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.

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.

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.

Indirect comparison meta-analysis of two enoxaparin regimens in patients undergoing major orthopaedic surgery. Impact on the interpretation of thromboprophylactic effects of new anticoagulant drugs.

Two enoxaparin dosage regimens are used as comparators to evaluate new anticoagulants for thromboprophylaxis in patients undergoing major orthopaedic surgery, but so far no satisfactory direct comparison between them has been published. Our objective was to compare the efficacy and safety of enoxaparin 3,000 anti-Xa IU twice daily and enoxaparin 4,000 anti-Xa IU once daily in this clinical setting by indirect comparison meta-analysis, using Bucher's method. We selected randomised controlled trials comparing another anticoagulant, placebo (or no treatment) with either enoxaparin regimen for venous thromboembolism prophylaxis after hip or knee replacement or hip fracture surgery, provided that the second regimen was assessed elsewhere versus the same comparator. Two authors independently evaluated study eligibility, extracted the data, and assessed the risk of bias. The primary efficacy outcome was the incidence of venous thomboembolism. The main safety outcome was the incidence of major bleeding. Overall, 44 randomised comparisons in 56,423 patients were selected, 35 being double-blind (54,117 patients). Compared with enoxaparin 4,000 anti-Xa IU once daily, enoxaparin 3,000 anti-Xa IU twice daily was associated with a reduced risk of venous thromboembolism (relative risk [RR]: 0.53, 95% confidence interval [CI]: 0.40 to 0.69), but an increased risk of major bleeding (RR: 2.01, 95% CI: 1.23 to 3.29). In conclusion, when interpreting the benefit-risk ratio of new anticoagulant drugs versus enoxaparin for thromboprophylaxis after major orthopaedic surgery, the apparently greater efficacy but higher bleeding risk of the twice-daily 3,000 anti-Xa IU enoxaparin regimen compared to the once-daily 4,000 anti-Xa IU regimen should be taken into account.

Impact of double-blind vs. open study design on the observed treatment effects of new oral anticoagulants in atrial fibrillation: a meta-analysis.

BACKGROUND: The prospective, randomized, open, blinded endpoint evaluation (PROBE) design has been proposed as a valid alternative to the double-blind (DB) design for trials comparing new oral anticoagulants (NOAs) with INR-adjusted vitamin K antagonists in patients with non-valvular atrial fibrillation (NVAF). OBJECTIVES: To determine whether the observed treatment effects of NOAs in patients with NVAF differ between PROBE/open-label trials and DB trials. METHODS: All phase II or III trials were eligible. The main efficacy and safety outcomes were stroke/systemic embolism (SSE) and major bleeding, respectively. Other outcomes included ischemic SSE, hemorrhagic stroke, intracranial and extracranial bleeding, myocardial infarction, and all-cause and cardiovascular mortality. Interaction (Cochran's chi-squared test) between PROBE and DB designs was tested. RESULTS: Thirteen studies (61 620 patients) were included. For SSE, a greater treatment effect of NOAs vs. INR-adjusted warfarin was observed in PROBE trials (RR 0.76, CI 0.65-0.89) compared with DB trials (RR 0.88, CI 0.78-0.98), but the interaction test was non-significant (P = 0.16). A significant 67% enhancement of treatment effect was found with PROBE/open-label trials compared with DB trials (interaction test, P = 0.05) for hemorrhagic stroke. No other interaction was significant. A non-significant interaction (P = 0.07) between oral direct thrombin inhibitors (RR 0.33; 0.22-0.51) and factor Xa inhibitors (RR 0.54; 0.40-0.72) was seen. No heterogeneity was found for any outcome. CONCLUSIONS: Our meta-analysis showed no significant interaction of study design for the main efficacy and safety outcomes. However, the non-significantly exaggerated reduction in SSE suggests interdependence of treatment effect and PROBE design, especially for hemorrhagic stroke.

Superficial vein thrombosis and recurrent venous thromboembolism: a pooled analysis of two observational studies.

BACKGROUND: The management strategies for symptomatic isolated superficial vein thrombosis (SVT) (without concomitant deep vein thrombosis [DVT] or pulmonary embolism [PE]) have yet to achieve widespread consensus. Concerns have been raised regarding the usefulness of prescribing anticoagulant treatments to all patients with isolated SVT. Determining the isolated SVT subgroups who have the highest risks of venous thromboembolism (VTE) recurrence (composite of DVT, PE, and new SVT) may facilitate the identification of patients who are likely to benefit from anticoagulant treatment. DESIGN AND METHODS: We performed a pooled analysis on individual data from two observational, multicenter, prospective studies, to determine predictors for VTE recurrence and their impact in an unselected population of symptomatic isolated SVT patients. RESULTS: One thousand and seventy-four cases of symptomatic isolated SVT were followed up at 3 months. VTE recurrence was observed in 3.9% of the patients; 16.2% of the patients did not receive anticoagulants, and 0.6% experienced a VTE recurrence. Cancer, personal history of VTE and saphenofemoral/popliteal involvement significantly increased the risk of subsequent VTE or DVT/PE in univariate analyses. Only male sex significantly increased the risk of VTE or DVT/PE recurrence in multivariate analyses. Twelve percent of the patients had cancer or saphenofemoral junction involvement, and were at higher risk of DVT/PE recurrence than patients without those characteristics (4.7% vs. 1.9%, P= 0.06). CONCLUSIONS: In patients with symptomatic SVT, only male sex significantly and independently increased the risk of VTE recurrence. Cancer or saphenofemoral junction involvement defined a population at high risk for deep VTE recurrence. Some SVTs might be safely managed without anticoagulants.

[Critical reading of clinical trials]. / L'interprétation des essais cliniques.

Clinical trials are playing an increasingly crucial role in modern evidence based medicine, allowing for rigorous scientific evaluation of treatment strategies and validation of patient care. The results of clinical trials often form the rational basis from which physicians draw information used to adapt their therapeutic practices. Critical reading and analysis of trials involves the assessment of whether the available data provide enough credible evidence that the treatment will result in a clinically significant and relevant improvement. Evaluating the quality of a clinical trial is a process that draws upon sometimes complex methodological and statistical concepts, with which the reader should nonetheless be familiar in order to come to impartial conclusions regarding the raw data presented in the clinical trials. The goal of the current article is to review the methodological and statistical concepts required for the design and interpretation of clinical trials, so as to allow for a critical analysis of publications or presentations of clinical trials. The first section describes the major methodological principles of clinical trial design required for a rigorous evaluation of the treatment benefit, as well as the various pitfalls or biases that could lead to erroneous conclusions. The second section briefly describes the main statistical tests used in clinical trials, as well as certain situations that may increase the risk of false positive findings (type 1 error), such as multiple, subgroup, intermediate and non-inferiority analysis.

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.

Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature.

We performed a meta-analysis of all published studies relating intratumoural microvessel density (MVD) (45 studies) or vascular endothelial growth factor (VEGF) expression (27 studies), both reflecting angiogenesis, to relapse free (RFS) and overall survival (OS) in colorectal cancer (CRC). For each study, MVD impact was measured by risk ratio between the two survival distributions with median MVD as cutoff. Eleven studies did not mention survival data or fit inclusion criteria, six were multiple publications of same series, leaving 32 independent studies for MVD (3496 patients) and 18 for VEGF (2050 patients). Microvessel density was assessed by immunohistochemistry, using antibodies against factor VIII (16 studies), CD31 (10 studies) or CD34 (seven studies). Vascular endothelial growth factor expression was mostly assessed by immunohistochemistry. Statistics were performed for MVD in 22 studies (the others lacking survival statistics) including nine studies (n = 957) for RFS and 18 for OS (n = 2383) and for VEGF in 17 studies, including nine studies for RFS (n = 1064) and 10 for OS (n = 1301). High MVD significantly predicted poor RFS (RR = 2.32 95% CI: 1.39-3.90; P < 0.001) and OS (RR = 1.44; 95% CI: 1.08-1.92; P = 0.01). Using CD31 or CD34, MVD was inversely related to survival, whereas it was not using factor VIII. Vascular endothelial growth factor expression significantly predicted poor RFS (RR = 2.84; 95% CI: 1.95-4.16) and OS (RR=1.65; 95% CI: 1.27-2.14). To strengthen our findings, future prospective studies should explore the relation between MVD or VEGF expression and survival or response to therapy (e.g. antiangiogenic therapy). Assessment of these angiogenic markers should be better standardised in future studies.

Relationship between lower urinary tract symptoms frequency assessed by the IPSS and bothersomeness (SPI) among men older than 50 years old.

OBJECTIVE: The International Prostatic Symptom Score (IPSS) evaluates urinary disorder symptoms frequently associated with benign prostatic obstruction, but does not take into account the bothersomeness they induce. The Symptom Problem Index (SPI) evaluates the degree of discomfort associated with each question on the IPSS. Our objective was to explore the relationships between these two rating scales. METHODS: The IPSS and SPI self-administered scores were administrated to a cohort of 907 patients presenting with LUTS suggestive of BPO (Benign Prostatic Obstruction), for which 722 patients were evaluable. This diagnosis was made by GP (General Practitioner) in the 3-month period before their inclusion in the study. The correlation between SPI and IPSS was investigated and each symptom was classified according to its frequency and according to the bothersomeness it induced. The degree of bothersomeness associated with each IPSS symptom was evaluated and quantified based on quadratic function estimates. RESULTS: The mean IPSS score was 12.6+/-6.4, the mean SPI score was 12.2+/-6.5. The correlation coefficient between the IPSS and SPI scores was 0.70; the scores from the 2 rating scales showed a very high variability. On a 0-100% scale, where 100% represents a maximum bothersomeness, the induced bothersomeness ranged from 0 to 22.6% depending on the 7 symptoms. CONCLUSIONS: The two questionnaires do not collect the same information. The extent of variability between the two scales confirms that one scale cannot be replaced by the other. Considering the importance of bothersomeness associated with lower urinary tract symptoms for the therapy decision, the joint use of the IPSS and SPI seems appropriate.

[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.

[Meta-analysis of surgery trials in refractory epilepsy]. / Méta-analyse des essais de chirurgie de l'épilepsie réfractaire.

OBJECTIVE: To examine the evidence for efficacy of surgery in the treatment of intractable epilepsy. METHOD: Meta-analysis of randomized clinical trials. RESULTS: One randomized clinical trial (n=80) and 3 observational studies are available. INTERPRETATION: Compared to medical treatment, the surgery increases the proportion of patients who were free of seizure impairing awareness at 1 year (relative risk: 7.67, IC 95% 2.5 à 23.51) CONCLUSION: The available evidence about the clinical efficacy of surgery for patient with intractable epilepsies is limited to an unique open randomized clinical trial, that enrolled patient in a single centre, without concealment of the randomization and with a partially subjective primary endpoint. However, this trial shows a substantial effect corresponding to a 8 fold increase in the number of patient without seizure at 1 year. The informational situation will be better when the results of a currently ongoing trial will be available.

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.

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. REVIEWER'S 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.