Estimating individualized treatment effects using an individual participant data meta-analysis.

BACKGROUND: One key aspect of personalized medicine is to identify individuals who benefit from an intervention. Some approaches have been developed to estimate individualized treatment effects (ITE) with a single randomized control trial (RCT) or observational data, but they are often underpowered for the ITE estimation. Using individual participant data meta-analyses (IPD-MA) might solve this problem. Few studies have investigated how to develop risk prediction models with IPD-MA, and it remains unclear how to combine those methods with approaches used for ITE estimation. In this article, we compared different approaches using both simulated and real data with binary and time-to-event outcomes to estimate the individualized treatment effects from an IPD-MA in a one-stage approach. METHODS: We compared five one-stage models: naive model (NA), random intercept (RI), stratified intercept (SI), rank-1 (R1), and fully stratified (FS), built with two different strategies, the S-learner and the T-learner constructed with a Monte Carlo simulation study in which we explored different scenarios with a binary or a time-to-event outcome. To evaluate the performance of the models, we used the c-statistic for benefit, the calibration of predictions, and the mean squared error. The different models were also used on the INDANA IPD-MA, comparing an anti-hypertensive treatment to no treatment or placebo ( N = 40 237 , 836 events). RESULTS: Simulation results showed that using the S-learner led to better ITE estimation performances for both binary and time-to-event outcomes. None of the risk models stand out and had significantly better results. For the INDANA dataset with a binary outcome, the naive and the random intercept models had the best performances. CONCLUSIONS: For the choice of the strategy, using interactions with treatment (the S-learner) is preferable. For the choice of the method, no approach is better than the other.

Barriers and Facilitators to the Use of Clinical Decision Support Systems in Primary Care: A Mixed-Methods Systematic Review.

PURPOSE: To identify and quantify the barriers and facilitators to the use of clinical decision support systems (CDSSs) by primary care professionals (PCPs). METHODS: A mixed-methods systematic review was conducted using a sequential synthesis design. PubMed/MEDLINE, PsycInfo, Embase, CINAHL, and the Cochrane library were searched in July 2021. Studies that evaluated CDSSs providing recommendations to PCPs and intended for use during a consultation were included. We excluded CDSSs used only by patients, described as concepts or prototypes, used with simulated cases, and decision supports not considered as CDSSs. A framework synthesis was performed according to the HOT-fit framework (Human, Organizational, Technology, Net Benefits), then a quantitative synthesis evaluated the impact of the HOT-fit categories on CDSS use. RESULTS: A total of 48 studies evaluating 45 CDSSs were included, and 186 main barriers or facilitators were identified. Qualitatively, barriers and facilitators were classified as human (eg, perceived usefulness), organizational (eg, disruption of usual workflow), and technological (eg, CDSS user-friendliness), with explanatory elements. The greatest barrier to using CDSSs was an increased workload. Quantitatively, the human and organizational factors had negative impacts on CDSS use, whereas the technological factor had a neutral impact and the net benefits dimension a positive impact. CONCLUSIONS: Our findings emphasize the need for CDSS developers to better address human and organizational issues, in addition to technological challenges. We inferred core CDSS features covering these 3 factors, expected to improve their usability in primary care.

SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials balancing their risks and benefits.

AIMS/HYPOTHESIS: Cardiovascular outcome trials (CVOTs) have demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, serious adverse drug reactions have been reported. The risk/benefit ratio of SGLT2i remains unquantified. We aimed to provide an estimation of their risk/benefit ratio in individuals with type 2 diabetes. METHODS: We conducted a systematic review (MEDLINE, up to 14 September 2021) and meta-analysis. We included randomised CVOTs assessing SGLT2i in individuals with type 2 diabetes with or without other diseases. We used the Cochrane 'Risk of bias' assessment tool. The primary outcomes were overall mortality, major adverse cardiovascular events (MACE), hospitalisation for heart failure (HHF), end-stage renal disease (ESRD), amputation, diabetic ketoacidosis (DKA) and reported genital infections. For each outcome, we estimated the incidence rate ratio (IRR) with a 95% CI; we then computed the number of events expected spontaneously and with SGLT2i. RESULTS: A total of 46,969 participants from five double-blind, placebo-controlled international trials (weighted mean follow-up 3.5 years) were included. The prevalence of previous CVD ranged from 40.6% to 99.2%. The definition of reported genital infections ranged from 'genital mycotic infection' to 'genital infections that led to discontinuation of the trial regimen or were considered to be serious adverse events'. The number of included studies for each outcomes was five. The use of SGLT2i decreased the risk of all-cause death (IRR 0.86 [95% CI 0.78, 0.95]), MACE (IRR 0.91 [95% CI 0.86, 0.96]), HHF (IRR 0.69 [95% CI 0.62, 0.76]) and ESRD (IRR 0.67 [95% CI 0.53, 0.84]), and increased the risk of DKA (IRR 2.59 [95% CI 1.57, 4.27]) and genital infection (IRR 3.50 [95% CI 3.09, 3.95]) but not of amputation (IRR 1.23 [95% CI 1.00, 1.51]). For 1000 individuals treated over 3.5 years, SGLT2i are expected, on average, to decrease the number of deaths from 70 to 61, to prevent nine MACE, 11 HHF and two cases of ESRD, while inducing two DKA occurrences and 36 genital infections; 778 individuals are expected to avoid all the following outcomes: MACE, HHF, ESRD, amputation, DKA and genital infection. CONCLUSIONS/INTERPRETATION: Our study is limited to aggregate data. In a population of individuals with type 2 diabetes and a high CVD risk, the cardiovascular and renal benefits of SGLT2i remain substantial despite the risk of DKA and even the hypothetical risk of amputation. TRIAL REGISTRATION: OSF Registries: https://doi.org/10.17605/OSF.IO/J3R7Y FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

A randomized controlled phase III study comparing hadrontherapy with carbon ions versus conventional radiotherapy - including photon and proton therapy - for the treatment of radioresistant tumors: the ETOILE trial.

BACKGROUND: Some cancers such as sarcomas (bone and soft tissue sarcomas) and adenoid cystic carcinomas are considered as radioresistant to low linear energy transfer radiation (including photons and protons) and may therefore beneficiate from a carbon ion therapy. Despite encouraging results obtained in phase I/II trials compared to historical data with photons, the spread of carbon ions has been limited mainly because of the absence of randomized medical data. The French health authorities stressed the importance of having randomized data for carbon ion therapy. METHODS: The ETOILE study is a multicenter prospective randomized phase III trial comparing carbon ion therapy to either advanced photon or proton radiotherapy for inoperable or macroscopically incompletely resected (R2) radioresistant cancers including sarcomas and adenoid cystic carcinomas. In the experimental arm, carbon ion therapy will be performed at the National Center for Oncological Hadrontherapy (CNAO) in Pavia, Italy. In the control arm, photon or proton radiotherapy will be carried out in referent centers in France. The primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival and local control, toxicity profile, and quality of life. In addition, a prospective health-economic study and a radiobiological analysis will be conducted. To demonstrate an absolute improvement in the 5-year PFS rate of 20% in favor of carbon ion therapy, 250 patients have to be included in the study. DISCUSSION: So far, no clinical study of phase III has demonstrated the superiority of carbon ion therapy compared to conventional radiotherapy, including proton therapy, for the treatment of radioresistant tumors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02838602 . Date of registration: July 20, 2016. The posted information will be updated as needed to reflect protocol amendments and study progress.

How do they add up? The interaction between the placebo and treatment effect: A systematic review.

AIM: The placebo effect and the specific effect are often thought to add up (additive model). Whether additivity holds can dramatically influence the external validity of a trial. This assumption of additivity was tested by Kleijnen et al in 1994 but the data produced since then have not been synthetized. In this review, we aimed to systematically review the literature to determine whether additivity held. METHODS: We searched Medline and PsychInfo up to 10 January 2019. Studies using the balanced placebo design (BPD), testing two different strengths of placebos, were included. The presence of interaction was evaluated by comparing each group in the BPD with analysis of variance or covariance. RESULTS: Thirty studies were included and the overall risk of bias was high: four found evidence of additivity and 16 studies found evidence of interaction (seven had evidence of positive additivity). CONCLUSION: Evidence of additivity between placebo and specific features of treatments was rare in included studies. We suggest interventions for placebo-sensitive ailments should be tested in trials designed to take interactions seriously once an exploratory RCTs has proven their efficacy with sufficient internal validity.

Needs for re-intervention on restored teeth in adults: a practice-based study.

OBJECTIVES: Evaluate the need for re-intervention on dental coronal restorations in adults seen in a network of general dental practitioners (ReCOL).  MATERIALS AND METHODS: This observational, cross-sectional, multicenter study involved 40 practitioners and 400 patients. Coronal restoration failures (needing re-intervention for unsatisfactory outcomes) were assessed with a simplified rating scale of seven criteria from the FDI World Dental Federation. The oral health status, the risk factors, and Oral Health Impact Profile-14 were also examined. Previous restoration characteristics (extent, technique, material) were analyzed according to the need for re-intervention (yes/no), the age group, and the risk profile. Qualitative variables were compared between "re-intervention" and "no re-intervention" group using Fisher exact test. RESULTS: The need for re-intervention was estimated at 74% (95% CI: 70; 79); it increased with age (49 to 90%), unfavorable risk profile (82 vs. 62%), and extent of the filling (32, 39, 44, and 44% on 1, 2, 3 surfaces, and crowns, respectively). More posterior than anterior teeth were restored (median per patient: 6 vs. 1) or needed re-intervention (median per patient: 1 vs. 0). CONCLUSIONS: The needs for re-intervention in adults are still high within a context of ever-changing materials and techniques, simplified and rationalized decision-makings, and demands for patient involvement. CLINICAL RELEVANCE: Meeting these needs requires the following: (i) consensus definitions and assessment methods for "failure" and (ii) reliable feedbacks on materials, procedures, and satisfaction. Building large and detailed databases fed by networks of motivated practitioners will help analyzing complex success/failure data by artificial intelligence and guiding treatment and research.

Basket clinical trial design for targeted therapies for cancer: a French National Authority for Health statement for health technology assessment.

During the past decade, health technology assessment bodies have faced new challenges in establishing the benefits of new drugs for individuals and health-care systems. A topic of increasing importance to the field of oncology is the so-called agnostic regulatory approval of targeted therapies for cancer (independent of tumour location and histology) granted on the basis of basket trials. Basket trials in oncology offer the advantage of simultaneously evaluating treatments for multiple tumours, even rare cancers, in a single clinical trial. To address the novel challenges introduced by these trials, an interdisciplinary panel was convened on behalf of the Transparency Committee of the French National Authority for Health to clarify an approach designed to guarantee a transparent, reproducible, and fair assessment of histology-agnostic treatments for reimbursement by the French National Health Insurance Fund. The requirements of this approach include the need for randomisation, clinically relevant endpoints, appropriate correction for multiple significance testing, characterisation of subgroup heterogeneity, and validation of underlying biomarker assays. A prospectively designated external control is encouraged when the implementation of a direct comparison is deemed infeasible. We also underline the importance of recording outcomes from basket trials in a registry for use as future external controls.

Evaluation of High-Throughput SARS-CoV-2 Serological Assays in a Longitudinal Cohort of Patients with Mild COVID-19: Clinical Sensitivity, Specificity, and Association with Virus Neutralization Test.

BACKGROUND: The association between SARS-CoV-2 commercial serological assays and virus neutralization test (VNT) has been poorly explored in mild patients with COVID-19. METHODS: 439 serum specimens were longitudinally collected from 76 healthcare workers with RT-PCR-confirmed COVID-19. The clinical sensitivity (determined weekly) of 9 commercial serological assays were evaluated. Clinical specificity was assessed using 69 pre-pandemic sera. Correlation, agreement, and concordance with the VNT were also assessed on a subset of 170 samples. Area under the ROC curve (AUC) was estimated at 2 neutralizing antibody titers. RESULTS: The Wantai Total Ab assay targeting the receptor binding domain (RBD) within the S protein presented the best sensitivity at different times during the course of disease. The clinical specificity was greater than 95% for all tests except for the Euroimmun IgA assay. The overall agreement with the presence of neutralizing antibodies ranged from 62.2% (95%CI; 56.0-68.1) for bioMérieux IgM to 91.2% (87.0-94.2) for Siemens. The lowest negative percent agreement (NPA) was found with the Wantai Total Ab assay (NPA 33% (21.1-48.3)). The NPA for other total Ab or IgG assays targeting the S or the RBD was 80.7% (66.7-89.7), 90.3% (78.1-96.1), and 96.8% (86.8-99.3) for Siemens, bioMérieux IgG, and DiaSorin, respectively. None of the commercial assays have sufficient performance to detect a neutralizing titer of 80 (AUC < 0.76). CONCLUSIONS: Although some assays show a better agreement with VNT than others, the present findings emphasize that commercialized serological tests, including those targeting the RBD, cannot substitute a VNT for the assessment of functional antibody response.

Individual participant data meta-analysis to examine interactions between treatment effect and participant-level covariates: Statistical recommendations for conduct and planning.

Precision medicine research often searches for treatment-covariate interactions, which refers to when a treatment effect (eg, measured as a mean difference, odds ratio, hazard ratio) changes across values of a participant-level covariate (eg, age, gender, biomarker). Single trials do not usually have sufficient power to detect genuine treatment-covariate interactions, which motivate the sharing of individual participant data (IPD) from multiple trials for meta-analysis. Here, we provide statistical recommendations for conducting and planning an IPD meta-analysis of randomized trials to examine treatment-covariate interactions. For conduct, two-stage and one-stage statistical models are described, and we recommend: (i) interactions should be estimated directly, and not by calculating differences in meta-analysis results for subgroups; (ii) interaction estimates should be based solely on within-study information; (iii) continuous covariates and outcomes should be analyzed on their continuous scale; (iv) nonlinear relationships should be examined for continuous covariates, using a multivariate meta-analysis of the trend (eg, using restricted cubic spline functions); and (v) translation of interactions into clinical practice is nontrivial, requiring individualized treatment effect prediction. For planning, we describe first why the decision to initiate an IPD meta-analysis project should not be based on between-study heterogeneity in the overall treatment effect; and second, how to calculate the power of a potential IPD meta-analysis project in advance of IPD collection, conditional on characteristics (eg, number of participants, standard deviation of covariates) of the trials (potentially) promising their IPD. Real IPD meta-analysis projects are used for illustration throughout.

Drug prescription goals in primary care: a cross-sectional study.

BACKGROUND: Care goals are often implicit, although their identification is a key element of any prescription process. This study aimed to describe the clinical goals of drug prescriptions in general practice, their determinants and the agreement between physicians and patients. METHODS: This was a cross-sectional study conducted by 11 resident trainees acting as observers in 23 general practices. The residents recorded the indication and main physician's goal for all drugs prescribed during five consultation days in each practice in December 2015, and the main patient's goal for a sub-sample of consultations. We used an eight-category generic classification of prescription goals, including three specific (mortality, morbidity and cure), three non-specific (symptoms, quality of life, functioning) and two non-specified (other goal, no goal) categories. Analyses were based on a multivariable, multilevel model and on the kappa statistic applied to the sub-sample of consultations. RESULTS: The sample encompassed 2141 consultations and 5036 drugs. The main physicians' goal of drug prescriptions was to relieve symptoms (43.3%). The other goals were to decrease the risk of morbidity (22.4%), to cure disease (11.7%), to improve quality of life (10.6%), to decrease the risk of mortality (8.5%) and to improve functioning (1.8%). The choice of a specific goal was more frequent in patients with the following characteristics: over 50 (OR [1.09;1.15]), of male gender (OR [1.09;1.39]), with full financial coverage for a long-term condition (OR [1.47;1.97]), known by the physician (OR [1.19;2.23]), or with a somatic health problem (OR [2.56;4.17]). Cohen's kappa for drug prescription goals between the patients and the physicians was 0.26 (0.23-0.30). CONCLUSIONS: Physicians' goals are poorly shared with patients. It remains to be assessed whether it is possible to collect and discuss information on prescription goals on a daily basis.

Investigation of one-stage meta-analysis methods for joint longitudinal and time-to-event data through simulation and real data application.

BACKGROUND: Joint modeling of longitudinal and time-to-event data is often advantageous over separate longitudinal or time-to-event analyses as it can account for study dropout, error in longitudinally measured covariates, and correlation between longitudinal and time-to-event outcomes. The current literature on joint modeling focuses mainly on the analysis of single studies with a lack of methods available for the meta-analysis of joint data from multiple studies. METHODS: We investigate a variety of one-stage methods for the meta-analysis of joint longitudinal and time-to-event outcome data. These methods are applied to the INDANA dataset to investigate longitudinally measured systolic blood pressure, with each of time to death, time to myocardial infarction, and time to stroke. Results are compared to separate longitudinal or time-to-event meta-analyses. A simulation study is conducted to contrast separate versus joint analyses over a range of scenarios. RESULTS: The performance of the examined one-stage joint meta-analytic models varied. Models that accounted for between study heterogeneity performed better than models that ignored it. Of the examined methods to account for between study heterogeneity, under the examined association structure, fixed effect approaches appeared preferable, whereas methods involving a baseline hazard stratified by study were least time intensive. CONCLUSIONS: One-stage joint meta-analytic models that accounted for between study heterogeneity using a mix of fixed effects or a stratified baseline hazard were reliable; however, models examined that included study level random effects in the association structure were less reliable.

INN or brand name drug prescriptions: a multilevel, cross-sectional study in general practice.

PURPOSE: The prescription in International Nonproprietary Names (INN) is a legal obligation for all physicians in France since January 2015. The objective of this study was to analyze the frequency and main factors of INN drug prescribing in general practice. METHODS: Multicenter cross-sectional study conducted with 11 interns acting as observers of 23 GP trainers between November 2015 and January 2016. Two evaluators analyzed all GPs' drug prescriptions to identify INN or brand name prescriptions. RESULTS: The database included 4957 drugs prescribed during 1647 visits. Of these, 1462 (29.5% [95% CI 28.2-30.8%]) were prescribed only in INN. According to the multivariate analyses, the factors favoring INN prescribing were as follows: at the drug level, its initial prescribing (OR = 1.4), a nonspecific prescribing objective (OR = 1.6), its listing in the generic drug index with (OR = 7.7) or without (OR = 2.9) efficiency objective included in the payment for public health objectives (PPHO) program, and the oral route of administration (OR from 0.4 for the percutaneous route to 0.2 for the pulmonary route); at the patient level, the male gender (OR = 1.3), the age of 15 years or more (OR = 1.9), and the absence of a long-term condition (OR = 1.3); at the physician level, the reception of a public healthcare insurance representative (OR = 4.1), the nonreception of pharmaceutical sales representatives (OR = 3.0), and the urban practice environment (OR = 2.8). CONCLUSIONS: In 2015, less than one third of drugs were prescribed in INN only in general practice. The use of various incentives and regulatory measures is likely to favor the prescription of INNs by practitioners.

Minoxidil versus placebo in the treatment of arterial wall hypertrophy in children with Williams Beuren Syndrome: a randomized controlled trial.

BACKGROUND: Insufficient elastin synthesis leads to vascular complications and arterial hypertension in children with Williams-Beuren syndrome. Restoring sufficient quantity of elastin should then result in prevention or inhibition of vascular malformations and improvement in arterial blood pressure. METHODS: The aim of this study was to assess the efficacy and safety of minoxidil on Intima Media Thickness (IMT) on the right common carotid artery after twelve-month treatment in patient with Williams-Beuren syndrome. We performed a randomized placebo controlled double blind trial. All participants were treated for 12 months and followed for 18 months. The principal outcome was assessed by an independent adjudication committee blinded to the allocated treatment groups. RESULTS: The principal outcome was available for 9 patients in the placebo group and 8 patients in the minoxidil group. After 12-month treatment, the IMT in the minoxidil group increased by 0.03 mm (95% CI -0.002, 0.06) compared with 0.01 mm (95%CI - 0.02, 0.04 mm) in the placebo group (p = 0.4). Two serious adverse events unrelated to the treatment occurred, one in the minoxidil and 1 in the placebo group. After 18 months, the IMT increased by 0.07 mm (95% CI 0.04, 0.10 mm) in the minoxidil compared with 0.01 mm (95% CI -0.02, 0.04 mm) in the placebo group (p = 0.008). CONCLUSION: Our results suggest a slight increase after 12 and 18-month follow-up in IMT. More understanding of the biological changes induced by minoxidil should better explain its potential role on elastogenesis in Williams-Beuren syndrome. TRIALS REGISTRATION: US National Institutes of Health Clinical Trial Register (NCT00876200). Registered 3 April 2009 (retrospectively registered).

The contribution of genomics in the medicine of tomorrow, clinical applications and issues.

Fifteen years after the completion of first human genome sequencing, the technique is almost a commodity but there is still little evidence of its usefulness as a diagnostic, prognostic or therapeutic tool. In France, the France genomics plan 2025 was launched in 2015 with the goal of integrating genomic tests into clinical practice and developing a National genomics network including industrial partnerships. Reflection on scientific applications and operational or societal issues is needed to make recommendations to help better associate Genomics and the medicine of tomorrow. In the perspective of personalized Evidence-based Medicine, studies with an appropriate methodological level to improve the definition of evidence should be promoted. The many operational challenges require the implementation of organisations and means to streamline the process of results reporting, and regulatory adaptations concerning the status of professions involved, the management of data generated, and the consent of patients. In parallel, genetic training for healthcare professionals and raising awareness on genetic tests for the public should be considered. The ethical stake should also be taken into account, especially on the participation of the patient in decisions concerning them and integrating the notion of uncertainty into the information given. The sociological effects on the experience and expectations of patients and the general population towards genomic medicine should also be evaluated to improve information, prevention and support for people. Finally, medico-economic studies must be conducted to inform policy-makers on the cost-effectiveness of complete genome sequencing for population health.

Investigation of 2-stage meta-analysis methods for joint longitudinal and time-to-event data through simulation and real data application.

BACKGROUND: Joint modelling of longitudinal and time-to-event data is often preferred over separate longitudinal or time-to-event analyses as it can account for study dropout, error in longitudinally measured covariates, and correlation between longitudinal and time-to-event outcomes. The joint modelling literature focuses mainly on the analysis of single studies with no methods currently available for the meta-analysis of joint model estimates from multiple studies. METHODS: We propose a 2-stage method for meta-analysis of joint model estimates. These methods are applied to the INDANA dataset to combine joint model estimates of systolic blood pressure with time to death, time to myocardial infarction, and time to stroke. Results are compared to meta-analyses of separate longitudinal or time-to-event models. A simulation study is conducted to contrast separate versus joint analyses over a range of scenarios. RESULTS: Using the real dataset, similar results were obtained by using the separate and joint analyses. However, the simulation study indicated a benefit of use of joint rather than separate methods in a meta-analytic setting where association exists between the longitudinal and time-to-event outcomes. CONCLUSIONS: Where evidence of association between longitudinal and time-to-event outcomes exists, results from joint models over standalone analyses should be pooled in 2-stage meta-analyses.

Hierarchical evaluation of electrical stimulation protocols for chronic wound healing: An effect size meta-analysis.

Electrical stimulation (ES) has been tested for decades to improve chronic wound healing. However, uncertainty remains on the magnitude of the efficacy and on the best applicable protocol. We conducted an effect size meta-analysis to assess the overall efficacy of ES on wound healing, to compare the efficacy of the different modalities of electrical stimulation, and to determine whether efficacy differs depending on the wound etiology, size, and age of the chronic wound. Twenty-nine randomized clinical trials with 1,510 patients and 1,753 ulcers were selected. Overall efficacy of ES on would healing was a 0.72 SMD (95% CI: 0.48, 1) corresponding to a moderate to large effect size. We found that unidirectional high voltage pulsed current (HVPC) with the active electrode over the wound was the best evidence-based protocol to improve wound healing with a 0.8 SMD (95% CI: 0.38, 1.21), while evaluation of the efficacy of direct current was limited by the small number of studies. ES was more effective on pressure ulcers compared to venous and diabetic ulcers, and efficacy trended to be inversely associated with the wound size and duration. This study confirms the overall efficacy of ES to enhance healing of chronic wounds and highlights the superiority of HVPC over other type of currents, which is more effective on pressure ulcers, and inversely associated with the wound size and duration. This will enable to standardize future ES practices.

Pharmacotherapy for hypertension in adults aged 18 to 59 years.

BACKGROUND: Hypertension is an important risk factor for adverse cardiovascular events including stroke, myocardial infarction, heart failure and renal failure. The main goal of treatment is to reduce these events. Systematic reviews have shown proven benefit of antihypertensive drug therapy in reducing cardiovascular morbidity and mortality but most of the evidence is in people 60 years of age and older. We wanted to know what the effects of therapy are in people 18 to 59 years of age. OBJECTIVES: To quantify antihypertensive drug effects on all-cause mortality in adults aged 18 to 59 years with mild to moderate primary hypertension. To quantify effects on cardiovascular mortality plus morbidity (including cerebrovascular and coronary heart disease mortality plus morbidity), withdrawal due adverse events and estimate magnitude of systolic blood pressure (SBP) and diastolic blood pressure (DBP) lowering at one year. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to January 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA: Randomized trials of at least one year' duration comparing antihypertensive pharmacotherapy with a placebo or no treatment in adults aged 18 to 59 years with mild to moderate primary hypertension defined as SBP 140 mmHg or greater or DBP 90 mmHg or greater at baseline, or both. DATA COLLECTION AND ANALYSIS: The outcomes assessed were all-cause mortality, total cardiovascular (CVS) mortality plus morbidity, withdrawals due to adverse events, and decrease in SBP and DBP. For dichotomous outcomes, we used risk ratio (RR) with 95% confidence interval (CI) and a fixed-effect model to combine outcomes across trials. For continuous outcomes, we used mean difference (MD) with 95% CI and a random-effects model as there was significant heterogeneity. MAIN RESULTS: The population in the seven included studies (17,327 participants) were predominantly healthy adults with mild to moderate primary hypertension. The Medical Research Council Trial of Mild Hypertension contributed 14,541 (84%) of total randomized participants, with mean age of 50 years and mean baseline blood pressure of 160/98 mmHg and a mean duration of follow-up of five years. Treatments used in this study were bendrofluazide 10 mg daily or propranolol 80 mg to 240 mg daily with addition of methyldopa if required. The risk of bias in the studies was high or unclear for a number of domains and led us to downgrade the quality of evidence for all outcomes.Based on five studies, antihypertensive drug therapy as compared to placebo or untreated control may have little or no effect on all-cause mortality (2.4% with control vs 2.3% with treatment; low quality evidence; RR 0.94, 95% CI 0.77 to 1.13). Based on 4 studies, the effects on coronary heart disease were uncertain due to low quality evidence (RR 0.99, 95% CI 0.82 to 1.19). Low quality evidence from six studies showed that drug therapy may reduce total cardiovascular mortality and morbidity from 4.1% to 3.2% over five years (RR 0.78, 95% CI 0.67 to 0.91) due to reduction in cerebrovascular mortality and morbidity (1.3% with control vs 0.6% with treatment; RR 0.46, 95% CI 0.34 to 0.64). Very low quality evidence from three studies showed that withdrawals due to adverse events were higher with drug therapy from 0.7% to 3.0% (RR 4.82, 95% CI 1.67 to 13.92). The effects on blood pressure varied between the studies and we are uncertain as to how much of a difference treatment makes on average. AUTHORS' CONCLUSIONS: Antihypertensive drugs used to treat predominantly healthy adults aged 18 to 59 years with mild to moderate primary hypertension have a small absolute effect to reduce cardiovascular mortality and morbidity primarily due to reduction in cerebrovascular mortality and morbidity. All-cause mortality and coronary heart disease were not reduced. There is lack of good evidence on withdrawal due to adverse events. Future trials in this age group should be at least 10 years in duration and should compare different first-line drug classes and strategies.

How to measure the net benefit of treatment?

Estimating net benefit makes possible to clarify the basis for therapeutic decisions on an individual and collective level. This clarification is a must in shared medical decision-making and evidence-based medicine. Numerous methods are available, although none outweigh the others. The complex specifications of net benefit estimation should be tailored to the expectations of the central stakeholder, patient or society, and the unlimited range of potential contexts. The challenges, limitations, constraints and skills to be acquired by all stakeholders were discussed by the participants of the round table. They are described in this article, enabling key messages and guidelines to be presented. The essential priority is to ensure that all stakeholders receive the required training.

[Acute analgesic effect of paracetamol in primary care: Incomplete evidence]. / Effet antalgique aigu du paracétamol en soins primaires : des preuves incomplètes.

This meta-analysis assessed the analgesic effect of a single oral dose of paracetamol versus placebo in adults, in primary care. Parallel randomized studies were searched on MEDLINE®, CENTRAL®, and EMBASE®. We found five studies on sore throat (842 patients) and 12 studies on headache (3433 patients). None related to low back pain. Regardless of the outcome, paracetamol was superior to placebo (number need to treat [NNT]=4-5; standardized mean difference [SMD]=0.51-0.92). Additional clinical trials in other primary care conditions, like low back pain, must be conducted.

Efficacy and safety of insulin in type 2 diabetes: meta-analysis of randomised controlled trials.

BACKGROUND: It is essential to anticipate and limit the social, economic and sanitary cost of type 2 diabetes (T2D), which is in constant progression worldwide. When blood glucose targets are not achieved with diet and lifestyle intervention, insulin is recommended whether or not the patient is already taking hypoglycaemic drugs. However, the benefit/risk balance of insulin remains controversial. Our aim was to determine the efficacy and safety of insulin vs. hypoglycaemic drugs or diet/placebo on clinically relevant endpoints. METHODS: A systematic literature review (Pubmed, Embase, Cochrane Library) including all randomised clinical trials (RCT) analysing insulin vs. hypoglycaemic drugs or diet/placebo, published between 1950 and 2013, was performed. We included all RCTs reporting effects on all-cause mortality, cardiovascular mortality, death by cancer, cardiovascular morbidity, microvascular complications and hypoglycaemia in adults ≥ 18 years with T2D. Two authors independently assessed trial eligibility and extracted the data. Internal validity of studies was analyzed according to the Cochrane Risk of Bias tool. Risk ratios (RR) with 95 % confidence intervals (95 % CI) were calculated, using the fixed effect model in first approach. The I(2) statistic assessed heterogeneity. In case of statistical heterogeneity, subgroup and sensitivity analyses then a random effect model were performed. The alpha threshold was 0.05. Primary outcomes were all-cause mortality and cardiovascular mortality. Secondary outcomes were non-fatal cardiovascular events, hypoglycaemic events, death from cancer, and macro- or microvascular complications. RESULTS: Twenty RCTs were included out of the 1632 initially identified studies. 18 599 patients were analysed: Insulin had no effect vs. hypoglycaemic drugs on all-cause mortality RR = 0.99 (95 % CI =0.92-1.06) and cardiovascular mortality RR = 0.99 (95 % CI =0.90-1.09), nor vs. diet/placebo RR = 0.92 (95 % CI = 0.80-1.07) and RR = 0.95 (95 % CI 0.77-1.18) respectively. No effect was found on secondary outcomes either. However, severe hypoglycaemia was more frequent with insulin compared to hypoglycaemic drugs RR = 1.70 (95 % CI = 1.51-1.91). CONCLUSIONS: There is no significant evidence of long term efficacy of insulin on any clinical outcome in T2D. However, there is a trend to clinically harmful adverse effects such as hypoglycaemia and weight gain. The only benefit could be limited to reducing short term hyperglycemia. This needs to be confirmed with further studies.