Randomized control trials and meta-analyses in gastroenterology: major achievements and future potential.
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Bias↗
Biomedical subjects
J Lau
Publications and source records attributed to J Lau.
Cesarean section to reduce perinatal transmission of human immunodeficiency virus. A metaanalysis.
OBJECTIVE: Individual epidemiologic investigations into the association between type of delivery and perinatal HIV transmission have been suggestive but inconclusive. Metaanalysis was used in an attempt to establish if there is, at present, adequate evidence concerning the effectiveness of cesarean section in reducing vertical HIV transmission rates. METHODS: The MEDLINE data retrieval system and other sources were used to identify studies containing data on the relationship between type of delivery and vertical HIV transmission. No randomized control trials were located. Six cohort studies identified were included in the metaanalysis. Crude and, in the only study in which these were available, adjusted data were extracted and pooled. RESULTS: The overall weighted risk of perinatal HIV infection was 20.2% and 14.0% after vaginal and cesarean delivery, respectively. Pooling data of all studies showed a statistically significant difference of HIV perinatal transmission rates between cesarean and vaginal delivery (odds ratio 0.65; 95% CI, 0.43 to 0.99; P = 0.044) (Random effects model: DerSimonian and Laird method). Approximately 16 (95% CI, 76 to 9) HIV-infected women must deliver by cesarean in order to prevent 1 case of HIV perinatal infection. CONCLUSIONS: Results of this study show that performing elective cesarean section in HIV-infected women is potentially an effective procedure. However, the nonexperimental nature of the available studies leads us to conclude that randomized control trials are indicated before setting specific guidelines for mode of delivery in HIV-infected women.
Bias↗
Early angiography and angioplasty following thrombolytic therapy of acute myocardial infarction. Metaanalysis of the randomized control trials.
STUDY OBJECTIVE: There have been at least 10 randomized control trials (RCTs) of early intervention in patients with acute myocardial infarction published, and all are inconclusive with regard to impact on mortality. Metaanalysis offers an opportunity to assess the efficacy of an early intervention following thrombolytic therapy in the treatment of acute myocardial infarction. DESIGN: Data on the number of patients who died in the hospital, and the total number of patients randomized to aggressive versus conservative therapies, were drawn from 9 publications and combined using both a fixed and a random-effects metaanalysis model. Quality of the trials was assessed under blinded conditions. SETTING: The 10 RCTs to be combined were each carried out in individual institutions. PATIENTS: A total of 5882 patients have been randomized, with 305 deaths (5.2%), indicating that this group of patients had a relatively low mortality rate compared to patients in general with acute myocardial infarction. COMPARISON OF TREATMENTS: No matter how the 10 trials were combined for analysis, there was no evidence that aggressive intervention was trending towards saving lives. Data on other endpoints such as need for repeat percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass grafting (CABG), or recurrent myocardial infarction were sparse, but the same adverse trend was apparent. CONCLUSION: In spite of the fact that early angiography and PTCA when indicated have been advocated for more than a decade, there is still no evidence that they reduce overall mortality after fibrinolysis in a specific subgroup. Further studies of early intervention should be done in an effort to answer subgroup questions which include the search for appropriate timing and patient selection for PTCA after fibrinolysis. As more RCTs with mortality data are published they will be added to these metaanalyses in The Online Journal of Current Clinical Trials.
Angioplasty, Balloon, Coronary↗
Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes.
Tight blood glucose control has been speculated to reduce late complications in insulin-dependent diabetics but results from individual studies have been inconsistent. We have done a meta-analysis of sixteen randomised trials of intensive therapy to estimate its impact on the progression of diabetic retinopathy and nephropathy and the risks of severe side-effects. In the intensive therapy group, the risk of retinopathy progression was insignificantly higher after 6-12 months of intensive control (odds ratio [OR] 2.11). After more than two years of intensive therapy the risk of retinopathy progression was lower (OR 0.49 [95% confidence interval 0.28-0.85], p = 0.011). The risk of nephropathy progression was also decreased significantly (OR 0.34 [0.20-0.58], p < 0.001). The incidence of severe hypoglycaemia increased by 9.1 episodes per 100 person-years (95% Cl -1.4 to +19.6) in the intensively treated patients. The incidence of diabetic ketoacidosis increased by 12.6 episodes per 100 person-years (95% Cl, 8.7-16.5) in the patients on continuous subcutaneous insulin infusion. Long-term intensive blood glucose control significantly reduces the risk of diabetic retinopathy and nephropathy progression but long-term continuous subcutaneous insulin infusion was associated with an increased incidence of diabetic ketoacidosis, and intensive therapy may cause more severe hypoglycaemic reactions.
Blood Glucose↗
Metaanalysis of the effects of intensive glycemic control on late complications of type I diabetes mellitus.
OBJECTIVE: To estimate the effects of intensive glycemic control on the progression of diabetic retinopathy and nephropathy, and to assess the risks of severe hypoglycemia and diabetic ketoacidosis. DESIGN: Metaanalysis of published randomized controlled trials. SETTING: As listed in each study. PATIENTS: Five hundred twenty-nine patients from 16 randomized controlled trials. MEASUREMENTS: We searched for all studies with sufficient data for analysis. The overall difference in the risk of retinopathy or nephropathy progression was analyzed, and the overall difference in the incidence of hypoglycemia or diabetic ketoacidosis was estimated. RESULTS: Compared to conventionally treated patients, the risk of retinopathy progression was statistically insignificantly higher after 6 to 12 months of intensive therapy (odds ratio [OR] 2.11; 95% confidence interval [CI], 0.54 to 8.31). After more than 2 years of intensive therapy the risk of retinopathy progression was lower (OR 0.49; 95% CI, 0.28 to 0.85). The risk of nephropathy progression was also decreased significantly in the intensive therapy group (OR 0.32; 95% CI, 0.19 to 0.55). When compared to conventional control, intensive therapy reduced glycosylated hemoglobin (%) by 1.4 with a 95% CI ranging from 1.1 to 1.8. The overall incidence of severe hypoglycemia increased by 9.1 episodes/100 person-years (95% CI, -1.4 to 19.6) in the intensively treated patients. The incidence of diabetic ketoacidosis increased by 12.6 episodes/100 person-years (95% CI, 8.7 to 16.5) in those who received continuous subcutaneous insulin infusion. CONCLUSION: Long-term intensive glycemic control significantly reduced the risks of diabetic retinopathy and nephropathy progression among type I diabetes patients when compared with randomly assigned controls. However, long-term continuous subcutaneous insulin infusion was associated with an increased incidence of diabetic ketoacidosis, and intensive therapy might cause more severe hypoglycemic reactions in some patients.
Blood Glucose↗
Meta-analysis of radiotherapy for small-cell lung cancer.
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Carcinoma, Small Cell↗
The prevalence of diabetes mellitus and impaired glucose tolerance among Hong Kong Chinese adults of working age.
We studied 1513 employees (910 men and 603 women) from a public utility company and a regional hospital to document the prevalence of diabetes mellitus (DM) and impaired glucose tolerance (IGT) in the Chinese working population of Hong Kong using a 75-g oral glucose tolerance test and World Health Organisation (1985) criteria. The overall prevalence of DM was 4.5 (95% confidence interval: 3.5-5.7%) and that of IGT 7.3 (6.0-8.6%). The prevalence of DM was 5.1 (3.7-6.5%) in men and 3.6 (2.1-5.1%) in women, while that of IGT was 7.4 (5.7-6.5%) in men and 7.1 (5.1-9.1%) in women. The truncated age-adjusted rate of DM for age 30-64 is 7.7% which is comparable to the age-adjusted prevalence rates among Chinese living in Singapore and Mauritius but in marked contrast to the low prevalence rate in Chinese living in Mainland China. Among the diabetic subjects, 38.2% had been previously diagnosed and 32% gave a family history affecting at least one first degree relative. Using polychotomous logistic regression analysis, the independent predictive factors for the development of DM include age (t = 7.31, P < 0.001), family history (t = 5.1, P < 0.001), waist hip ratio (t = 4.05, P < 0.001) and body mass index (t = 4.62, P < 0.001). Our data further confirm that Hong Kong Chinese have a moderate to high susceptibility to non-insulin-dependent diabetes (NIDDM) when exposed to sufficient environmental and lifestyle factors. The high prevalence of IGT indicates a potential for the prevalence of DM to continue to rise unless effective preventive measures are implemented.
Adolescent↗
Bone mineral content of two populations of Chinese children with different calcium intakes.
Bone mineral content (BMC) of 5-year-old Chinese children (115 children in Jiangmen, China and 128 children in Hong Kong) was evaluated by single-photon absorptiometry at the distal 1/3 radius. The mean (S.D.) calcium intakes of children of Jiangmen and Hong Kong were 244 (46) and 542 (332) mg/day, respectively. The mean BMC, weight and height of Jiangmen children were significantly less than Hong Kong children by 14%, 10% and 4%, respectively (P < 0.001). Multiple regression analysis showed that 62% of the variance in BMC was explained by bone width (BW), weight and regional location (P < 0.0001). A regional difference in BMC of 0.0303 g/cm (P < 0.0001) still remained after adjusting for BW and weight by multiple regression analysis. When comparing sub-groups of children in the two regions with comparable low current calcium intake at 5 years, the BMC of Jiangmen children was still significantly lower than Hong Kong children even when potential confounders were adjusted (P < 0.003). The study suggests that the regional discrepancy in BMC might be explained by long-term habitual calcium intake and physical activity.
Absorptiometry, Photon↗
Assessing the effectiveness of ambulatory cardiac monitoring for specific clinical indications. Introduction.
This introduction and the three essays that follow examine ambulatory cardiac monitoring for specific clinical indications. They also examine the ways in which evidence from the literature may be synthesized through the framework of decision analysis to guide its appropriate use and identify areas in which more research is needed. The essays discuss ambulatory cardiac monitoring for evaluation of syncope in the elderly; detection of silent ischemia after a myocardial infarction; and selection of antiarrhythmic drugs for malignant ventricular arrhythmias.
Aged↗
Noninvasive testing of asymptomatic patients for the detection of silent ischemia after an infarction. A decision analysis.
This decision analysis estimates the overall gain in life expectancy and the relative efficacy of predischarge submaximal exercise electrocardiography, ambulatory cardiac monitoring, and thallium-201 scintigraphy for the identification of silent ischemia in asymptomatic postinfarct patients. A small, virtually equal increase in life expectancy can be obtained from any of the noninvasive tests (as compared to no testing). Large differences in life expectancy may result only when the prevalence of residual coronary artery disease and the probability of left-main and three-vessel lesions are high.
Aged↗
Relationship between long-term calcium intake and bone mineral content of children aged from birth to 5 years.
This study evaluated Ca intake in Hong Kong Chinese children and examined the association between long-term Ca intake and bone mineral content (BMC) in children. Longitudinal dietary intake from birth to 5 years was obtained in 128 children (sixty-seven boys, sixty-one girls). Ca intakes were evaluated by dietary history and cross-checked with food frequency and 24 h recall. At age 5 years BMC was determined at the one-third distal radius of the right arm using single-photon absorptiometry. The mean Ca intake of 133 children at 5 years was 546 (SD 325) mg/d. Milk was the chief source of Ca (43.5%). From birth to 5 years, 90% of the children had been taking milk regularly. The mean BMC and bone width (BW) of these children were 0.317 (SD 0.042) g/cm and 0.756 (SD 0.074) cm respectively. BMC was not correlated with current intakes of Ca, energy and protein but was positively correlated with weight (r 0.57), height (r 0.47) and BW (r 0.66). However, cumulative Ca intake throughout the past 5 years showed significant correlation with BMC (r 0.235, P = 0.0133). The significant correlation remained even after weight, height, BW, sex, and cumulative intakes of energy and protein were adjusted in multiple regression analysis (r 0.248, P = 0.0107). Moreover, using principal component analysis, Ca intake during the 2nd year of life had the strongest correlation with BMC at 5 years (r 0.240, P = 0.02). Ca intake of Hong Kong Chinese children was higher than the RDA of the Food and Agriculture Organization/World Health Organization (1962) and achieved 66% of the current US recommendation (National Research Council, 1989). The increased regular milk consumption reflects a significant change in dietary habits of the younger generation. Children with a habitually higher Ca intake throughout the past 5 years, particularly in the 2nd year, were found to have higher BMC.
Absorptiometry, Photon↗
Association of negative symptoms with tardive dyskinesia in schizophrenic patients.
In recent years, a great deal of interest has been focused on the association between negative symptoms of schizophrenia and tardive dyskinesia, but the literature is far from conclusive. Thirty-six schizophrenic patients with tardive dyskinesia and 76 without were surveyed using the Scale for Assessment of Negative Symptoms. On univariate analysis, the composite score and scores of certain subscales were associated with tardive dyskinesia, but this association was lost on multivariate analysis. After adjusting for confounding variables like age, education and antipsychotic dose, no association of negative symptoms and tardive dyskinesia was found.
Adult↗
Usefulness of the Widal test in diagnosing childhood typhoid fever in endemic areas.
Data are presented for 2382 children investigated for fever in a Malaysian hospital between 1984 and 1987 when Widal tests and blood cultures were a routine part of every fever screen. There were 145 children who were culture positive (TYP-CP) for Salmonella typhi, while 166 were culture negative but were diagnosed as having typhoid (TYP-CN). Analyses of the sensitivity and specificity of combinations of initial Widal titres in predicting a positive S. typhi culture in a febrile child (culture positive vs the rest) showed the best model to be an O- and/or H-titre of > or = 1 in 40 (sensitivity 89%; specificity 89%). While the negative predictive value of the model was high (99.2%) the positive predictive value remained below 50% even for very high titres of O and H (> 1 in 640), at which point the specificity was 98.5%, supporting the clinical view that a high proportion of the TYP-CN patients really were typhoid but were missed by culture. The TYP-CN patients showed a very similar clinical and age profile to TYP-CP patients. The length of history of fever did not affect the initial Widal titre in culture positive cases. The Widal test in children remains a sensitive and specific 'fever screen' for typhoid although it will not identify all cases. In children, lower cut-off points for O- and H-titres should be used than are generally recommended.
Agglutinins↗
Treatment of respiratory syncytial virus infection with recombinant interferon alfa-2a.
A prospective randomised, double blind, controlled trial was conducted in 52 infants to determine whether recombinant interferon alfa-2a (INF-alpha-2a) would reduce the morbidity of acute bronchiolitis and the respiratory syncytial virus shedding time. All infants had a positive direct antigen immunofluorescence test for respiratory syncytial virus. INF-alpha-2a (50,000 IU/kg/day) or placebo was administered by daily intramuscular injection for three consecutive days. Sixteen infants received INF-alpha-2a and 36 received placebo treatment. The two groups were similar in demographic characteristics and initial oxygenation. The treatment group, however, had a significantly higher overall score for severity of illness at the start of treatment. More rapid drop of the clinical score was observed in the INF-alpha-2a group after treatment in the first three days and the two groups had similar clinical severity by day 3. There was no significant difference of the duration of viral shedding in the two groups. In conclusion, the overall clinical improvement was greater in the treatment group over the first three days, but the duration of viral shedding was not altered.
Double-Blind Method↗
Meta-analytic stimulus for changes in clinical trials.
The advent of meta-analysis, especially when performed cumulatively, raises many questions about how best to approach the conduct of clinical trials in the evaluation of new treatments. We need to be assured that bias is minimized by proper experimental procedures and that clinical data, on the whole and in subgroups, are presented so that they can be effectively combined in meta-analysis. We need to re-examine the idea that we should not start a randomized control trial unless sufficient patients are available to avoid reasonable type I and II errors. Meta-analyses will come to the rescue, provided trials continue to be published at the present rate. We need to perform meta-analyses before undertaking each additional trial, and we need to base estimates of trial size on past data as well as the expected control rates and the differences we do not want to miss. In clinical trials of new interventions attempting to disprove the null hypothesis may be inappropriate because past data so often suggest or even establish that it is not true. Furthermore we need to recognize that trends (p > 0.05) can be both clinically and statistically important, and we must abandon the notion that if p is not < 0.05, the treatment is ineffective. In performing meta-analyses we need to worry about minimizing bias and error and consider the differences between the random and fixed effects models and between reporting results as an odds ratio versus difference in risk, with the control rates given. Experiences with cumulative meta-analysis have required that we think about all of these problems.
Meta-Analysis as Topic↗
A clinical study monitoring low-intensity anticoagulant therapy with a standard-sensitivity thromboplastin.
The ability of the prothrombin time to measure the anticoagulant effect of warfarin sodium varies depending on the particular tissue thromboplastin used in performing the test. Based on studies using sensitive thromboplastins, lower therapeutic ranges of anticoagulation are recommended. The adequacy of monitoring therapy in this lower range with the relatively insensitive thromboplastins commonly used in North America is unestablished. This 16-month prospective study used a standard North American thromboplastin to monitor 157 anticoagulated patients treated in a low therapeutic range. Of the 1734 prothrombin times generated, 876 (56%) were therapeutic, with 400 (23%) below and 458 (26%) above the therapeutic range. These results are comparable with those published in trials in which more sensitive thromboplastins were used in a similar therapeutic range. We conclude that standard North American thromboplastins are adequately suited to monitor therapy in this lower range.
Aged↗
Cumulative meta-analysis of therapeutic trials for myocardial infarction.
BACKGROUND: The large volume of published randomized, controlled trials has led to a need for meta-analyses to track therapeutic advances. Performing a new meta-analysis whenever the results of a new trial of a particular therapy are published permits the study of trends in efficacy and makes it possible to determine when a new treatment appears to be significantly effective or deleterious. We describe the use of such a procedure, cumulative meta-analysis, to assess therapeutic trials among patients with myocardial infarction. METHODS: We performed cumulative meta-analyses of clinical trials that evaluated 15 treatments and preventive measures for acute myocardial infarction. RESULTS: An example of this method is its application to the use of intravenous streptokinase as thrombolytic therapy for acute infarction. Thirty-three trials evaluating this therapy were performed between 1959 and 1988. We found that a consistent, statistically significant reduction in total mortality (odds ratios, 0.74; 95 percent confidence interval, 0.59 to 0.92) was achieved in 1973, after only eight trials involving 2432 patients had been completed. The results of the 25 subsequent trials, which enrolled an additional 34,542 patients through 1988, had little or no effect on the odds ratio establishing efficacy, but simply narrowed the 95 percent confidence interval. In particular, two very large trials, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico trial in 1986 (11,712 patients) and the Second International Study of Infarct Survival trial in 1988 (17,187 patients) did not modify the already established evidence of efficacy. We used a similar approach to study the accumulating evidence of efficacy (or lack of efficacy) of 14 other therapies and preventive measures for myocardial infarction. CONCLUSIONS: Cumulative meta-analysis of therapeutic trials facilitates the determination of clinical efficacy and harm and may be helpful in tracking trials, planning future trials, and making clinical recommendations for therapy.
Confidence Intervals↗
A clinical trials database as a research tool in health care.
OBJECTIVE: The rapid, efficient, and accurate communication of clinical research findings to both clinicians and researchers is essential to the process of improving medical care. This information should be conveyed in a form that facilitates the interpretation of the complete body of research on a specific condition. Unfortunately, the prevailing system for dissemination of clinical research fails to meet these criteria. This paper proposes a system for cataloging clinical trials and communicating their results in a comprehensive and comprehensible format. METHOD: The system involves the use of a hierarchical matrix structure that allows for the selection and evaluation of related groups of clinical trials. The format of the data is tailored to the requirements of metaanalysis. RESULTS: An example is presented using the treatment of acute Crohn's disease and including a sample metaanalysis of immunosuppressive therapy for this condition. CONCLUSIONS: The hierarchical matrix structure in conjunction with a comprehensive database of clinical trials holds the potential to facilitate access to and interpretation of clinical research.
Acute Disease↗