiate addiction. All studies were conducted in standard outpatient opiate addiction treatment clinics. Most patients were men from lower socioeconomic strata. A statistically significant risk difference favoring methadone was detected for retention-in-treatment and discontinuation of treatment because of side effects. The risk difference for illicit drug use favored LAAM, but was not significant. A small treatment difference in favor of methadone was noted. LAAM does appear to be a relatively effective alternative in the treatment of opiate addiction, more so in certain select situations.

Safety of nifedipine in patients with hypertension: a meta-analysis.

Our objective was to compare cardiovascular event rates in patients with mild or moderate hypertension who received nifedipine with active drug controls. We performed a MEDLARS search using the MeSH heading "hypertension" and the text word "nifedipine" to identify all articles that were published between 1966 and August 1995 in English, French, German, Italian, and Spanish languages and that involved human subjects. The computerized search was supplemented by a manual search of article bibliographies. Review of 1880 citations revealed 98 randomized controlled clinical trials that met protocol criteria. Articles were extracted independently by two doctors who were blinded for author, institution, and treatment regimen, using a structured, pretested extraction form. Differences of opinion were resolved by consensus. Fourteen events occurred in 5198 exposures (0.27%) to nifedipine and 24 events in 5402 exposures (0.44%) to other active drug controls. Unadjusted odds ratios for nifedipine versus controls were 0.49 (95% confidence interval [CI], 0.22-1.09) for definitive events (death, nonfatal myocardial infarction or stroke, revascularization procedure) and 0.61 (95% CI, 0.31-1.17) for all events (definitive plus increased angina). The odds ratio for nifedipine monotherapy (sustained- or extended-release in 91% of exposures) was nonsignificantly higher for definitive and all events (odds ratio, 1.40; 95% CI, 0.49-4.03 and odds ratio, 1.39; 95% CI, 0.59-3.32, respectively). The odds ratio for nifedipine in combination with another drug was significantly lower for definitive and all events (odds ratio, 0.09; 95% CI, 0.01-0.66 and odds ratio, 0.15; 95% CI, 0.03-0.65, respectively). Differences in odds ratio for nifedipine monotherapy and combined therapy were statistically significant (P=.02 for definitive events and P=.001 for all events). Results support the safety of sustained- and extended-release nifedipine in the treatment of mild or moderate hypertension when it is used in combination with other drugs.

Comparative efficacy of epidural, subarachnoid, and intracerebroventricular opioids in patients with pain due to cancer.

BACKGROUND AND OBJECTIVES: Although rarely used, intracerebroventricular opioid therapy (ICV) is an option for the control of intractable pain due to cancer when systemic treatments have failed. The aim of the present study is to use available data from published trials to compare ICV with the more common epidural (EP) and subarachnoid (SA) opioid treatments in an attempt to establish the utility and safety of ICV. METHODS: Because there are no published controlled trials comparing these routes of administration, the combined data from multiple uncontrolled trials were used, with differences between the treatments analyzed statistically. Trials assessing ICV (13 trials, 268 patients). EPI (29 trials, 909 patients) and SA (21 trials, 410 patients) in cancer patients were identified; data on analgesic efficacy, common pharmacologic side effects, and complications were then extracted and the accumulated incidence data analyzed. RESULTS: The findings (weighted means) indicated ICV to be at least as effective against pain as other neuraxial treatments, with 75% of ICV-treated patients obtaining excellent pain relief as compared with 72% of EPI- and 58% of SA-treated patients (not significant). The failure rate of both spinal treatments tended to be greater than that of ICV and was significantly higher in the case of EPI (P = .045). In general, persistent side effects appeared to be more of a problem with the spinal treatments, while transient symptoms occur more often with ICV. Persistent nausea, urinary retention, and pruritus all were more frequent with the two spinal treatments than with ICV, but transient nausea and respiratory depression occurred more often with ICV. Sedation and confusion appeared to occur more often with ICV than with spinal therapy, while constipation and headache were rarely encountered with ICV. There were no real differences in infectious complication rates among the three treatments (except for a lower rate of infection when an implanted pump was used), but technical problems such as catheter blockage, misplacement, or leakage tended to occur less often with ICV. CONCLUSIONS: Intracerebroventricular therapy appears to be at least as effective against pain as other neuraxial treatments. The ICV technique is the only fixed system that is associated with fewer technical problems than the use of simple percutaneous epidural catheters (difference 9%, standard error of the difference 3.4). The present state of evidence indicates that ICV is a successful treatment for patients with intractable cancer pain and compares well with spinal opioid treatments in terms of efficacy, side effects, and complications.

Dr. Tom Chalmers, 1917-1995: the tribulations of a trialist. Interview by Malcolm Maclure.

This article is the second part of an interview Dr. Malcolm Maclure had with Dr. Thomas Chalmers shortly before Chalmers' death late in 1995. It probes his role as a champion of randomized clinical trials.

Large trials vs meta-analysis of smaller trials: how do their results compare?

OBJECTIVE: To evaluate the results of large clinical trials vs the pooled results of smaller trials. DATA IDENTIFICATION: Meta-analyses with at least 1 "large" study were identified from the Cochrane Pregnancy and Childbirth Database and from MEDLINE (1966-1995). STUDY SELECTION: We used a sample size approach to select 79 meta-analyses with at least 1 large study of 1000 or more patients. We used a statistical power approach to select 61 meta-analyses with at least 1 large study based on statistical power considerations. DATA EXTRACTION: The outcome of interest for each meta-analysis was the primary one stated in the original publication or, when not clearly specified, was decided on clinically. DATA SYNTHESIS: By random effects calculations, we found agreement between large and smaller trials in 90% of the meta-analyses selected by the sample size approach and in 82% of the meta-analyses selected by the statistical power approach. Twice as many disagreements appeared when the variability among large studies and among smaller studies was not considered (ie, fixed effects calculations). Of the 15 disagreements between results of large and smaller trials using the random effects model, plausible explanations were identified in 10 meta-analyses: 5 with differences in the control rate of events between large and smaller trials, 4 with specific protocol or study differences, and 1 with potential publication bias. Two other disagreements were not clinically important, and tentative reasons could be identified for 2 of the remaining 3 disagreements. CONCLUSIONS: Results of smaller studies are usually compatible with the results of large studies, but discrepancies do occur even when the diversity among both large studies and smaller studies is considered. Clinically important differences without a potential explanation are extremely uncommon. Future research should further examine sources of heterogeneity between the results of large and smaller trials.

Gender-based mortality follow-up from the Program on the Surgical Control of the Hyperlipidemias (POSCH) and meta-analysis of lipid intervention trials. Women in POSCH and other lipid trials.

OBJECTIVE: The authors assessed the clinical results of lipid-lowering therapy in women. SUMMARY BACKGROUND DATA: The Program on the Surgical Control of the Hyperlipidemias (POSCH) has demonstrated that effective lowering of total cholesterol and low-density lipoprotein cholesterol in a postmyocardial infarction population significantly reduces atherosclerotic coronary heart disease (ACHD) mortality, ACHD mortality combined with a new confirmed nonfatal myocardial infarction, and the number of coronary artery bypass grafting and angioplasty procedures performed. METHODS: A review and meta-analysis were performed of the seven primary or secondary lipid/ atherosclerosis intervention trials-including POSCH-published in the English-language literature that included women and published results in women separate from the results in men or in the entire trial population. The main outcome measure analyzed was overall mortality. RESULTS: The Scottish Physicians Clofibrate Study, the Newcastle upon Tyne Clofibrate Study, and the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I) Trial may have demonstrated a possible benefit in ACHD prognosis from effective lipid intervention in women. The other four available trials did not. The Minnesota Coronary Survey reported a 15.6% increase in overall mortality rate and a 30.6% increase in a combined cardiovascular endpoint rate in the lipid-intervention group. The Upjohn Colestipol Study demonstrated statistically significant reductions in overall and ACHD mortality in the men, but not in the women. The Scandinavian.

Searching for signals: mortality and cardiovascular events in published randomized control trials of nifedipine in ischemic heart disease and hypertension.

UNLABELLED: META-ANALYSIS: A meta-analysis of published randomized control trials of nifedipine in hypertension and stable angina pectoris was performed. RESULTS: The results suggest a formulation-dependent increased risk of mortality and adverse cardiovascular outcomes for monotherapy use in patients with stable angina pectoris. No increased risk was seen in the hypertension studies.

Changes in clinical trials mandated by the advent of meta-analysis.

Service on the Data Monitoring Committee of the CPEP (Calcium for Pre-eclampsia Prevention) has led us to four conclusions about clinical trials which we should like to present to this gathering of biostatisticians for their reactions: (i) meta-analyses of the pertinent published trials of the same therapy should always be undertaken before the start of a new trial, and the results examined to help determine the design of a new trial or determine if a trial should be undertaken at all; (ii) assuming that a decision is made to go ahead, the results of the past trials should be used in sizing the new one; (iii) in the course of the new one, regardless of the size estimates, stopping early should be considered if the trends conform to the results of the meta-analysis; and (iv) heterogeneity of patients entering clinical trials is desirable and should be specifically studied, and it should never be concluded that an average outcome is applicable to all future patients.

Functional electrostimulation in poststroke rehabilitation: a meta-analysis of the randomized controlled trials.

OBJECTIVE: To assess the efficacy of functional electrical stimulation (FES) in the rehabilitation of hemiparesis in stroke. DESIGN: A meta-analysis combined the reported randomized controlled trials of FES in stroke, using the effect size method of Glass, and the DerSimonian-Laird Random Effects Method for pooling studies. SETTING: The included studies were published between 1978 and 1992. They were conducted in academic rehabilitation medicine settings. PATIENTS: In all included studies, patients were in poststroke rehabilitation. The mean time after stroke varied from 1.5 to 29.2 months. INTERVENTION: FES applied to a muscle or associated nerve in a hemiparetic extremity was compared to No FES. MAIN OUTCOME MEASURE: Change in paretic muscle force of contraction following FES was compared to change without FES. RESULTS: For the four included studies, the mean effect size was .63 (95% CI: .29, .98). This result was statistically significant (p < .05). CONCLUSION: Pooling from randomized trials supports FES as promoting recovery of muscle strength after stroke. This effect is statistically significant. There is a reasonable likelihood of clinical significance as well.

The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis.

BACKGROUND: Dietary protein has long been thought to play a role in the progression of chronic renal disease, but clinical trials to date have not consistently shown that dietary protein restriction is beneficial. PURPOSE: To use meta-analysis to assess the efficacy of dietary protein restriction in previously published studies of diabetic and nondiabetic renal diseases, including the recently completed Modification of Diet in Renal Disease Study. DATA SOURCES: The English-language medical literature published from January 1966 through December 1994 was searched for studies examining the effect of low-protein diets in humans with chronic renal disease. A total of 1413 patients in five studies on nondiabetic renal disease (mean length of follow-up, 18 to 36 months) and 108 patients in five studies of type I diabetes mellitus (mean length of follow-up, 9 to 35 months) were included. STUDY SELECTION: Randomized, controlled studies were selected for nondiabetic renal disease; randomized, controlled studies or time-controlled studies with nonrandomized crossover design were selected for diabetic nephropathy. DATA EXTRACTION: Data in tables, figures, or text were independently extracted by two of the authors. DATA SYNTHESIS: The relative risk for progression of renal disease in patients receiving a low-protein diet compared with patients receiving a usual-protein diet was calculated by using a random-effects model. In five studies of nondiabetic renal disease, a low-protein diet significantly reduced the risk for renal failure or death (relative risk, 0.67 [95% Cl, 0.50 to 0.89]). In five studies of insulin-dependent diabetes mellitus, a low-protein diet significantly slowed the increase in urinary albumin level or the decline in glomerular filtration rate or creatinine clearance (relative risk, 0.56 [Cl, 0.40 to 0.77]). Tests for heterogeneity showed no significant differences in relative risk among studies of either diabetic or nondiabetic renal disease. No significant differences were seen between diet groups in pooled mean arterial blood pressure (diabetic and nondiabetic patients) or glycosylated hemoglobin level (diabetic patients only). CONCLUSION: Dietary protein restriction effectively slows the progression of both diabetic and nondiabetic renal diseases.

Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis.

The purpose of this study was to validate the results of a meta-analysis showing the efficacy of fish oil in rheumatoid arthritis with the results of a re-analysis of the complete primary data set. A Medline search yielded seven published papers. Three additional trials were found by contacting authorities in the field. Inclusion criteria included (1) a double-blind, placebo-controlled study, (2) use of at least one of seven predetermined outcome measures, (3) results reported for both placebo and treatment groups at baseline and follow-up, (4) randomization, and (5) parallel or cross-over design. Papers were scored for quality. Demographic and outcomes variables were collected. For the re-analysis of the primary data, the same variables were abstracted for the 395 individual patients randomized. The meta-analysis demonstrated that dietary fish oil supplementation for 3 months significantly reduced tender joint count (rate difference [RD] [95% CI] = -2.9 [-3.8 to -2.1] [p = 0.001]) and morning stiffness (RD [95% CI] = -25.9 [-44.3 to -7.5] [p < 0.01]) as compared with heterogeneous dietary control oils. The re-analysis of the primary data confirmed a significant reduction in tender joint count (p = 0.001) and in morning stiffness (p < 0.02) in the parallel analysis that ignored interaction terms. The analyses that included an interaction term between site and treatment again confirmed a significant reduction in tender joint count. The results for morning stiffness were similar to the meta-analysis, but did not quite reach statistical significance (p = 0.052-0.083). The relative improvements in the other outcome variables did not reach statistical significance. Use of fish oil improved the number of tender joints and duration of morning stiffness at 3 months as analyzed by both meta- and mega-analysis. The fuller mega-analysis confirmed the results of the meta-analysis. The advantages of mega-analysis were as follows: (1) the ability to analyze the homogeneity of the patient populations, (2) the ability to make clinically sensible adjustments in the form of the comparison, and (3) the ability to examine subsets of the data.