Clomiphene citrate and neural tube defects: a meta-analysis of controlled observational studies.

BACKGROUND: At the end of the 1980s, several studies suggested a potential increased risk of neural tube defects (NTDs) with ovulation induction/fertility drugs, especially with clomiphene citrate (CC). A previous meta-analysis of observational studies evaluating the risk of NTDs associated with the use of CC performed in 1995 found a risk ratio of 1.08 (95% CI 0.76-1.51). Since then, additional studies have been published and the risk of NTDs associated with periconceptional CC exposure may have changed. OBJECTIVE: To perform an updated quantitative meta-analysis of the risk of NTDs associated with periconceptional CC exposure. SEARCH STRATEGY: MEDLINE, Web of Science, and Scopus were searched (October 2018). SELECTION CRITERIA: Comparative cohort and case-control studies investigating the risk of NTDs after periconceptional CC exposure. DATA COLLECTION AND ANALYSIS: Pooled effect sizes with corresponding 95% CIs were calculated using random effects models, comparing the risk of NTDs between pregnancies exposed and not exposed to CC. MAIN RESULTS: Thirteen studies met the inclusion criteria, totalling 218 819 pregnancies. Periconceptional exposure to CC was not significantly associated with an increased risk of NTDs (pooled odds ratio 1.21, 95% CI 0.88-1.66). No heterogeneity between studies was observed (I2  = 26%). A funnel plot and asymmetry test were not suggestive of publication bias. CONCLUSION: Our meta-analysis confirms that exposure to CC before or in early pregnancy was associated with a 21% increased risk of NTD in relation to CC exposure; however, this increased risk is not statistically significant. TWEETABLE ABSTRACT: A new meta-analysis finds that clomiphene citrate exposure before or in early pregnancy is not associated with an increased risk of NTDs.

Statistical controversies in clinical research: limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events-a meta-analysis.

Background: Previous meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA. Materials and methods: We searched Medline, Cochrane, ClinicalTrials.gov databases and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (ORs) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of OR, by dividing the OR values obtained in open-label trials by those obtained in DB trials. Results: The literature-based meta-analysis included 166 trials (72 024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 [95% confidence interval (95% CI) 2.12-2.73; P < 0.001], but this risk was overestimated by 1.68 (95% CI 1.33-2.13) in open-label studies. Concerning VTE, the OR was 1.19 (95% CI 1.04-1.35; P = 0.012) overall with AA, but this effect disappears when considering only DB trials (OR 0.99, 95% CI 0.83-1.17). The corresponding ratio of OR showed a significant overestimation of 1.53 (95% CI 1.19-1.96) in open-label trials. For ATE, an OR of 1.59 (95% CI 1.30-1.94; P < 0.001) was observed, associated with a significant overestimation of 1.65 (95% CI 1.13-2.43) in open-label trials. Conclusions: Open-label studies overestimated the risk of vascular adverse events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials.

Publication bias in pharmacogenetics of adverse reaction to antiseizure drugs: An umbrella review and a meta-epidemiological study.

Publication bias may lead to a misestimation in the association between pharmacogenetic biomarkers (PGx) and antiseizure drug's adverse effects (AEs). We aimed to assess its prevalence in this field. We searched for systematic reviews assessing PGx of antiseizure drug's AEs. For each unique association between a PGx, a drug and its AE, we used the available odds ratio (ORs) to generate corresponding funnel plots. We estimated the prevalence of publication bias using visual inspections and asymmetry tests. We explored the impact of publication bias using ORs adjusted for potential publication bias. Twenty-two associations were available. Our visual analysis suggested a publication bias in five out twenty-two funnel plots (23% [95%CI: 8; 45]). The Egger's test showed a significant publication bias in one (HLA-B*15:02 and phenytoin-induced Stevens-Johnson syndrome or toxic epidermal necrolysis, p = 0.03) out of nine (11% [95%CI: 0; 48]) and the Begg's test in one (HLA-B*15:02 and carbamazepine-induced serious cutaneous reactions, p = 0.02) out of ten (10% [95%CI: 0; 45]) assessable funnel plots. Adjusting for publication bias may reduce by half the ORs of the pharmacogenetics associations. Publication bias in the pharmacogenetic of antiseizure drug's AEs is not uncommon and may affect the estimation of the effect of such biomarkers. When conducting pharmacogenetic studies, it is critical to publish also the negative one.

Twice- or Once-Daily Dosing of Direct Oral Anticoagulants, a systematic review and meta-analysis.

AIM: The direct oral anticoagulants (DOAC) have similar half-lives, but the dosing regimen varies between once daily (QD) or twice daily (BID). For some prescribers, the QD regimen improves compliance. Others prefer BID regimens to promote better stability of plasma concentrations, particularly in the event of missed doses. Limited level of evidence provides guidance about the best treatment strategy. The purpose of this study was to compare the treatment effect of QD vs. BID administration of DOACs in major orthopedic surgery (MOS), non-valvular atrial fibrillation (NVAF), venous thromboembolism (VTE), and acute coronary syndrome (ACS). METHODS: We conducted a systematic review up to April 2020. We included phase II clinical trials comparing DOAC QD vs BID with same daily dose. We extracted data for the occurrence of major thrombosis (proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke) and major hemorrhage (ISTH criteria and recommendations of the European Medicines Agency for surgical patients). Relative risks (RR) were combined using a fixed and random effects weighted meta-analysis. RESULTS: Twelve randomized, controlled, phase II trials were included (10,716 patients), representing 24 dosing regimen comparisons of apixaban, darexaban, edoxaban, rivaroxaban, letaxaban, and dabigatran. There was no difference for major thrombotic event (RRBID/QD = 1.06, 95%IC 0.86-1.30) nor for major bleeding (RRBID/QD = 1.02, 95%IC 0.84-1.23) between the BID vs QD regimens, without heterogeneity (I2 = 0%). CONCLUSION: Our study does not support a global difference in term of efficacy and safety of the BID and QD regimens of DOAC in MOS, NVAF, VTE and ACS.

Association between difference in blood pressure reduction and risk of cardiovascular events in a type 2 diabetes population: A meta-regression analysis.

AIM: Recent US recommendations indicate a target blood pressure (BP) of 130/80mmHg for patients with type 2 diabetes (T2D). Our aim was to characterize the association between risk of cardiovascular events and differences in BP decreases in randomized trials of a T2D population. METHODS: A systematic search was made for randomized clinical trials assessing the effects of antihypertensive treatments in T2D patients on mortality, and fatal and non-fatal cardiovascular events, using a meta-regression technique to explore the influence of BP decreases on treatment effects. RESULTS: A total of 88,503 patients from 44 randomized trials were included. There was no significant association between BP decreases and risk of all-cause or cardiovascular mortality, cardiovascular events or myocardial infarction. However, stroke risk was influenced by BP decreases: compared with no reduction, a 10-mmHg reduction in systolic BP was associated with a relative odds ratio (OR) decrease of 33% (OR: 0.67, 95% CI: 0.54-0.82), and a 5-mmHg diastolic BP reduction was associated with a relative OR decrease of 38% (OR: 0.62, 95% CI: 0.50-0.76). Restricting the analysis to double-blind studies did not change the results for diastolic BP. CONCLUSION: A reduction in BP lowers the risk of stroke, but does not appear to affect the risk of other cardiovascular events in a T2D population.

WITHDRAWN: Primary angioplasty versus intravenous thrombolysis for acute myocardial infarction.

BACKGROUND: Intravenous thrombolytic therapy is the standard care for patients with acute myocardial infarction, based upon its widespread availability and ability to reduce patient mortality well demonstrated in randomised trials. Despite its proven efficacy, thrombolytic therapy has limitations. Many patients are ineligible for treatment with thrombolytics. Of those given thrombolytic therapy, 10 to 15 percent have persistent occlusion or reocclusion of the infarct-related artery. Consequently, primary angioplasty (primary PTCA) has been advocated as a better treatment of myocardial infarction. OBJECTIVES: To determine whether primary coronary angioplasty is superior to thrombolytic therapy for the treatment of patients with acute myocardial infarction. SEARCH STRATEGY: Electronic search of The Cochrane Library (1998; Issue 2). MEDLINE (to January 1998); references from reviews, trials and previously published meta-analyses; and experts. Date of most recent searches January 1998. SELECTION CRITERIA: All unconfounded, randomised controlled trials comparing primary angioplasty against intravenous thrombolysis in patients with acute myocardial infarction DATA COLLECTION AND ANALYSIS: At least two independent reviewers abstracted data on morbidity and mortality and trial characteristics. The following outcomes were assessed: total mortality at the end of the study, reinfarction, stroke of any type, composite endpoint of death and reinfarction, recurrent ischemia, severe bleeding and coronary artery bypass grafting. MAIN RESULTS: Ten trials including 2573 subjects were identified. Compared to thrombolytic therapy, primary angioplasty was associated with a significant reduction in short-term mortality at the end of the studies (relative reduction in risk RRR = 32% 95%CI = 5%;50%). Similar reductions were observed for the rate of reinfarction (RRR = 52%, 95%CI = 30%;67%), recurrent ischemia (RRR = 54%; 95%CI = 39%,66%) and for the combined criteria death or reinfarction (RRR = 46%; 95%CI=30%;58%). The frequency of strokes of any cause was significantly decreased by 66% (95%CI=28%;84%). No significant difference was observed for the incidence of major bleeding (relative risk RR =1.18, 95%CI = 0.73;1.90) but the confidence interval was large. The superiority of the primary angioplasty over thrombolysis in terms of the composite endpoint (mortality and reinfarction) was less with accelerated t-PA (RR=0.70, 95%CI=0.51;0.97) than with streptokinase (RR=0.30, 95%CI=0.17;0.53). The biggest and most recent trial, Gusto 2B (GUSTO-2B 97), which involved general as well as highly specialised centres, obtained less favorable results. AUTHORS' CONCLUSIONS: This meta-analysis suggests that angioplasty provides a short-term clinical advantage over thrombolysis which may not be sustained. Primary angioplasty when available promptly at experienced centres, may be considered the preferred strategy for myocardial reperfusion. In most situations, however, optimal thrombolytic therapy should still be regarded as an excellent reperfusion strategy.

[Non-inferiority trial used in venous thromboembolic disease. A warily interpretation is necessary!]. / Essais de non-infériorité dans la maladie thromboembolique veineuse. Une lecture critique est nécessaire!

INTRODUCTION: Equivalence trials are actually frequently used to prove non-inferiority in anticoagulant therapy. Equivalence trials consist to demonstrate that two treatments are not too much different. This difference has to be under a margin previously determined. The margin corresponds to an efficacy loss that is defined to be acceptable, in accordance to the advantages due to the new treatment. The aim of this work is to explore the equivalence trial published in the thromboembolic disease by focus on the non-inferiority margin used. METHODS: We identified published equivalence trials in the venous thromboembolic disease, by a systematic search in Medline. We calculated the efficacy loss by reference with the value of the smallest effect size of the standard treatment compared to placebo. RESULTS: We found 9 equivalence trials used in venous thromboembolic disease. The mean value of the efficacy loss was 434%, and the median value was 357%. Eighty-five percent of the values of the efficacy loss were above 100%. DISCUSSION: Eighty-five percent of the equivalence trials conclude to equivalence despite a complete efficacy loss of the effect of the standard treatment compared to placebo. The results of equivalence trials should be interpreted warily. The corresponding non-inferiority margin should be chosen more rigorously and by reference with the value of the smallest effect size of the standard treatment compared to placebo.

Assessment of clinically relevant bleeding as a surrogate outcome for major bleeding: validation by meta-analysis of randomized controlled trials.

Essentials Surrogacy of clinically relevant bleeding (CRB) for major bleeding has never been validated. Our meta-analysis evaluated CRB surrogacy in trials of new versus traditional anticoagulants. Surrogacy was not validated in orthopedic surgery, venous thromboembolism or atrial fibrillation The difficulty in demonstrating the surrogacy may reflect a lack of homogeneity in its definition SUMMARY: Background Clinically relevant bleeding (CRB), comprising major bleeding and clinically relevant non-major bleeding, has been used as a surrogate for major bleeding in most anticoagulant trials. The validity of this surrogate to estimate trade-off between thrombotic and bleeding events in clinical trials was never assessed. Methods We systematically reviewed randomized phase III trials comparing new anticoagulants with the standard of care for venous thromboembolism prevention following major orthopedic surgery, venous thromboembolism (VTE) treatment, or stroke and systemic embolism prevention in atrial fibrillation (AF), and reporting both major bleeding and CRB rates. The validity of CRB as a surrogate for major bleeding was assessed according to the strength of the association between the relative risks of major bleeding and CRB, measured by the use of R2trial and its 95% confidence interval (CI). Results In the postoperative prophylactic setting (13 studies), major bleeding and CRB rates were 1.12% and 3.56%, respectively, and R2trial was 0.69 (95% CI 0.34-0.93). For acute VTE studies (n = 12), major bleeding and CRB rates were 1.87% and 9.07%; the corresponding R2trial values were 0.28 (95% CI 0.01-0.80) and 0.68 (95% CI 0.09-1.00) when only double-blind studies were considered (n = 7). For AF studies (n = 7; 22 strata), major bleeding and CRB rates were 4.82% and 15.3%, and R2trial was 0.59 (95% CI 0.15-0.82). Conclusion Despite an apparent correlation between CRB and major bleeding in major orthopedic surgery, AF, and double-blind acute VTE studies, the wide CIs suggest that CRB might not be an acceptable surrogate outcome in any of these settings.

Efficiency of physical therapy on postural imbalance after stroke: study protocol for a systematic review and meta-analysis.

INTRODUCTION: Stroke frequently results in balance disorders, leading to lower levels of activity and a diminution in autonomy. Current physical therapies (PT) aiming to reduce postural imbalance have shown a large variety of effects with low levels of evidence. The objectives are to determine the efficiency of PT in recovering from postural imbalance in patients after a stroke and to assess which PT is more effective. METHODS AND ANALYSIS: We will search several databases from inception to October 2015. Only randomised controlled trials assessing PT to recover from poststroke postural imbalance in adults will be considered.Outcome measures will be the Berg Balance Scale (BBS), the Postural Assessment Scale for Stroke (PASS), the 'weight-bearing asymmetry' (WBA), the 'centre of pressure' (COP) and the 'limit of stability' (LOS). WBA, COP and LOS are measured by a (sitting or standing) static evaluation on force plate or another device.Two independent reviewers will screen titles, abstracts and full-text articles, evaluate the risk of bias and will perform data extraction. In addition to the outcomes, measures of independence will be analysed. This study will aim at determining the effects of PT on the function (WBA, COP, LOS), the activity (BBS, PASS) and the independence of patients. Subgroup analyses will be planned according to the location of brain lesion (hemispheric, brainstem or cerebellum), the time since stroke (early, late, chronic), the PT (type, main aim (direct effect or generalisation), overall duration), the type of approaches (top-down or bottom-up) and the methodological quality of studies. ETHICS AND DISSEMINATION: No ethical statement will be required. The results will be published in a peer-reviewed journal. This meta-analysis aims at managing the rehabilitation after postural imbalance by PT after a stroke. TRIAL REGISTRATION NUMBER: Prospero CRD42016037966;Pre-results.

Revisiting the effect compartment through timing errors in drug administration.

The variations in the pharmacological effects induced by timing errors in drug intake are compared for two drugs, one acting by way of an effect compartment and the other directly from the central compartment. A simulation was performed for two drugs having the same concentration-effect relationship at the receptor site, the same mean effect at equilibrium and identical concentrations in the central compartment. In this article. Patrice Nony, Michel Cucherat and Jean-Pierre Boissel discuss how, for the same variability of concentrations in the central compartment, the variations in mean effects are different. When there is a large variability in the interval separating two consecutive doses, the model that includes an effect compartment dampens the pharmacokinetic variability present in the central compartment. Such an approach may be useful for the prescription recommendations of drugs, especially those with narrow therapeutic indices.

[Correlation between cranial vault size and brain size over time: preliminary MRI evaluation]. / Evolution comparative de la voûte crânienne et du parenchyme cérébral avec l'âge: étude préliminaire en IRM.

OBJECTIVES: To correlate changes of cranial vault measurements of an adult population during the aging process with brain size using the maximum width of the third ventricle in the axial AC-PC plane. MATERIALS AND METHODS: Prospective study of 126 adult subjects (range: 20 to 80 years) with normal brain MRI and without history of neuropsychiatric disorder. MEASUREMENTS INCLUDED: Cranial vault (Maximum length: Glabella-Opisthocranion, Maximum width: euryon-euryon, and maximum height: Basion-Vertex) measurements and maximum width of the third ventricle in the A C-PC plane. RESULTS: Vault measurements (length, width, high) were similar for every age group, irrespective of gender. The variability of cranial vault measurements between individuals was low (<1 cm). Cranial vault measurements were larger for men, but this was not significant when adjusted for body height Comparatively, a gradual widening of the third ventricle, with an exponential behavior, was observed with advancing age. CONCLUSION: Our results indicate that cranial vault measurements are stable over time (between 20-80 years) comparatively to brain atrophy with advancing age. The low variability of cranial vault measurements and their stability over time should be taken into account during segmentation and normalization of brain parenchymal structures.

Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis.

Osteoporosis is the main cause of spine and hip fractures. Morbidity, mortality, and costs arising from hip fractures have been well documented. Thyroid hormones (TH) are widely prescribed, mainly in the elderly. Some studies (but not all) found a deleterious effect of suppressive TH therapy on bone mass. These conflicting data raised a controversy as to the safety of current prescribing and follow-up habits, which, in turn, raised major health-care issues. To look for a detrimental effect on bone of TH therapy, we performed a meta-analysis (by pooling standardized differences, using a fixed effect model) of all published controlled cross-sectional studies (41, including about 1250 patients) concerning the impact of TH therapy on bone mineral density (BMD). Studies with women receiving estrogen therapy were excluded a priori, as were studies with a high percentage of patients with postoperative hypoparathyroidism, when no separate data were available. We decided to stratify the data according to anatomical site, menopausal status, and suppressive or replacement TH therapy, resulting in 25 meta-analysis on 138 homogeneous subsets of data. The main sources of heterogensity between studies that we could identify were replacement or suppressive TH therapy, menopausal status, site (lumbar spine, femoral neck, Ward's triangle, greater trochanter, midshaft and distal radius, with various percentages of cortical bone), and history of hyperthyroidism, which has recently been found to impair bone mass in a large epidemiological survey. To improve homogeneity, we excluded a posteriori 102 patients from 3 studies, who had a past history of hyperthyroidism and separate BMD data, thus allowing assessment of the TH effect in almost all 25 subset meta-analyses. However, controls were usually not matched with cases for many factors influencing bone mass, such as body weight, age at menarche and at menopause, calcium dietary intake, smoking habits, alcohol intake, exercise, etc. For lumbar spine and hip (as for all other sites), suppressive TH therapy was associated with significant bone loss in postmenopausal women (but not in premenopausal women), whereas, conversely, replacement therapy was associated with bone loss in premenopausal women (spine and hip), but not in postmenopausal women. The detrimental effect of TH appeared more marked on cortical bone than on trabecular bone. Only a large long term prospective placebo-controlled trial of TH therapy (e.g. in benign nodules) evaluating BMD (and ideally fracture rate) would provide further insight into these issues.

Implication of evidence-based medicine in prescription guidelines taught to French medical students: current status in the cardiovascular field.

OBJECTIVES: To study how satisfactory the contents of introductory courses in cardiovascular therapeutics, given to medical students in France, are with respect to the concepts of evidence-based medicine. METHODS: Medical school lecturers were asked to provide written course material used as part of medical school courses. Best-available evidence was classified as existent (including two therapeutic subclasses: indicated and contraindicated), and nonexistent. Four scores (from 0 to 10) were given, according to conformity with best-available evidence, and citation of randomized clinical trials (RCT), meta-analyses and therapeutic objectives. RESULTS: Thirty-four written documents were obtained from 43 faculties. Although the score (mean +/- SEM) of conformity with best-available evidence was 5.43 +/- 0.28 for the existent best-available evidence class, the corresponding scores for the citation of RCT, meta-analyses, and therapeutic objectives were, respectively, 1 +/- 0.2, 0.16 +/- 0.07, and 2.7 +/- 0.3. The four scores were highest when the best-available evidence belonged to the indicated class, intermediate when best-available evidence was nonexistent, and lowest for the contraindicated class (P < .05). These scores were significantly higher when the printed material was intended for specialists. CONCLUSION: Despite some limitations, the extent of agreement with the best-available evidence is only moderate. Pathophysiologic reasoning is largely preferred to justify the choice of therapeutics recommended to medical students.

Prevention of venous thromboembolism in orthopedic surgery with vitamin K antagonists: a meta-analysis.

BACKGROUND: The benefit-to-risk ratio of vitamin K antagonists (VKA), relative to active comparators, especially low-molecular-weight heparins (LMWH), for preventing venous thromboembolism in patients undergoing major orthopedic surgery is debated. OBJECTIVES: We performed a meta-analysis of all randomized trials in orthopedic surgery comparing adjusted doses of VKA to control treatments. PATIENTS AND METHODS: An exhaustive literature search, both manual and computer-assisted, was performed. Studies were selected on the basis of randomization procedure (VKA vs. a control group). At least one of the following outcome measures was to be evaluated: deep vein thrombosis (DVT), pulmonary embolism (PE), death, major hemorrhage or wound hematoma. Four reviewers assessed each article to determine eligibility for inclusion and outcome measures. RESULTS: VKAs were more effective than placebo or no treatment in reducing DVT [567 patients, relative risk (RR) = 0.56, 95% confidence interval (CI) 0.37, 0.84, P < 0.01] and clinical PE (651 patients, RR = 0.23, 95% CI 0.09, 0.59, P < 0.01). These results were obtained at the cost of a higher rate of wound hematoma (162 patients, RR = 2.91, 95% CI 1.09, 7.75, P = 0.03). VKAs were also more effective than intermittent pneumatic compression (534 patients, RR = 0.46, 95% CI 0.25, 0.82, P = 0.009) in preventing proximal DVT. In contrast, VKAs were less effective than LMWH in preventing total DVT and proximal DVT (9822 patients, RR = 1.51, 95% CI 1.27, 1.79, P < 0.001; and 6131 patients, RR = 1.51, 95% CI 1.04, 2.17, P = 0.028, respectively). The differences between VKA and LMWH in major hemorrhage and wound hematoma were not significant. CONCLUSIONS: In patients undergoing major orthopedic surgery, VKAs are less effective than LMWH, without any significant difference in the bleeding risk.

Cytomegalovirus prophylaxis with antiviral agents in solid organ transplantation: a meta-analysis.

BACKGROUND: The aim of this meta-analysis was to assess the efficacy of antiviral agents to prevent, in solid organ transplant recipients, cytomegalovirus infection and symptomatic disease and to decrease the incidence of acute rejection, graft loss, and death. METHODS: Of the studies identified, 13 met the following inclusion criteria: prospective randomized study, in adults or pediatric recipients of a solid organ transplant, where one group in the study received a prophylactic treatment with acyclovir and/or ganciclovir begun before the cytomegalovirus infection and a control group was not treated or receive placebo. RESULTS: Prophylactic treatment was found to be associated with a significant decrease of cytomegalovirus disease compared with placebo or no treatment, using the logarithm of relative risk method (relative risk=0.50; 95% confidence interval, 0.40-0.62; P-value for chi-square association <0.001). Prophylactic treatment decreased also the rate of cytomegalovirus infection (relative risk=0.74; 95% confidence interval, 0.62-0.88; P<0.001). Our analysis failed to show a significant decrease of graft loss, acute rejection, and death in the prophylactic treatment group. Subgroup analysis based on the type of antiviral agent (acyclovir or ganciclovir) and on the type of organ (kidney or liver) gave comparable results. CONCLUSION: The use of antiviral agents for the prevention of cytomegalovirus disease and cytomegalovirus infection in solid organ transplantation is supported by this meta-analysis.

Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials.

BACKGROUND: The prevention of venous thromboembolic disease is less studied in medical patients than in surgery. METHODS: We performed a meta-analysis of randomised trials studying prophylactic unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) in internal medicine, excluding acute myocardial infarction or ischaemic stroke. Deep-vein thrombosis (DVT) systematically detected at the end of the treatment period, clinical pulmonary embolism (PE), death and major bleeding were recorded. RESULTS: Seven trials comparing a prophylactic heparin treatment to a control (15,095 patients) were selected. A significant decrease in DVT and in clinical PE were observed with heparins as compared to control (risk reductions = 56% and 58% respectively, p <0.001 in both cases), without significant difference in the incidence of major bleedings or deaths. Nine trials comparing LMWH to UFH (4,669 patients) were also included. No significant effect was observed on either DVT, clinical PE or mortality. However LMWH reduced by 52% the risk of major haemorrhage (p = 0.049). CONCLUSIONS: This meta-analysis, based on the pooling of data available for several heparins, shows that heparins are beneficial in the prevention of venous thromboembolism in internal medicine.

Persistent reduction of mortality for five years after one year of acebutolol treatment initiated during acute myocardial infarction. The APSI Investigators. Acebutolol et Prévention Secondaire de l'Infarctus.

The APSI trial was a randomized placebo-controlled trial designed to assess the efficacy of 1 year of treatment by acebutolol in high-risk patients who had survived an acute myocardial infarction. At 1 year there was a statistically significant 48% relative reduction in total mortality (p = 0.019) in favor of acebutolol. In 1995 a long-term mortality survey was undertaken through an administrative inquiry and contacts with investigators. The vital status of 586 of the 607 (96.5%) patients enrolled was known at the cutoff date and all these patients were followed up for at least 5 years. During follow-up (in-trial and post-trial period), 74 deaths (24.8%) occurred in the acebutolol group and 96 (31.1%) in the placebo group (p = 0.10). No difference between the 2 groups was observed for the number of deaths that occurred after the end of the trial: 55 deaths (19.6%) among the 281 survivors in the acebutolol group and 59 deaths (21.7%) (p = 0.70) among the 272 survivors in the placebo group. The annual hazard rate (annual death rate), calculated year by year using the actuarial method, was significantly different (p < 0.01) only for the first year and was not significantly different thereafter. Thus, the initial benefit obtained in 1 year of treatment by acebutolol lasts for 5 years.

A meta-analysis of the effects of cognitive therapy in depressed patients.

BACKGROUND: Cognitive therapy (CT) has been studied in 78 controlled clinical trials from 1977 to 1996. METHOD: The meta-analysis used Hedges and Olkin d+ and included 48 high-quality controlled trials. The 2765 patients presented non-psychotic and non-bipolar major depression, or dysthymia of mild to moderate severity. RESULTS: At post-test CT appeared significantly better than waiting-list, antidepressants (P < 0.0001) and a group of miscellaneous therapies (P < 0.01). But, CT was equal to behaviour therapy. As between-trial homogeneity was not met, the comparisons of CT with waiting-list or placebo, and other therapies should be taken cautiously. In contrast, between-trial homogeneity was high for the comparisons of CT with behaviour therapy and antidepressants. A review of eight follow-up studies comparing CT with antidepressants suggested that CT may prevent relapses in the long-term, while relapse rate is high with antidepressants in naturalistic studies. CONCLUSION: CT is effective in patients with mild or moderate depression.

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.