Polypharmacy, functional outcome and treatment effect of intravenous alteplase for acute ischaemic stroke.

BACKGROUND AND PURPOSE: Polypharmacy is an important challenge in clinical practice. Our aim was to determine the effect of polypharmacy on functional outcome and treatment effect of alteplase in acute ischaemic stroke. METHODS: This was a post hoc analysis of the randomized, placebo-controlled WAKE-UP trial of magnetic resonance imaging guided intravenous alteplase in unknown onset stroke. Polypharmacy was defined as an intake of five or more medications at baseline. Comorbidities were assessed by the Charlson Comorbidity Index (CCI). The primary efficacy variable was favourable outcome defined by a score of 0-1 on the modified Rankin Scale at 90 days. Logistic regression analysis was used to test for an association of polypharmacy with functional outcome, and for interaction of polypharmacy and the effect of thrombolysis. RESULTS: Polypharmacy was present in 133/503 (26%) patients. Patients with polypharmacy were older (mean age 70 vs. 64 years; p < 0.0001) and had a higher score on the National Institutes of Health Stroke Scale at baseline (median 7 vs. 5; p = 0.0007). A comorbidity load defined by a CCI score ≥ 2 was more frequent in patients with polypharmacy (48% vs. 8%; p < 0.001). Polypharmacy was associated with lower odds of favourable outcome (adjusted odds ratio 0.50, 95% confidence interval 0.30-0.85; p = 0.0099), whilst the CCI score was not. Treatment with alteplase was associated with higher odds of favourable outcome in both groups, with no heterogeneity of treatment effect (test for interaction of treatment and polypharmacy, p = 0.29). CONCLUSION: In stroke patients, polypharmacy is associated with worse functional outcome after intravenous thrombolysis independent of comorbidities. However, polypharmacy does not interact with the beneficial effect of alteplase.

Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. The EMIAT and CAMIAT Investigators.

BACKGROUND: Investigations with in vitro and animal models suggest an interaction between amiodarone and beta-blockers. The objective of this work was to explore if an interaction with beta-blocker treatment plays a role in the decrease of cardiac arrhythmic deaths with amiodarone in patients recovered from an acute myocardial infarction. METHODS AND RESULTS: A pooled database from 2 similar randomized clinical trials, the European Amiodarone Myocardial Infarction Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), was used. Four groups of post-myocardial infarction patients were defined: beta-blockers and amiodarone used, beta-blockers used alone, amiodarone used alone, and neither used. All analyses were done on an intention-to-treat basis. Unadjusted and adjusted relative risks for all-cause mortality, cardiac death, arrhythmic cardiac death, nonarrhythmic cardiac death, arrhythmic death, or resuscitated cardiac arrest were lower for patients receiving beta-blockers and amiodarone than for those without beta-blockers, with or without amiodarone. The interaction was statistically significant for cardiac death and arrhythmic death or resuscitated cardiac arrest (P=0.05 and 0.03, respectively). Findings were consistent across subgroups. CONCLUSIONS: These findings are based on a post hoc analysis. However, they confirm prior results from in vitro and animal experiments suggesting an interaction between beta-blockers and amiodarone. In practice, not only is the adjunct of amiodarone to beta-blockers not hazardous, but beta-blocker therapy should be continued if possible in patients in whom amiodarone is indicated.

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.

Predictive value of repeated measurements of CD4 lymphocyte counts on progression to AIDS.

OBJECTIVE: Description of the relationship between repeated measurements of CD4 lymphocyte count and development of AIDS in asymptomatic HIV-infected patients. DESIGN: Repeated measurements of CD4 lymphocyte counts over an AIDS-free period in asymptomatic HIV-infected patients, and follow-up of the cohort to record subsequent clinical progression to AIDS. METHODS: The cohort was studied in a double-blind randomized clinical trial. CD4 lymphocyte counts were measured on three occasions over 8 months in 851 patients. RESULTS: Eighty subsequent clinical progressions to AIDS were recorded during a median follow-up period of 15.3 months. Each of the three measurements of CD4 lymphocyte count were separately predictive of subsequent progression to AIDS. However, when the three measurements were included simultaneously in a predictive model only the last measurement showed a significant predictive value. Change in individual CD4 count was also related to the risk of developing AIDS, but was no longer significant when the most recent measurement was included in the model. CONCLUSION: These results indicate the closeness of the relationship between the actual state of the immune system and subsequent progression to AIDS.

[Identification and prediction of responders to a therapy. A model and its preliminary application to hypertension]. / Identification des sujets répondeurs à une thérapeutique. Proposition de modèle et application préliminaire à l'hypertension.

The effect of a given treatment for a given disease may be estimated from randomized controlled clinical trials, expressed as a single treatment effect averaged over the trial population. However, in recent years there has been an increasing willingness to individualize therapeutic decisions. The method we report here identifies responders by assessing the individual probability of an event, according to the treatment group. We used a treatment-stratified Cox regression model including interaction between treatment and patient's covariates, with common regression coefficients for treated and untreated, except for the special case of a prognostic variable which has an interaction with treatment. Further, we used a discriminate function based on the final model, representing the absolute individual therapeutic effect, to identify the patients to be treated according to a given threshold of clinical efficacy. The model was explored on the INDANA database (which pools individual patient data from clinical trials of anti-hypertensive drug intervention). Data on 36,444 patients, from five randomized controlled trials were included. The results show the relationship between the proportion of avoided events among the avoidable ones, and the proportion of patients treated who were responders, as a function of the threshold of absolute benefit defining responders. The confidence intervals of the absolute therapeutic benefit for each individual were calculated, by using the Monte Carlo simulation method. A comparison of the survival of treated and controlled individuals, in both subgroups of responders and non responders, illustrated the relevance of the model. We conclude that the tools for predicting individual therapeutic benefit do exist. It will be important to assess the reproducibility of these results in other models or in other populations before widespread application. It will be necessary to have a properly computerized environment and to train doctors to use these tools.

[Presentation of OCTAVE II. A current epidemiologic study in France of the added prognostic value of ambulatory blood pressure monitoring]. / Présentation d'OCTAVE II. Une étude épidémiologique en cours en France sur la valeur pronostique ajoutée par la mesure ambulatoire de la pression artérielle.

The diagnosis of "white coat" hypertension, the measurement of indices of 24 hour variability of the blood pressure and increased accuracy of blood pressure estimation are some of the advantages of ambulatory blood pressure monitoring. They are part of the reason why the method has been adopted by ambulatory blood pressure monitoring is really useful in the treatment of hypertension is fragile: although the correlation with target organ complications seems better than with conventional blood pressure measurement, it remains to be shown that this information helps to predict and then improve the prognosis of hypertension. With respect to this first stage of demonstration of the added prognostic value attributable to ambulatory blood pressure monitoring, several studies have been undertaken, one of which is OCTAVE II. The goals were to analyse the predictive values of the indices obtained by ambulatory blood pressure monitoring in terms of cardiovascular morbidity and mortality after having described the correlations between these indices and the characteristics of individual patients. Two hundred and sixty six cardiologists, members of the French College of Cardiology, included 3,569 patients in whom an indication for ambulatory blood pressure monitoring had been retained, over a period of 10 months in 1991. These patients were 56.4 year old on average, with 52.6% men, hypertensive or not. The 5 year follow-up should end at the beginning of 1997.

A score for predicting risk of death from cardiovascular disease in adults with raised blood pressure, based on individual patient data from randomised controlled trials.

OBJECTIVE: To create a risk score for death from cardiovascular disease that can be easily used. DESIGN: Data from eight randomised controlled trials of antihypertensive treatment. SETTING: Europe and North America. PARTICIPANTS: 47 088 men and women from trials that had differing age ranges and differing eligibility criteria for blood pressure. MAIN OTUCOME MEASURE: 1639 deaths from cardiovascular causes during a mean 5.2 years of follow up. RESULTS: Baseline factors were related to risk of death from cardiovascular disease using a multivariate Cox model, adjusting for trial and treatment group (active versus control). A risk score was developed from 11 factors: age, sex, systolic blood pressure, serum total cholesterol concentration, height, serum creatinine concentration, cigarette smoking, diabetes, left ventricular hypertrophy, history of stroke, and history of myocardial infarction. The risk score is an integer, with points added for each factor according to its association with risk. Smoking contributed more in women and in younger age groups. In women total cholesterol concentration mattered less than in men, whereas diabetes had more of an effect. Antihypertensive treatment reduced the score. The five year risk of death from cardiovascular disease for scores of 10, 20, 30, 40, 50, and 60 was 0.1%, 0.3%, 0.8%, 2.3%, 6.1%, and 15.6%, respectively. Age and sex distributions of the score from the two UK trials enabled individual risk assessment to be age and sex specific. Risk prediction models are also presented for fatal coronary heart disease, fatal stroke, and all cause mortality. CONCLUSION: The risk score is an objective aid to assessing an individual's risk of cardiovascular disease, including stroke and coronary heart disease. It is useful for physicians when determining an individual's need for antihypertensive treatment and other management strategies for cardiovascular risk.

[Monitoring of clinical trials and interim analysis. 1. Monitoring committee]. / Surveillance d'essais cliniques et analyses intermédiaires. 1. Les comités de surveillance.

In order to fulfil the ethical principles linked to the protection of patients randomized in a controlled clinical trial, monitoring procedures need to be set up. In this context, a committee of experts, called the data monitoring committee is in charge of reviewing regularly unblinded data to assess the quality and the relevance of the trial, to evaluate the evidence of an emerging treatment difference and to control the rate of occurrence of serious adverse events. After each meeting, the monitoring committee reports to the steering committee its recommendation to continue or to stop the trial prematurely. Protocol modifications might be proposed as well. Illustrated with several examples, this article reviews different situations a monitoring committee might have to tackle with.

[Monitoring of clinical trials and interim analysis. 2. Statistic methods]. / Surveillance d'essais cliniques et analyses intermédiaires. 2. Méthodes statistiques.

Although the decision to continue or to stop prematurely a clinical trial is not solely based on statistical tests, they bring useful objective arguments to the data monitoring board. However, the multiple use of statistical tests leads to increase the risk of false positive conclusions in favor of one of the treatments, and several methods have been developed to address this problem. This article presents the four major strategies that are being used for monitoring clinical trials, as well as the rationale for planning and using such statistical monitoring procedures.

[The problem of therapeutic efficacy indices. 2. Description of the indices]. / Aperçu sur la problématique des indices d'efficacité thérapeutique, 2: description des indices.

The four indices for a binary outcome or therapeutic objective are: the odds ratio, the relative risk, the absolute benefit and the number of patients to treat. For a continuous outcome, the effect size is the best choice. The odds ratio approximates the relative risk. The difference may be large in some instances. The number of patients to treat is the reciprocal of the absolute benefit. Although they are built on the same two quantities, they are not interchangeable and should not be considered in the same way. Moreover, their meaning is not straightforward and they can be misused.

[The problem of therapeutic efficacy indices. 1. Elements of the problem]. / Aperçu sur la problématique des indices d'efficacité thérapeutique, 1: eléments de la problématique. Groupe d'Etude des Indices d'Efficacité.

Efficacy indices measure the efficacy of therapies. They derive, by definition, from two quantities, the basal or control risk of event, Rc, observed in the control group, and the on-treatment risk, Rt, observed in the treated group. In clinical trials and meta-analyses, each is an unbiased measure of efficacy. Although they are a combination of frequencies, these indices are used in clinical practice to predict the benefit in treated patients. Their relevance to express efficacy depends on the type of clinical condition, and is better for acute diseases than for chronic diseases. In order to be useful for prescribers, they should meet certain specifications. In addition, they should be considered in the more general framework of effect models.

[Outline of the problem of indices of therapeutic efficacy. 4. Expression of efficacy when the underlying illness is incurable. Study Group for the Indices of Efficacy]. / Aperçu sur la problématique des indices d'efficacité thérapeutique, 4: expression de l'efficacité lorsque la maladie sous-jacente ne guérit pas. Groupe d'Etude des indices d'Efficacité.

In chronic illness, when death or a non-fatal event can occur at any time, the current efficacy indices are no longer appropriate to express the effect of the treatment on the potential therapeutic objectives. The inappropriateness is not dependent on the effect model. Clues for solutions are proposed.

[The problem of therapeutic efficacy indices. 3. Comparison of the indices and their use]. / Aperçu sur la problématique des indices d'efficacité thérapeutique, 3: comparaison des indices et utilisation. Groupe d'Etude des Indices D'efficacité.

Efficacy indices do not contain the same information although they are all combinations of the same two quantities. Therefore, one should choose the proper index. Actually, none is entirely appropriate. Each more or less meets the specifications, depending on the underlying effect model for the therapy considered. However, one can say that the absolute benefit is more appropriate from the patient's point of view, the relative from the scientific point of view and the number of patients to treat from the policy maker's point of view. Nevertheless, this classification needs to be considered with caution. Finally, it emerges from the review that none is fully relevant to express the efficacy of a therapy, even in the most suitable condition, the acute illness.

INDANA: a meta-analysis on individual patient data in hypertension. Protocol and preliminary results.

The overall effect of antihypertensive drug treatment has been well documented. The proportion of patients who benefit varies according to their baseline cardiovascular risk, and is small for the majority of people treated. Some investigators propose limiting the treatment target population to patients at high cardiovascular risk, but several assumptions must be made to justify this procedure. The INDANA project is a meta-analysis based on individual patient data, and thus offers the opportunity to check the validity of these assumptions. Its main objective is to identify responders (and non-responders) in the drug treatment of hypertension. The rationale and methods for such an approach are presented here, with the solution for some technical problems. The conclusion of the data collection has shown that the project is feasible. The results of the main analysis should be available in 1996, and should contribute to the selection of responders and to the individualization of the treatment of hypertension.

Fetal thrombotic vasculopathy is associated with thromboembolic events and adverse perinatal outcome but not with neurologic complications: a retrospective cohort study of 54 cases with a 3-year follow-up of children.

OBJECTIVE: to test the hypothesis that placental fetal thrombotic vasculopathy (FTV) is associated with obstetric complications and predisposes the child to unfavorable outcomes. METHODS: 54 placentas with FTV lesions and 100 placentas without FTV lesions were collected over a 5-year period at the Croix-Rousse Pathology Department. Clinical findings including maternal, fetal, neonatal condition and pediatric outcome up to three years were collected for each case and control observation. The statistical analyses were assessed with Wald's chi-square derived from conditional logistic regression modeling. RESULTS: FTV was associated with a significantly higher frequency of obstetric complications: (pregnancy-induced hypertension (OR 3.620, CI 1.563-8.385), preeclampsia (OR 3.674, CI 1.500-8.998), emergency delivery procedures (OR 3.727, CI 1.477-9.403), cesarean sections (OR 2.684, CI 1.016-7.088)), poor fetal condition (intrauterine growth restriction (IUGR) (OR 5.440, CI 2.007-14.748), nonreassuring fetal heart tracing (OR 6.062, CI 2.280-16.115), difficulties in immediate ex utero adaptation (OR 3.416, CI 1.087-10.732)) and perinatal or early childhood demise (OR 3.043, CI 1.327-6.978). On pathological examination, FTV was associated with marginal cord insertion (OR 3.492, CI 1.350-9.035), cord stricture and hypercoiled cord (OR 3.936, CI 1.209-12.813). Thromboembolic events were significantly more frequent in cases with FTV (OR 2.154, CI 1.032-5.622). Neurological complications within the first 3 years of life were also more frequent in the FTV group compared to the control group, but this association was not statistically significant. CONCLUSIONS: FTV is associated with maternal complications, pathological findings in the placenta, especially gross cord abnormalities, IUGR, and poor perinatal or early childhood outcome. It may also predispose children to somatic thromboembolic events.

Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder associated with abnormal angiogenesis and disabling epistaxis. Tranexamic acid (TA) has been widely used in the treatment of these severe bleeds but with no properly designed trial. OBJECTIVES: To demonstrate the efficacy of TA in epistaxis in HHT patients and to explore its safety of use. PATIENTS/METHODS: A randomized, placebo-controlled, double-blind, cross-over trial was conducted. Participants were randomized to receive TA (3 g a day) then placebo or the opposite sequence. The main analysis compared intra-individual mean duration of epistaxis under TA vs. placebo on a log scale. The primary outcome was the mean duration of epistaxis per month, assessed with specific grids to be completed by participants. The number of epistaxis episodes was recorded as a secondary outcome. RESULTS: A total of 118 randomized patients contributed to the statistical analysis. The mean duration of epistaxis per month was significantly shorter with TA than placebo (0.19 on the log scale; SD = 0.07; P = 0.005), corresponding to a decrease of 17.3% (15.7 min) in the duration of epistaxis per month (CI 95%, 5.5-27.6). The median number of epistaxis episodes per month was 22.1 episodes in the placebo arm vs. 23.3 episodes in the TA arm. No thrombophlebitis was observed. CONCLUSIONS: In the ATERO study, we demonstrated a significant decrease in the duration of epistaxis in HHT patients taking TA. No safety issues were recorded in our cohort of patients.

Efficacy of a home-based intervention programme on the physical activity level and functional ability of older people using domestic services: a randomised study.

OBJECTIVE: Our main objective was to assess whether a home-based program supervised by home helpers (HH) during their normal working hours can prevent excessive sedentariness (mainly maximum walking time and distance) and preserve functional status in elderly people at risk for frailty or disability and using domestic services. DESIGN: A four-month, open label, randomised trial with two groups called "prevention" and "control". SETTING: In the homes of study participants. PARTICIPANTS: The participants were all over 78 years old, lived independently at home, and received the visits of HHs at least once a week. INTERVENTION: The intervention combined a self-administered exercise program, with 10 g amino-acid supplementation under the supervision of HHs. MEASUREMENTS: Main outcome measures included physical activity (the PASE questionnaire), functional tests, nutritional and autonomy scores, and compliance (50% or more was considered satisfactory). Non-parametric methods were used for comparisons between the two groups. A linear regression model was fitted to assess the effect of the intervention on the relative variation of outcomes, adjusted for unbalanced baseline co-variables. RESULTS: One hundred and two persons (prevention n=53, control n=49) with a median age of 85 years were included. Their median Activities of Daily Living and Instrumental Activities of Daily Living (IADL) scores were 6 and 7 respectively. Twenty-three (44%) were good compliers for both interventions. The maximum walking time remained stable while decreasing by 25% in the control group (p=0.0015); and fewer participants had a worsened IADL score in the prevention group (p=0.05). The baseline IADL Score was significantly associated with good compliance to the prevention program (p=0.0011). In good compliers, maximum walking distance and maximum walking time increased by 29.15% (0.0 to 66.7) and 33.3% (-20.0 to 50.0) respectively. CONCLUSION: This study confirms the feasibility of a prevention program supervised by HHs, and some benefit from the intervention and identifies predictors for better compliance. It will help in the design of prevention trials for elderly people at risk for frailty.

Modelling the progression towards duodenal cancer among patients with familial polyposis on the basis of two different score profiles.

The objective was to design a method that considers, on clinical arguments, the likely existence of patient subgroups with different evolution profiles. The method is applied in familial adenomatous polyposis to predict the proportion of patients that would develop duodenal cancer. A subject-specific linear mixed-effects model was elaborated to explicitly model heterogeneity in regression parameters. The estimates of the parameters were obtained by Bayesian inference using Gibbs sampling. The application concerned two potential polyposis subgroups: stable-state and progressive. Each patient's score was expressed in function of his putative subgroup, the reference subgroup mean score (intercept), the rate of change (slope), and time. The estimated proportion of stable-state patients was 35%. In progressive-state patients, the estimated annual score increase was 0.38 (95% CI: 0.27-0.48). The regression model predicted that the proportion of patients with a score > or = 9 is near 43% at age 60 (36-50%) and 50% at 70 (43-57%). The method indicates the evolution profile of each subject, which facilitates therapeutic decisions. The modelling may be extended to other more complex situations with several subgroups, with different change rates, or with various genetic or therapeutic profiles.

Thrombolytic therapy with streptokinase in acute ischemic stroke.

BACKGROUND: In patients with acute ischemic stroke, early treatment with thrombolytic agents is thought to permit reperfusion of ischemic neurons and to promote recovery of function. The Multicenter Acute Stroke Trial-Europe (MAST-E) was designed to assess the efficacy and safety of streptokinase in patients with acute ischemic stroke. METHODS: Patients with moderate-to-severe ischemia in the territory of the middle cerebral artery were randomly assigned to receive streptokinase (1.5 million units over a period of one hour) or placebo within six hours after the onset of stroke. The primary efficacy outcome was a binary criterion combining mortality and severe disability at six months, with severe disability defined as a score of 3 or higher on the Rankin scale. The primary safety outcomes were mortality at 10 days and cerebral hemorrhage. RESULTS: All randomized patients (156 in the streptokinase group and 154 in the placebo group) were evaluated at six months. The incidence of the primary efficacy outcome was similar in the two groups (124 patients in the streptokinase group and 126 in the placebo group died or had a Rankin score > or = 3). However, the mortality rate at 10 days was significantly higher in the streptokinase group than in the placebo group (34.0 percent vs. 18.2 percent, P = 0.002). The higher rate in the streptokinase group was mainly due to the hemorrhagic transformation of ischemic cerebral infarcts. At six months, more deaths had occurred in the streptokinase group than in the placebo group (73 vs. 59, P = 0.06). CONCLUSIONS: In patients with acute ischemic stroke, treatment with streptokinase resulted in an increase in mortality. The routine use of streptokinase cannot be recommended in acute ischemic stroke.

Thrombolysis in Acute Stroke Pooling Project: a meta-analysis on individual patient data.

To assess the efficacy and safety of thrombolytic therapy in acute ischaemic stroke, randomised clinical trials have been undertaken. Their results suggest that further research should be attempted to identify patients for whom the benefit/risk ratio of thrombolysis is beneficial. The Thrombolysis in Acute Stroke Pooling Project (TAS-PP) group will pool individual patient data from recent studies and meta-analyse these. A Steering Committee drafted the protocol and defined access rules to the common file. The objectives are to assess the efficacy of thrombolysis to reduce death or severe disability, to identify predictors of death and haemorrhagic transformation, and to identify subgroups with a better response to treatment, using logistic regression, survival curve comparison (log rank test), multivariate modelling (with treatment, baseline characteristics, delay from symptom to treatment as covariates). This project will help defining subpopulations that are more likely to benefit from this treatment, which cannot be achieved using tabulated data, and designing future trials. Copyright 1999 Harcourt Publishers Ltd.