Dynamical modeling of pro- and anti-inflammatory cytokines in the early stage of septic shock.

A dynamical model of the pathophysiological behaviors of IL18 and IL10 cytokines with their receptors is tested against data for the case of early sepsis. The proposed approach considers the surroundings (organs and bone marrow) and the different subsystems (cells and cyctokines). The interactions between blood cells, cytokines and the surroundings are described via mass balances. Cytokines are adsorbed onto associated receptors at the cell surface. The adsorption is described by the Langmuir model and gives rise to the production of more cytokines and associated receptors inside the cell. The quantities of pro and anti-inflammatory cytokines present in the body are combined to give global information via an inflammation level function which describes the patient's state. Data for parameter estimation comes from the Sepsis 48 H database. Comparisons between patient data and simulations are presented and are in good agreement. For the IL18/IL10 cytokine pair, 5 key parameters have been found. They are linked to pro-inflammatory IL18 cytokine and show that the early sepsis is driven by components of inflammatory character.

Pharmacokinetic/pharmacodynamic model of a methionine starvation based anti-cancer drug.

A new therapeutic approach against cancer is developed by the firm Erytech. This approach is based on starved cancer cells of an amino acid essential to their growth (the L-methionine). The depletion of plasma methionine level can be induced by an enzyme, the methionine-γ-lyase. The new therapeutic formulation is a suspension of erythrocytes encapsulating the activated enzyme. Our work reproduces a preclinical trial of a new anti-cancer drug with a mathematical model and numerical simulations in order to replace animal experiments and to have a deeper insight on the underlying processes. With a combination of a pharmacokinetic/pharmacodynamic model for the enzyme, substrate, and co-factor with a hybrid model for tumor, we develop a "global model" that can be calibrated to simulate different human cancer cell lines. The hybrid model includes a system of ordinary differential equations for the intracellular concentrations, partial differential equations for the concentrations of nutrients and drugs in the extracellular matrix, and individual based model for cancer cells. This model describes cell motion, division, differentiation, and death determined by the intracellular concentrations. The models are developed on the basis of experiments in mice carried out by Erytech. Parameters of the pharmacokinetics model were determined by fitting a part of experimental data on the concentration of methionine in blood. Remaining experimental protocols effectuated by Erytech were used to validate the model. The validated PK model allowed the investigation of pharmacodynamics of cell populations. Numerical simulations with the global model show cell synchronization and proliferation arrest due to treatment similar to the available experiments. Thus, computer modeling confirms a possible effect of treatment based on the decrease of methionine concentration. The main goal of the study is the development of an integrated pharmacokinetic/pharmacodynamic model for encapsulated methioninase and of a mathematical model of tumor growth/regression in order to determine the kinetics of L-methionine depletion after co-administration of Erymet product and Pyridoxine.

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.

Impact of terminating reimbursement of symptomatic slow-acting drugs in osteoarthritis in France on volume and cost of drug deliveries, assessed with administrative databases.

WITH OSTEOARTHRITIS (OA): As one of the leading causes of disability in adults worldwide, its toll on patients and its economic burden for payers are substantial. The issue of change in OA management with the evolution of reimbursement schemes needs to be addressed. OBJECTIVE: To assess the impact of terminating the reimbursement of symptomatic slow-acting drugs in OA (SYSADOAs) in France in terms of volume and cost, from a healthcare payer perspective. PRINCIPAL RESULTS: We obtained costs and volumes from French public national databases. We considered three exposure periods around cutoff dates according to decisions of decreased then terminated SYSADOA reimbursement. The periods included 19 345 (control), 20 066 (secondary), and 16 200 (primary) patients, respectively. Mean ages were 66.2 (±11.8), 65.3 (±11.6) and 64.6 (±11.5) years and about 70% were women. The volume of nonsteroidal anti-inflammatory drug (NSAID) deliveries estimated by defined daily doses (DDDs) decreased during the periods from 40.5 (±76.3) DDDs per patient in 2008 to 29.6 (±66.4) in 2015. The volume of analgesic deliveries increased slowly over the three periods, from 70.2 (±108.9) DDDs in 2008 to 76.9 (±123.1) in 2015 for all patients. MAJOR CONCLUSIONS: Our results did not show a measurable impact of terminating SYSADOA reimbursement on the delivery of NSAIDs and analgesics or on hospitalizations. However, neither do they allow for concluding that terminating SYSADOA reimbursement did not generate an increase in deliveries of non-reimbursed drugs, with their associated potential risks for public health.

[Active drug monitoring of adverse drug reactions in pediatric emergency department]. / Recueil systématique et actif des évènements indésirables médicamenteux chez les enfants admis aux urgences pédiatriques.

OBJECTIVES: The aim of this study was to systematically evaluate adverse drug reactions (ADRs) in children consulting at the pediatric emergency unit during a 6-month period. METHOD: The regional pharmacovigilance center (CRPV) and the department of clinical pharmacology prospectively and systematically recorded all potential ADRs among patients younger than 18 years of age in the pediatric emergency unit reported at the daily staff meetings. All cases were then screened and validated by the CRPV. For validated cases, preventability, seriousness, and off-label use were evaluated. RESULTS: During the study period, from 1 March to 1 September 2005, 90 children presented potential adverse drug events. ADRs were confirmed in 43 patients, 19 females and 24 males. Thirty-four patients (79%) were under the age of 5. According to the European definition, 14 patients (33%) had serious ADRs. One anaphylactic shock after amoxicillin injection; antimalarial prophylaxis misuse leading to convulsive status epilepticus, convulsion, and coma after hepatitis B and MMR vaccines were deemed life-threatening. Three ADRs were considered avoidable. Antibiotics and vaccines were the most common possible cause of ADRs (76%). Skin reactions (n=27), fever (n=8), and gastric disorders (n=5) were the most common clinical manifestations. CONCLUSIONS: Because ADRs were reported by clinicians on a voluntary basis, serious ADRs were probably reported more systematically. Compared to a similar period without active monitoring, active drug monitoring of ADRs doubled the number of confirmed cases 43 vs 17, p<0.001. Close collaboration between the pharmacovigilance center, pharmacologists, and clinicians is necessary and seems feasible for improving the monitoring of ADRs in children.

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.

[Some reflexions about double blind]. / Quelques réflexions sur le double insu.

LITERATURE FINDINGS: Randomized, double blind, placebo-controlled clinical trials are currently the best means of demonstrating the clinical effectiveness of drugs. The double blind procedure, when ethically and technically feasible, is a necessary condition for validating results and for causal attribution of the observed difference between the two groups to the tested drug's pharmacological effect. COMMENTS: In practice, however, it appears that patients and independent investigators can guess who receives the drug and who receives a placebo through side effects, which are usually more frequent in patients receiving the drug. This phenomenon effectively "breaks the blind" and represents as such a major methodological bias, which cannot be avoided as it is inseparable of the drug's effect. CONCLUSION: The impact of this "unavoidable" double blind breach nevertheless remains unclear. While it can reasonably be assumed that it may modify subjective symptoms such as anxiety or pain through suggestion, its influence on objective criteria remains to be demonstrated.

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.

Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials.

BACKGROUND: Guidelines for type 2 diabetes (T2D) recommend reducing HbA1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial. METHODS: A systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia. RESULTS: A total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR=1.03, 95% confidence interval [CI]=0.95-1.12), cardiovascular mortality (RR=1.02, 95% CI=0.92-1.12), myocardial infarction (RR=0.98, 95% CI=0.89-1.08), strokes (RR=1.02, 95% CI=0.88-1.17), renal failure (RR=1.06, 95% CI=0.88-1.27), severe hypoglycaemia (RR=1.14, 95% CI=0.95-1.36) and pancreatic cancer (RR=0.54, 95% CI=0.28-1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR=1.13, 95% CI=1.01-1.26) and of acute pancreatitis (RR=1.57, 95% CI=1.03-2.39). CONCLUSION: There is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.

Identification of risk factors in hypertensive patients: contribution of randomized controlled trials through an individual patient database.

BACKGROUND: Predicting individual risk is needed to target preventive interventions toward people with the highest probability of benefit over a given time period. We assessed which prognostic factors should be used in predicting risk for hypertensive patients and in searching for treatment modifiers. METHODS AND RESULTS: Data from 24 390 hypertensive participants who constituted the control groups from 8 controlled trials (1726 deaths over 5 years) were analyzed in multivariate survival models. Outcomes were coronary heart disease death, stroke death, and cardiovascular death. We explored systematically the heterogeneity of results between trials. Left ventricular hypertrophy was electrocardiographically confirmed to be a powerful risk factor and should be included in risk scoring. Height, glomerular filtration rate, and serum uric acid deserve further exploration. Body mass index and heart rate were not confirmed as independent cardiovascular risk factors in this population. The association between male sex and coronary heart disease death was significantly stronger in British cohorts. The lack of prognostic value of diastolic blood pressure was explained by an interaction with age, with a positive association before 65 years and a negative association thereafter. Previous antihypertensive treatment was a significant risk factor. CONCLUSIONS: Clinical trials provide valuable information for risk prediction. Carefully exploring the heterogeneity among trials is a way to assess the generalizability of findings. This approach, if systematically performed, should increase the ability to identify risk modifiers and to predict individual therapeutic benefit.

[Readability of informed consent forms for subjects participating in biomedical research: updating is required]. / Lisibilité de l'information écrite destinée aux sujets se prêtant à une recherche biomédicale: une nécessaire remise en question.

OBJECTIVE: We compared informed consent forms of subjects participating in biomedical research with those of references texts in order to determine the factors that influence readability. METHODS: We assessed the readability of 73 informed consent forms of research protocols conducted in the clinical investigation centres in the Rhone-Alpes area, and then compared them with 33 reference texts corresponding to 5 French school grades (first year infant, primary school, GCS level, high school, and classics aggregation), using the Flesch test and Cordial" analyser. RESULTS: Median Flesch scores were 66 for the first year infant level, 62 for the primary school level, 58 for the GCS level, 42 for the high school level, and 43 for the aggregation level. It was 22 for the informed consent forms. Median Cordial scores were 86 for the first year infant level, 77 for the second, 74 for the third, 49 for the fourth, 43 for the fifth. It was 1 for the informed consent forms. No methodological factor correlated with Flesch and Cordial" results. CONCLUSION: The quantitative readability scores for informed consent forms for subjects participating in biomedical research are low, lower than those proposed to aggregation candidates, whatever the type of protocol. Some thought must be given to the impact of the reduced readability on patients' understanding, and steps should be taken to improve the readability of the forms.

Efficacy of diuretics and beta-blockers in diabetic hypertensive patients. Results from a meta-analysis. The INDANA Steering Committee.

OBJECTIVE: To review the effectiveness of diuretic or beta-blocker-based treatment of hypertension in diabetic patients. RESEARCH DESIGN AND METHODS: A meta-analysis on individual patient data was performed on four trials of the treatment of hypertension in which diabetic patients were included and treated with first-line diuretics or beta-blockers. The main outcomes were the relative risk of death, fatal or nonfatal stroke, fatal or nonfatal coronary events, and major cardiovascular events. RESULTS: There were 92 diabetic patients who received first-line beta-blockers and 1,008 who received diuretics. In the control groups, diabetic patients had nearly twice the risk of any outcome when compared with nondiabetic patients. The same blood pressure reduction was achieved under treatment in the diabetic and nondiabetic patients, except for systolic pressure, which decreased more in the nondiabetic patients at 1 year. In the 15,843 nondiabetic patients, the risk of all four outcomes was reduced significantly in the treated group. In the 2,254 diabetic patients, the risk reduction was significant only for fatal and nonfatal stroke (36%, P = 0.011) and major cardiovascular events (20%, P = 0.032), but not for death (5%, P = 0.65) and fatal or nonfatal coronary events (15%, P = 0.23). However, no heterogeneity was detected between diabetic patients and nondiabetic patients for any outcome. The numbers of outcomes avoided for 1,000 patients treated for 5 years were higher in diabetic patients (e.g., 38 major cardiovascular events) than with nondiabetic patients (e.g., 28 major cardiovascular events). CONCLUSIONS: These results show that hypertensive diabetic patients benefit from first-line treatment with diuretics. No conclusion can be drawn for beta-blockers, owing to the small sample size.

Multivariate meta-analysis using individual participant data.

When combining results across related studies, a multivariate meta-analysis allows the joint synthesis of correlated effect estimates from multiple outcomes. Joint synthesis can improve efficiency over separate univariate syntheses, may reduce selective outcome reporting biases, and enables joint inferences across the outcomes. A common issue is that within-study correlations needed to fit the multivariate model are unknown from published reports. However, provision of individual participant data (IPD) allows them to be calculated directly. Here, we illustrate how to use IPD to estimate within-study correlations, using a joint linear regression for multiple continuous outcomes and bootstrapping methods for binary, survival and mixed outcomes. In a meta-analysis of 10 hypertension trials, we then show how these methods enable multivariate meta-analysis to address novel clinical questions about continuous, survival and binary outcomes; treatment-covariate interactions; adjusted risk/prognostic factor effects; longitudinal data; prognostic and multiparameter models; and multiple treatment comparisons. Both frequentist and Bayesian approaches are applied, with example software code provided to derive within-study correlations and to fit the models.

Is HbA1c a valid surrogate for macrovascular and microvascular complications in type 2 diabetes?

Recent recommendations regarding type 2 diabetes (T2D) patients' treatments have focused on personalizing glycosylated haemoglobin (HbA1c) targets. Because the relationship between HbA1c and diabetes prognosis has been established from large prospective cohorts, it is valid to question the extrapolation from population-based risk reduction estimations to individual predictions. Our study aimed to investigate the relationship between HbA1c reductions and clinical outcomes in randomized controlled trials (RCTs), using a meta-regression approach. Included were RCTs comparing intensive vs. standard glucose-lowering regimens for cardiovascular events and microvascular complications in T2D patients. Eight studies (33,396 patients) providing data for HbA1c reductions were found. In our meta-regression, HbA1c decreases were not significantly associated with reductions in our main study outcomes: total and cardiovascular mortality. They were also not associated with any of the secondary endpoints, including myocardial infarction, stroke and severe hypoglycaemia. Sensitivity analysis showed a significant correlation only between HbA1c-lowering and severe hypoglycaemia (P = 0.014). Meta-regression analysis could find no significant association between HbA1c-lowering and a decrease in clinical outcomes, thereby questioning the use of HbA1c as a surrogate outcome for T2D-related complications. Thus, RCTs vs. placebo are urgently required to evaluate the risk-benefit ratios of therapeutic strategies beyond HbA1c control in T2D patients.

Can we identify response markers to antihypertensive drugs? First results from the IDEAL Trial.

Current antihypertensive strategies do not take into account that individual characteristics may influence the magnitude of blood pressure (BP) reduction. Guidelines promote trial-and-error approaches with many different drugs. We conducted the Identification of the Determinants of the Efficacy of Arterial blood pressure Lowering drugs (IDEAL) Trial to identify factors associated with BP responses to perindopril and indapamide. IDEAL was a cross-over, double-blind, placebo-controlled trial, involving four 4-week periods: indapamide, perindopril and two placebo. Eligible patients were untreated, hypertensive and aged 25-70 years. The main outcome was systolic BP (SBP) response to drugs. The 112 participants with good compliance had a mean age of 52. One in every three participants was a woman. In middle-aged women, the SBP reduction from drugs was -11.5 mm Hg (indapamide) and -8.3 mm Hg (perindopril). In men, the response was significantly smaller: -4.8 mm Hg (indapamide) and -4.3 (perindopril) (P for sex differences 0.001 and 0.015, respectively). SBP response to perindopril decreased by 2 mm Hg every 10 years of age in both sexes (P=0.01). The response to indapamide increased by 3 mm Hg every 10 years of age gradient in women (P=0.02). Age and sex were important determinants of BP response for antihypertensive drugs in the IDEAL population. This should be taken into account when choosing drugs a priori.

New meta-analysis of treatment trials of hypertension: improving the estimate of therapeutic benefit.

The objectives of this sub group meta-analysis on the treatment of hypertension was to: (1) high-light specific results of well-designed trials; (2) group trials according to their specific clinical context; (3) express results of the meta-analysis in absolute reduction terms; and (4) estimate the bias of withdrawal because of blood pressure increase. This meta-analysis is based on summarised published results from randomised controlled trials, comparing a drug treatment versus placebo or no treatment, with morbi-mortality as the principle outcome. The following data were analysed: (1) total mortality; (2) cardiovascular mortality; (3) stroke; (4) major coronary events; and (5) congestive heart failure. The treatment significantly reduced the incidence of all outcomes in trials involving older patients, avoiding up to nine strokes (OR = 0.66, 95% Cl: 0.56-0.77) and four major coronary events (OR = 0.79, 95% Cl: 0.68-0.92) every 1000 patient-years when the bias of withdrawal was taken into account. The only outcome significantly influenced by treatment in younger patients with mild-to-moderate hypertension was stroke, with one stroke avoided every 1000 patient-years (OR = 0.51, 95% Cl: 0.39-0.66). There was insufficient statistical power in the trials which enrolled patients with non-moderate hypertension to reach clinical significance, except for the reduction in the incidence of congestive heart failure. However, the results indicated a trend towards greater absolute benefit under treatment. Trials enrolling patients with post-stroke hypertension also had insufficient power, but suggested benefit by the reduction of the incidence of stroke recurrence and congestive heart failure under treatment. In conclusion, the most constant treatment benefit concerned stroke, although the absolute reduction was very modest in younger patients with mild-to-moderate hypertension. Only the results from trials in older patients showed a significant reduction of major coronary events. Such results need further analyses, ideally based on individual patient data.

Pharmacotherapy for hypertension in women of different races.

OBJECTIVES: To assess whether the relative and absolute benefit of hypertension treatment in women varies with age or race. SEARCH STRATEGY: Literature search of studies from 1966 to 1998 using MEDLINE, reviews, and consultation with experts. SELECTION CRITERIA: Studies were eligible if they were randomized controlled trials of pharmacological treatment of primary hypertension, with cardiovascular morbidity and mortality outcomes, and with over one hundred women enrolled. DATA COLLECTION AND ANALYSIS: The pooled population included 23,000 women. Relative risks were combined for each endpoint to form summary risk ratios (RR) using meta-analytic techniques based on a random-effects model. Summary RR's were converted to numbers needed to treat (NNT). Data were dichotomized by age to approximate menopausal status (30 to 54 years, and 55 years and older), and by race (white and African American). MAIN RESULTS: In women ages 55 years or older (90% white), hypertension treatment results in a 38% risk reduction in fatal and nonfatal cerebrovascular events (95% confidence interval (CI) 27-47%, 5 year NNT 78), a 25% reduction in fatal and nonfatal cardiovascular events (95% CI 17-33%, 5 year NNT 58), and a 17% reduction in cardiovascular mortality (95% CI 3-29%, 5 year NNT 282). In women ages 30 to 54 years (79% white), hypertension treatment results in a 41% risk reduction in fatal and nonfatal cerebrovascular events (95% CI 8-63%, 5 year NNT 264), and a 27% risk reduction in fatal and nonfatal cardiovascular events (95% CI 4-44%, 5 year NNT 259). Hypertension treatment in African American women (mean age 52 years) reduced the risk of fatal and nonfatal cerebrovascular events by 53% (95% CI 29-69%, 5 year NNT 39), fatal and nonfatal cardiovascular events by 45% (95% CI 18-63%, 5 year NNT 21), fatal and nonfatal coronary events by 33% (95% CI 6-52%, 5 year NNT 48), and all cause mortality by 34% (95% CI 14-49%, 5 year NNT 32). Analyses in white women 30 to 54 years old did not show any statistically significant treatment benefit or harm. REVIEWER'S CONCLUSIONS: Hypertension treatment lowers the relative and absolute risk of cardiovascular morbidity and mortality in women ages 55 years and older, and in African American women of all ages. A greater effort should be made to increase awareness and treatment in these groups of women. Although relative risk reductions for cerebrovascular and cardiovascular events are similar for younger and older women, the NNT of younger women is at least 4 times higher. Decisions for treatment of hypertension in younger white women should be influenced by the individual patient's absolute risk of cardiovascular disease.

[Value of a new fast CK-MB determination for the diagnosis of myocardial infarction during the 1st hours. Preliminary study]. / Intérêt d'un nouveau dosage rapide de la CK-MB pour le diagnostic de l'infarctus du myocarde dans les premières heures. Etude préliminaire.

This study evaluated the time for a new, rapid and reliable CK-MB analysis to become positive in myocardial infarction and compared it with classical total CK analyses. Serial analyses of total CK and CK-MB were performed in 49 consecutive patients referred to the Coronary Care Unit for suspected acute myocardial infarction. Twenty of these patients had myocardial infarction with rising enzyme levels, which enabled comparison of the precocity of one analysis compared to another. In these patients, the CK-MB analysis became positive on average 85 to 110 minutes before that of total CK. This result shows that CK-MB analysis can be a diagnostic sign of acute myocardial infarction at an earlier stage than the total CK analysis. The authors discuss the clinical value of this test in difficult indications of fibrinolytic therapy and underline that it enables a more objective assessment of the time of onset of necrosis than clinical data alone.

[The Hypertension Cochrane Review Group. Presentation and user's guide]. / Le groupe de revues Cochrane en hypertension. Présentation et mode d'emploi.

Cochrane collaboration has been developing since 1992 as an international network aiming at performing systematic reviews of available data on therapeutic effectiveness. The fundamental principles of this organisation are trying to avoid duplication of efforts, seeking the best reliability, using reproducible and quantitative synthesis techniques, offering constantly updated results. All health domains are progressively covered. The production unit in one domain is the review group. The Hypertension Cochrane Review Group (HTN CRG) has been officially registered on May 15th 1996. Information and products from the group are available through its news letter, through the Cochrane Library CD-ROM, regularly updated, and on the Internet (http://merece.uthscsa.edu/htncrg). The Hypertension Cochrane Review Group includes an editorial board (with an administrator and three editors), the authors of systematic reviews, internal and external reviewers. The geographic link is the San Antonio Cochrane Centre (Texas, USA). Invitations to participate have been sent to people interested in hypertension and who where known to the Cochrane collaboration, and to authors of previous reviews in hypertension. It is possible to collaborate with the HTN CRG through: performing a systematic review; reviewing protocols and systematic reviews; hand-searching medical journals; being a member of the editorial team. The first protocol for a systematic review edited by the group concerns antihypertensive treatment in the elderly, and is available in the 1996 and subsequent editions of the Cochrane Library. The group welcomes other reviews from domains awaiting registration, and collaborates with related domains review groups such as Diabetes CRG, or Stroke CRG. The group contributes to the effort of hand-searching medical literature, Pr Plouin being responsible for the Archives des Maladies du Coeur et des Vaisseaux. The second edition in 1996 of the Cochrane Library included 114 systematic reviews and 131 protocols, being the only media with similar objectives.

[Antihypertensive therapy and improved life expectancy without cerebrovascular accident or coronary artery disease]. / Traitements antihypertenseurs et gain en espérance de vie sans accident vasculaire cérébral ni coronaropathie.

The absolute benefit from antihypertensive therapy increases with the baseline risk. However, age is a major determinant of cardiovascular risk, so it is important to express therapeutic efficacy with indices for which age is not a confounder. With this aim we explored the expected gain in life expectancy without cardiovascular events according to age at the initiation of the treatment. The treatment effect estimated from the INDANA meta-analysis, was applied to the cardiovascular risk of a French hypertensive population, simulated from national vital statistics. The gain in life expectancy was estimated from the area between survival curves without events. The treatment effect varied according three different hypotheses: increasing, decreasing or constant effect. When assuming a constant treatment effect, our results show a 29 month gain without stroke for a man who began his treatment at 40 years, and 15 months if hypertension is screened and treatment initiated at 75 years. The gains without coronary heart disease are respectively of 11 and 6 months. The variation of treatment effect over time could have a major impact on the treatment benefit. The gain in life expectancy without events is a relevant decision tool, completing usefully the absolute benefit, since it takes into account the influence of age.