Meta-analysis of randomised controlled trials of fluoxetine v. placebo and tricyclic antidepressants in the short-term treatment of major depression.

BACKGROUND: Previous meta-analyses of fluoxetine as an antidepressant have many methodological problems, including diagnosis of major depression, validity of outcome measures and lack of intention-to-treat analyses. AIMS: To provide an estimate of the effect of fluoxetine compared with placebo and tricyclic antidepressants (TCAs), and to investigate reasons for early discontinuation from acute treatment. METHOD: Randomised trials were analysed using both intention-to-treat, efficacy and end-point. RESULTS: Fluoxetine was superior to placebo but effect size was low. In trials comparing fluoxetine v. TCA, the results for all trials and for the USA trials showed a trend in favour of fluoxetine. Those for the non-USA trials showed a trend in favour of TCA. When combined, the results showed that significantly fewer patients on fluoxetine discontinued treatment because of adverse events. CONCLUSION: Fluoxetine is superior to placebo, irrespective of the analytical approach use, whereas the results obtained v. TCAs depend on the approach used. Hence, the results should be interpreted in this light.

Evidence of clinical efficacy of homeopathy. A meta-analysis of clinical trials. HMRAG. Homeopathic Medicines Research Advisory Group.

OBJECTIVE: To establish, using a systematic review and meta-analysis, whether there is any evidence from randomised controlled clinical trials of the efficacy of homeopathic treatment in patients with any disease. DATA SOURCES: Published and unpublished reports of controlled clinical trials available up to June 1998, identified by searching bibliographic databases (Medline, Embase, Biosis, PsychInfo, Cinahl, British Library Stock Alert Service, SIGLE, Amed), references lists of selected papers, hand searching homeopathic journals and conference abstracts, and contacting pharmaceutical companies. TRIALS SELECTION: Trials were selected using an unblinded process by two reviewers. The selection criteria were randomised, controlled trials in which the efficacy of homeopathic treatment was assessed relative to placebo in patients using clinical or surrogate endpoints. Prevention trials or those evaluating only biological effects were excluded. One hundred and eighteen randomised trials were identified and evaluated for inclusion. Sixteen trials, representing 17 comparisons and including a total of 2,617 evaluated patients, fulfilled the inclusion criteria. DATA EXTRACTION: Data were extracted by two reviewers independently, using a summary form. Disagreements were resolved by a third person. DATA SYNTHESIS: The evidence was synthesised by combining the significance levels (P values) for the primary outcomes from the individual trials. The combined P value for the 17 comparisons was highly significant P = 0.000036. However, sensitivity analysis showed that the P value tended towards a non-significant value (P = 0.08) as trials were excluded in a stepwise manner based on their level of quality. CONCLUSIONS: There is some evidence that homeopathic treatments are more effective than placebo; however, the strength of this evidence is low because of the low methodological quality of the trials. Studies of high methodological quality were more likely to be negative than the lower quality studies. Further high quality studies are needed to confirm these results.

EasyMA: a program for the meta-analysis of clinical trials.

Meta-analysis of clinical trial data is an increasingly important method in clinical research, particularly in the field of therapeutic evaluation. This method uses some specific statistical techniques which are not all available on standard packages and therefore require specific developments. This paper describes a program designed to help medical researchers perform meta-analyses of clinical trial data with dichotomous outcomes. This program includes the various statistical methods of meta-analysis and enables cumulative meta-analysis and sub-groups to be performed. A robustness index can be determined and the results obtained in table and graphic formats. Data-editing and data-manipulating facilities are also possible. Much care has been taken to make the user interface as user-friendly as possible, so that the program is within the reach of all medical researchers.

Pre-hospital and hospital time delays in thrombolytic treatment in patients with suspected acute myocardial infarction. Analysis of data from the EMIP study. European Myocardial Infarction Project.

OBJECTIVES: To compare the components of the time delay involved in pre-hospital and hospital thrombolytic therapy in patients presenting with suspected acute myocardial infarction. MATERIAL AND METHODS: From October 1988 to January 1992 a total of 198 mobile emergency units in 15 European countries and Canada randomized 5469 patients to receive either pre-hospital thrombolytic treatment, followed by placebo in hospital (pre-hospital group), or pre-hospital (hospital group) in the European Myocardial Infarction Project trial. We performed a post hoc analysis of these data to correlate components of the interval between symptom onset and treatment with baseline patient characteristics. RESULTS: The delay between onset of symptoms and calling for an ambulance was significantly longer for female patients (P = 0.0001), older patients (> 65 years old; P = 0.0001), those who had experienced pain within the previous 24 h (P = 0.0001), and those with pulmonary oedema (P = 0.04). This delay was significantly shorter in patients with previous myocardial infarction (P = 0.02), those with ventricular fibrillation (P = 0.0001), and those in shock (P = 0.0001). The delay between the two injections was significantly longer for older patients (> 65 years old; P = 0.02), those with previous myocardial infarction (P = 0.03), and those in shock (P = 0.003). CONCLUSIONS: Action undertaken to reduce delays between symptom onset and treatment should focus on modifiable factors such as patients who are likely to be late callers i.e. women and those over 65 years of age.

Clinical trial registries and ethics review boards: the results of a survey by the FICHTRE project.

Clinical trial registries could make an important contribution to research by playing a role in the avoidance of trial duplication as well as serving as a source of information on the existence of clinical trials for those wishing to perform overviews. In order to fulfil their role efficiently, these registries should contain information about all trials. However, resources of existing registries are not exhaustive. Currently, all protocols for clinical trials must be submitted to an ethics review board for approval-thus these boards could provide an invaluable source of information about what trials are being performed. One of the objectives of our project was to assess the attitudes of the ethics review boards (ERBs) to providing this type of information to clinical trial registries. We received 115 replies from 281 questionnaires sent to ERBs in seven European countries. More than 70% replied that they would be willing to communicate information about the trials they review, and there seemed to be general agreement that clinical trial registries should be funded and supported by governments. Although ERBs could provide a useful source of information, only an official body such as the Ministry of Health or a drug regulatory body could establish and run a clinical trials registry efficiently.

Standardization of terminology in meta-analysis: a proposal for working definitions.

In this paper we present a brief overview of the growing concern to standardize definitions and terminology in meta-analysis. This tool has become inescapable in both drug research and therapeutic evaluation. The performed and published meta-analyses are increasing, as well as the variation in the meaning of the terms used in meta-analysis. In the second part of the paper we propose glossary of the most common terms used in reports of meta-analyses. The glossary has been written by only one group of scientists, the definitions are therefore proposed to the scientific community as working definitions, to be subject to reactions from leaders in meta-analysis.

[The Cochrane Collaboration: the need for international collaboration]. / La Collaboration Cochrane: la nécessité d'une collaboration internationale.

The Cochrane Collaboration has undergone an unexpected growth since its inauguration during an international meeting in 1993. This collaboration was established in response to the criticisms of a British physician, Archie Cochrane, who criticised the medical profession because it had not organised a critical summary of all relevant randomised controlled trials. The driving force of the collaboration is the collaborative review groups who collect, sort and synthesize data concerning treatment efficacy in their particular area of interest. The Cochrane Centres and the Field Coordinations help them to do this and together the produce the Cochrane Database of Systematic Reviews. The need for international cooperation is obvious because the information necessary to this system is produced throughout the world, and only some of this information is published.

[Information system for prescriptors and consumers]. / Un système d'information pour les prescripteurs et les consommateurs.

The efficient dissemination of current research data requires a suitable information system and an ideal intermediary as the liaison between the data source and the targeted users, i.e. prescribers and consumers. Here we present the specifications and possible technical solutions which will enable these data to be efficiently transmitted.

Critical reading of the meta-analysis of clinical trials.

In this paper we shall present the general principles of meta-analysis and will then discuss the various factors needed to evaluate a meta-analysis: description of the problem; definition of the outcome(s) (primary and secondary); methods for identifying and selecting trials for inclusion; statistical methods used; and the presentation and discussion of the results. We shall then examine other problems such as the detection of bias, the validity of the information provided by the meta-analysis, the problem of heterogeneity, the sensitivity and robustness of the meta-analysis, quality criteria for a meta-analysis, and how to locate published meta-analyses. Finally we present a decision algorithm which should help answer the question: should and can the results from the meta-analysis be integrated into clinical practice?

[Introduction to meta-analytic methodology]. / Introduction à la méthodologie métaanalytique.

General considerations about meta-analysis and the different steps of this technique are successively discussed: definition of the main objective, identification of the outcome, description of the retrieval and selection of trials, description of the statistical analysis and interpretation of the results. Advantages and drawbacks of the meta-analytical technique are then described: 1) scientific approach, possible quantification of the therapeutic effect, increase of the power of a future clinical trial, synthesis of contradicting results, assessment of the homogeneity, subgroup analysis, analysis of sensibility, scientific collaboration, help for therapeutic information. 2) retrospective approach, inconsistency among trials, potential biases, persistence of some unsolved methodological problems, difficulties for a critical reading and for the interpretation of conclusions. In addition, some examples of published meta-analyses are given to illustrate the advantages and limits mentioned above.

Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individuals. HYCAR Study Group.

The objective of this trial was to assess the effects of 6-month daily treatment with two doses of ramipril on left ventricular mass and the dependence of this on blood pressure changes in hypertensive patients with left ventricular hypertrophy. After a selection phase of 4 to 6 weeks with patients under antihypertensive therapy with 20 mg furosemide daily, 115 patients with either controlled or uncontrolled hypertension and left ventricular hypertrophy were randomized in a double-blind manner to receive either placebo (n = 40), 1.25 mg (low dose, n = 38), or 5 mg (regular dose, n = 37) ramipril daily for 6 months. Treatment with furosemide was continued unchanged during this phase. The main outcome measured was left ventricular hypertrophy regression as assessed from central blind reading of echocardiograms recorded at randomization and after 6 months. No significant differences were observed for changes in casual or ambulatory blood pressure between the three groups. Left ventricular mass index was found to be significantly reduced in patients receiving 5 mg ramipril compared with those receiving placebo (-10.8 +/- 3.7 versus +4.1 +/- 4.0 g/m2, P = .008); in patients receiving 1.25 mg ramipril, the difference was close to borderline significance compared with placebo (-7.0 +/- 4.3 g/m2, P = .06). Similar results were observed for changes in left ventricular mass (-20.3 +/- 6.6 and -13.0 +/- 7.8 g in the 5- and 1.25-mg ramipril groups, respectively, versus +9.1 +/- 7.2 g in the placebo group; P = .004 and .04, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Survey of the attitudes to management of acute pyelonephritis in children. GEP.

Although urinary tract infections are of particular concern in young children, as they may lead to permanent health problems, there is no consensus for their acute management. We carried out a mailed survey of 455 general practitioners, 143 paediatricians (randomly selected from a list of physicians in the Rhône-Alpes region of France) and 45 paediatric nephrologists (all the members of the "Société de Néphrologie Pédiatrique") to examine their attitudes to the management of a fictitious case of a young girl with symptoms indicative of acute pyelonephritis. The responses given by the general practitioners and paediatricians were similar, whereas those given by the paediatric were similar, whereas those given by the paediatric nephrologists were often different, for example 20% of the general practitioners and 17% of the paediatricians said they would hospitalize the child, compared with 69% of the paediatric nephrologists. The majority of the general practitioners and paediatricians favoured single oral antibiotic therapy, whereas the paediatric nephrologists were split between single and combined antibiotic therapy, but preferred intravenous administration. The most frequently prescribed drug was a penicillin. The heterogeneity of the results from this survey stresses the need for the assessment of various strategies in terms of their efficacy for preventing kidney scarring and their risk-to-benefit ratios in well-designed randomised controlled trials.

The role of an initial single-blind placebo period in phase I clinical trials.

The effect of an initial single-blind placebo period in a phase I clinical trial was assessed in 12 volunteers who underwent five weekly treatment periods, consisting of treatment on the first day and a six-day wash-out period. An initial single-blind placebo period was followed by three different single doses of a platelet-aggregation factor inhibitor and another placebo period, under a double-blind Latin square design. Reports of abnormal symptoms were collected using a questionnaire designed by our group. A total of 13 abnormal symptoms were reported during the first period and only nine for the following four periods, indicating a clear placebo period effect. These preliminary results suggest that an initial single-blind period may be usefully included in phase I clinical trials.

Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients. A meta-analysis.

We examined the influence of phosphodiesterase inhibitors (PDIs) on mortality in patients with overt chronic heart failure. A total of 13 randomised, placebo-controlled trials of PDIs involving 2808 patients were selected. Meta-analysis, using data for all patients, showed that there was a non-significant (P = 0.16) increase of about 17% in the mortality rate of patients receiving a PDI [odds ratio (OR) 1.17, 95% confidence interval (CI) 0.94-1.46]. However, the observed treatment effects were found to be heterogeneous due to the results from the trials on vesnarinone. The heterogeneity became non-significant (P = 0.77) when these trials were removed, and a significant increase in the mortality rate was observed under treatment with the other PDIs (OR 1.41, 95% CI 1.11-1.79). In the subgroups of patients with or without additional vasodilator (VD) treatment, similar results were observed (PDI with VD: OR 1.3, 95% CI 1.03-1.7; PDI without VD: OR 2.04, 95% CI 1.1-3.8). These results indicate that PDIs (with the exception of vesnarinone) should not be prescribed for long-term use in patients with overt chronic heart failure. Additional vasodilator treatment in patients receiving PDIs for chronic heart failure does not explain the increased mortality seen with PDIs. This toxicity must, therefore, arise by other mechanisms. Further experimental and clinical evaluation is needed to confirm the beneficial influence of vesnarinone on survival in chronic heart failure patients and to identify the mechanism(s) differentiating this agent's therapeutic effect from that of other PDIs.

Electrophysiologic effects of a potassium channel activator (pinacidil) on repolarization parameters in healthy volunteers: a surface ECG study.

About a quarter to a third of patients receiving pinacidil, a new cyanoguanidine vasodilator, show ECG changes, in particular T-wave modifications that sometimes mimic myocardial ischemia. To investigate these changes, we performed a randomized placebo-controlled trial in 10 carefully selected, healthy subjects who received single oral doses of either pinacidil (25 mg), quinidine (330 mg), and placebo. Quinidine, which induces specific modifications to the surface ECG signal, was used as an internal control. The complete experimental design involved five consecutive administrations of the drugs in random order: pinacidil (twice), quinidine (twice), and placebo (once), separated by a week-long washout period. Electrophysiologic data acquisition and signal analysis were performed with the Lyon vectocardiographic processing system. Pinacidil decreased T-wave amplitude (-0.26 +/- 0.1 mV) significantly as compared with placebo (-0.14 +/- 0.06 mV), but did not change the duration of the T-wave. Although the cardiac rate increased with pinacidil, the QTc interval remained constant. Conversely, quinidine did not modify the RR interval but significantly increased duration of the T-wave (+67 +/- 20 ms) and QTc interval (+53 +/- 13 ms) as compared with placebo (+17 +/- 13 and +18 +/- 11 ms). In addition, no specific ischemic changes to the T-loop were observed with pinacidil. The modifications to the surface ECG signal caused by pinacidil appear to be drug-specific and related to its electrophysiologic properties rather than involving any ischemic mechanism. Such an approach may be useful for describing morphologic ECG changes caused by new drugs and identifying possible underlying electrophysiologic mechanism(s), which should then be confirmed in further studies.

Factor Xa inhibition: correlation between the plasma levels of anti-Xa activity and occurrence of thrombosis and haemorrhage.

A multicentre, double-blind, randomised trial was conducted to compare the efficacy of a low-molecular-weight (LMW) heparin, Logiparin, with that of an unfractionated (UF) heparin in the prophylactic treatment of thrombosis in patients undergoing general surgery. A total of 1,290 patients were randomised to receive a single daily dose of Logiparin (2,500 IU: 431 patients; 3,500 IU: 430 patients) or UF heparin (2 x 5,000 IU: 429 patients). The incidence of the main end point, deep venous thrombosis, was found to be significantly different between the groups (p = 0.03), whereas the incidence of severe haemorrhage was not (p = 0.05). The plasma anti-Xa activity was found to be correlated with body weight, but correlated only very weakly with antithrombotic activity (p = 0.045) after adjustment in a stepwise multivariate analysis, and did not significantly correlate with the incidence of haemorrhage. Logiparin at 3,500 IU and UF heparin showed similar efficacy. Although a correlation between plasma anti-Xa activity and body weight was observed, there is not sufficient evidence to recommend the adjustment of the Logiparin dose on patient's weight for prophylaxis in general surgery patients.

Low molecular weight heparin in prevention of perioperative thrombosis.

OBJECTIVE: To determine whether prophylactic treatment with low molecular weight heparin reduces the incidence of thrombosis in patients who have had general or orthopaedic surgery. DESIGN: Meta-analysis of results from 52 randomised, controlled clinical studies (29 in general surgery and 23 in orthopaedic surgery) in which low molecular weight heparin was compared with placebo, dextran, or unfractionated heparin. SUBJECTS: Patients who had had general or orthopaedic surgery. INTERVENTION: Once daily injection of a low molecular weight heparin compared with placebo, dextran, or unfractionated heparin. MAIN OUTCOME MEASURES: Incidence of deep venous thrombosis, pulmonary embolism, major haemorrhages, and death. RESULTS: The results confirm that low molecular weight heparins are more efficacious for the prophylactic treatment of deep venous thrombosis than placebo (common odds ratio 0.31, 95% confidence interval 0.22 to 0.43; p < 0.001) and dextran (0.44, 0.30 to 0.65; p < 0.001). The results suggest that low molecular weight heparins are also more efficacious than unfractionated heparin (0.85, 0.74 to 0.97; p = 0.02), with no significant difference in the incidence of major haemorrhages (1.06, 0.93 to 1.20; p = 0.62). CONCLUSIONS: Low molecular weight heparins seem to have a higher benefit to risk ratio than unfractionated heparin in preventing perioperative thrombosis. However, it remains to be shown in a suitably powered clinical trial whether low molecular weight heparin reduces the risk of fatal pulmonary embolism compared with heparin.

Prescription intentions in relation to therapeutic information: a study of 117 French general practitioners.

In 1987 we conducted a mailed questionnaire survey involving 250 GPs, randomly drawn from the 3061 GPs in the 'Rhône-Alpes' region in France, in order to study how general practitioners (GPs) react to information about drugs in terms of their prescribing practices. The aim of the questionnaire was to investigate the GPs reactions (prescription intentions) to 25 statements containing information concerning drugs. These included results from randomized clinical trials with adequate clinical criteria (pertinent information), but there were also some statements containing non-relevant information such as intermediate criteria, physiopathological or pharmacological information, and some containing general information such as advice from colleagues, the established position of the drug etc. The GPs were also asked through which channels they commonly received therapeutic information (i.e. medical journals, conferences). A total of 117 GPs returned completed questionnaires. We found the prescription intentions, for pertinent information to be between 76.9% and 95.7%, whilst the intentions, as a result of personal knowledge and/or success with a drug were around 93%. More theoretical information resulted in prescription intentions which were more widely scattered (between 23.1% and 80.3%), and for external advice the intentions were not as high but they were also widely scattered (between 3.4% and 65%). The search for latent dimensions corresponding to GPs reactions to therapeutic information, with both principal component analysis and Rasch Modelling, showed that two orthogonal latent dimensions, i.e. 'sensitivity to clinical and theoretical information', and 'sensitivity to external standards', best explained the responses to the questionnaire. These two dimensions appeared to be independent of age, sex, medical school and type of practice (urban, rural). The use of the journal 'Prescrire' by GPs was found to be significantly associated (P less than 0.005) with low scores, or good quality of perception of pertinent information in the first dimension. The use of specialists' prescriptions was associated with similar scores for the first dimension, but also with poor quality of perception of pertinent information scores (i.e. high scores) for the second dimension. These results could be used to draw up proposals for the improvement of post-graduate medical education, which should take into consideration these two dimensions of therapeutic information assessment by doctors, in order to obtain better quality of perception profiles for information assessment and prescription by doctors.