Florent Boutitie

Effect of Antihypertensive Drug Treatment on Cardiovascular Outcomes in Women and Men: A Meta-Analysis of Individual Patient Data from Randomized, Controlled Trials

The effectiveness of antihypertensive drug treatment is well established and has been quantified in terms of overall reduction in the relative risk for stroke and other cardiovascular disease events [1, 2]. Risk for cardiovascular events (especially myocardial infarction) differs greatly between men and women, and these differences are not explained by other risk factors [3]. It remains unclear, however, whether the effect of antihypertensive treatment in reducing cardiovascular risk is dependent on sex. In a 1986 review, MacMahon and colleagues [4] stated that event rates, particularly those for fatal events and nonfatal myocardial infarction, were substantially lower in women than in men. The striking benefits of study treatments for the risk of fatal and non-fatal stroke were evident for both men and women. A reduction in total mortality could not be demonstrated for women, but the treatment effect for women was not significantly different from that in men, among whom there was an important and statistically significant reduction in mortality. This comment was based on the results of two trials: the Hypertension Detection and Follow-up Program (HDFP) [5] and the Medical Research Council trial of treatment of mild hypertension (MRC35-64) [6]. In their 1991 analysis of data from these trials plus data from the European Working Party on High Blood Pressure in the Elderly (EWPHE) trial [7] and the Australian therapeutic trial in mild hypertension [8], Anastos and colleagues [9] concluded that the few data that do exist suggest that gender, like race and age, significantly influences the natural course of hypertension and the response to treatment . The data regarding aggressive treatment of white women are equivocal; there is concern that such treatment may actually be harmful. Since these reviews were published, reports of three additional trials of antihypertensive treatment in older hypertensive men and women have appeared in print: the Medical Research Council trial of treatment of hypertension in older adults (MRC 65-74) [10], the Systolic Hypertension in the Elderly Program (SHEP) [11], and the Swedish Trial in Old Patients with Hypertension (STOP) [12]. More recently, other reviewers have stated that antihypertensive medications do not appear to be as effective in women as in men [13] and that when treated, women often achieve less benefit than do men [14]. The INDANA (INdividual Data ANalysis of Antihypertensive intervention trials) project [15] offers the opportunity to provide more evidence on the effects of antihypertensive treatment in women; results are based on individual patient data from all of the randomized, controlled trials mentioned in the preceding paragraphs. The two main objectives of the current study are to quantify the average treatment effect in each sex separately and to determine whether treatment effect differs significantly between women and men. Methods The INDANA project (whose rationale, objectives, and methods are described in detail elsewhere [15]) is a collaboration of representatives from most of the large randomized, controlled trials of antihypertensive drug treatment. Its results are derived from centralized files of the baseline and follow-up data available for all patients enrolled in the trials. The Trials Our report is based on seven trials [5-710-12, 16] (Table 1) in which both men and women were enrolled. The inclusion criteria for the trials in the INDANA project are discussed elsewhere [15]. In summary, the steering group of the project made the following decisions: The data from the Australian trial [8] were not included in the analysis because separate outcomes are not available without censoring bias; the EWPHE trial [7] data were included only for the analysis of mortality end points (separate nonfatal outcomes are not available without censoring bias); and the data from HDFP [5] were considered in a sensitivity analysis (analysis was done with and without these data because of the originality of the trial design, which compared specific antihypertensive care systems with usual care). The data from the Veterans Administration and National Heart, Lung, and Blood Institute feasibility trial [17] are available in the INDANA database but have not yet been submitted to control and extraction procedures. Thus, these data were not used in our analysis. Because this trial has only a small weight in terms of patient-years and observed events, its exclusion is unlikely to change the results presented here. Table 1. Main Characteristics of the Seven Antihypertensive Drug Trials That Enrolled Men and Women* Outcomes According to the INDANA protocol, seven outcomes were analyzed: 1) fatal strokes; 2) fatal and nonfatal strokes, excluding transient ischemic attacks; 3) fatal coronary events [including sudden death, which was defined as unexpected and unexplained death occurring within a maximal interval of 24 hours after symptom onset]; 4) fatal and nonfatal major coronary events (using criteria for major coronary heart disease obtained from patient histories in HDFP) [1]; 5) cardiovascular-related mortality, including death from pulmonary thromboembolism; 6) major cardiovascular events [combining the second, fourth, and fifth outcomes and excluding such minor cardiovascular events as angina pectoris, intermittent claudication, or nonfatal congestive heart failure]; and 7) total mortality. Statistical Analysis Summarized data (number of patients and number of events) were extracted from the INDANA database by sex and by trial according to the intention-to-treat principle. For the group assigned to receive active treatment, the odds ratio compared with controls was estimated by sex for each outcome according to the Peto method [18]. The odds ratio in women was compared with the odds ratio in men by determining whether the ratio was different from 1. This interaction between sex and treatment effect was checked after adjustment for the main baseline risk factors (age, baseline smoking habits, systolic blood pressure, serum cholesterol level, presence of diabetes, and history of stroke or myocardial infarction) in a multivariate logistic model [19] fitted by outcome. For HDFP [5], we censored data at the date of the end of the trial intervention. Two deaths in the trial by Coope and Warrender [16] that were caused by pulmonary embolism were included with cardiovascular-related mortality in our analysis; one early cancer-related death in this trial was included in the analyses of total mortality because of the intention-to-treat principle. To illustrate the difference in the treatment effect between men and women, we applied two graphical approaches to the second and fourth outcomes (all strokes and all coronary events). First, each trial was represented by sex in a treatment-effect graph [20] in which the x-axis is the risk observed in the control group (Rc) and the y-axis is the risk observed in the treated group (Rt) (Figure 1). The odds ratio line, with a slope equal to the odds ratio and a null intercept, indicates the treatment effect by sex. The principal diagonal of the plane Rt x Rc represents the absence of treatment effect (Rt = Rc; odds ratio, 1). The vertical distance between the odds ratio line and the principal diagonal indicates the absolute risk reduction for a given untreated risk. Second, the absolute risk reduction attributable to treatment and its CI were computed by tertiles of individually predicted risk for each sex and were plotted against the average predicted risk in each tertile (Figure 2). The predicted risk was derived from individual scoring built on the results of a multivariate logistic model, including the major risk factors mentioned above. Tertiles were computed to contain similar numbers of events. Figure 1. Effect of antihypertensive treatment on absolute risk for fatal and nonfatal stroke (left) and fatal and nonfatal coronary events (right). Figure 2. Absolute risk reduction of fatal and nonfatal stroke (left) and fatal and nonfatal coronary events (right) by untreated risk level and sex. Meta-analysis computations were done using Easy-MA software [21]; data management and logistic regression were done using SAS software [22]. Results The key features of the seven trials are presented in Table 1. Five of the trials addressed hypertension in older persons, and two studied mild to moderate hypertension in younger persons. The drugs used in the trials were primarily thiazide diuretics, -blockers, or both. The data for these seven trials contained in the INDANA database represent 97.5% of all existing data from all applicable trials in terms of patient-years of follow-up during the active phase of the trials. The combined trial data on risk factors by sex (Table 2) show that, on average, women were older; had a higher baseline cholesterol level, a higher systolic blood pressure, and a lower smoking rate; and less frequently had a history of myocardial infarction. Because these baseline characteristics were similar for the active treatment and control groups, these groups are combined in Table 2. Table 2. Main Cardiovascular Risk Factors by Sex* For each of the seven outcomes, Table 3 and Table 5 shows the number of events in the active treatment and control groups that occurred in men and women, both within each trial and in all trials combined. Table 3. Events by Trial and Sex* Table 5. Table 3. Continued The exclusion of the HDFP data from the analysis changes neither the direction nor the magnitude of the odds ratio for either sex and does not affect the differences between men and women. These data are therefore included in the results presented. In Table 4, the combined odds ratios for all trials are shown separately for men and women; these odds ratios were estimated using a fixed-effects method. In women, odds ratios favoring treatment were statistically significant for strokes (both fatal and either fatal or nonfatal) and major car

J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data.

Context Lowering blood pressure in hypertensive patients decreases the risk for cardiovascular events. However, clinical trials show a discrepancy between observed and expected risk reduction, possibly because of a J-shaped relationship between blood pressure and risk reduction. Contribution The authors analyzed individual-patient data from seven randomized clinical trials of both treated and untreated hypertensive patients. All-cause death rates were higher among patients with high diastolic pressure and those with low diastolic pressure. Low diastolic pressure was associated with an increased death rate, even among untreated patients. Implications Excessive antihypertensive treatment may increase the death rate. Poor health may also cause low blood pressure and increase the risk for death. The Editors The benefit of antihypertensive treatments in reducing the risk for cardiovascular events in persons with high blood pressure has been well established (1-3). Despite this evidence, epidemiologic studies have shown that after adjustment for other risk factors, treated hypertensive patients with normalized blood pressure are still at higher risk for cardiovascular diseases than normotensive persons (4). Moreover, in clinical trials the observed risk reduction for coronary events has been smaller than could be expected from the log-linear relationship between blood pressure and risk according to epidemiologic data (5). Clinical trials have reported a 5to 6mm Hg difference between the diastolic blood pressures of treatment and control groups; the risk reduction of 14% (95% CI, 4% to 22%) for coronary events contrasts with the 20% to 25% reduction noted in epidemiologic reports. These discrepancies may be related to the existence of a J-shaped relationship between blood pressure and risk, in which treated patients with low blood pressure are at increased risk for coronary events. The reports of a J-shaped relationship have come from longitudinal cohort studies of treated hypertensive patients (6-10) or clinical trial data on antihypertensive treatment groups and, in some trials, control groups (11-13). Interpretation of such results has varied. Some researchers have believed that overtreatment with blood pressurereducing drugs may compromise coronary blood flow, especially in hypertensive patients with a history of myocardial infarction (14), while others have considered that the increased risk in patients with low blood pressure is independent of treatment and may be attributed to confounding factors related to deteriorating heath (12, 15, 16) or pulse pressure (17). The INDANA (INdividual Data ANalysis of Antihypertensive intervention trials) project is a meta-analysis of individual-patient data collected from randomized clinical trials of antihypertensive medication versus placebo or no intervention, with follow-up for cardiovascular events and deaths (18). INDANA offers the opportunity to further explore the J-shaped curve. Specifically, this database allows assessment of the evolution of risk according to achieved blood pressure separately for treated and untreated patients who in all other aspects are similar because of the randomization process. Methods Study Sample Data from five randomized clinical trials in elderly patients (Coope and Warrender [13]; European Working Party on High Blood Pressure in Elderly patients [EWPHE] [19], Medical Research Council trial in older adults [MRC2] [20], Systolic Hypertension in the Elderly Program [SHEP] [21], and Swedish Trial in Old Patients [STOP] [22]) and two trials in middle-aged patients (Hypertension Detection and Follow-up Program [HDFP] [23] and Medical Research Council trial in mild hypertension [MRC1] [24]) were pooled in a common file with information on baseline patient characteristics, blood pressure measurements over time, and occurrence of major clinical events. For this analysis, we did not use the data from three other trials available at the INDANA coordinating center. First, the Multiple Risk Factor Intervention Trial (MRFIT) (25) could not directly relate a change in cardiovascular risk to a change in blood pressure because this study assessed the effects of cholesterol and smoking reduction in addition to that of blood pressure reduction. Next, we excluded the Australian National Blood Pressure Study (ANBPS) data (26) because of the risk for informative censoring (the end point was a combined criteria that included several soft events directly related to hypertension). Finally, the Veterans AdministrationNational Heart, Lung, and Blood Institute feasibility trial (VANHLBI) (27) had not been pooled in the database at the time of analysis but would have contributed only marginally to the overall results because few events were observed. Blood Pressure Data We did not include blood pressure at study entry in the analysis because these values were heavily conditioned by the trial-specific selection criteria for blood pressure. At least one blood pressure measurement per each year of follow-up was available. For trials that obtained several measurements per year, we used in our analysis the measurement obtained closest to the annual visit. Because systolic blood pressure in HDFP was measured only after 5 years of follow-up, this trial was not included in statistical analyses involving systolic blood pressure or pulse pressure. Clinical Events and Follow-up After study entry (baseline), the trials in the database monitored patients for occurrence of myocardial infarction, stroke, and death during a mean follow-up period ranging from 2.2 years in STOP to 5.8 years in MRC2. To make our results more robust, we focus on fatal events (classified as cardiovascular or noncardiovascular death). We did not analyze nonfatal events because they were monitored and reported less consistently than fatal events (for example, HDFP did not note the time to occurrence of strokes and EWPHE did not record nonfatal events after the occurrence of a nonfatal end point). In the analysis, follow-up for mortality started 1 year after randomization. For each subsequent yearly period, the risk for death was assessed according to the systolic and diastolic blood pressures obtained closest to the beginning of the year. Statistical Analysis As a first descriptive approach, we estimated the adjusted death rates by treatment group in successive categories of ongoing diastolic blood pressure ( 65, 66 to 75, 76 to 85, 86 to 95, 96 to 105, 106 mm Hg) and systolic blood pressure ( 120, 121 to 130, 131 to 140, 141 to 150, 151 to 160, 161 to 170, 171 to 180, 181 mm Hg) while controlling for any confounding effect of age, sex, study, and year of blood pressure measurement since study entry (28). For all patients, each successive 1-year period of follow-up was used to relate the blood pressure level at the beginning of that period to the risk for death during that period. This method allowed us to consider the influence of blood pressure on risk as it evolved over time. We used a Poisson linear regression model to relate the risk for dying (on a log scale) to the set of covariates (29). In addition to blood pressure, age, and time since entry (with each updated at every period), the other covariates were sex, history of medical events (myocardial infarction, stroke, and diabetes) before study entry, and smoking habits. Occurrence of nonfatal myocardial infarctions during follow-up was a further time-dependent covariate. To determine whether the relationship between blood pressure and risk was J-shaped, we fitted a model with both a linear and a quadratic (squared) term for blood pressure. This model assumes a curved relationship, with the risk for death decreasing to a minimum value with decreasing blood pressure before eventually increasing. Next, we estimated the minimum (nadir) and associated confidence interval from the coefficients of the linear and quadratic terms and their variance (30). Finally, to verify that an increase in risk with lower blood pressure was not a result of constraints of the quadratic model, we fitted blood pressure measurements at the left and right of the nadir with two independent curvilinear relationships, as proposed by Goetghebeur and Pocock (31). We repeated such modeling by using increasing nadir values (at intervals of 2 mm Hg for diastolic blood pressure and 5 mm Hg for systolic blood pressure) and determined the optimum nadir by the model with the best goodness of fit. We performed all statistical analyses by using the SAS software package for Windows, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source The funding source had no role in the collection, analysis, and interpretation of the data or in the decision to submit the paper for publication. Results Of the 40 777 patients randomly assigned to active treatment or control groups in the seven trials, we analyzed data on the 40 233 total patients alive at 1 year after study entry (Table 1). The mean follow-up was 3.9 years. Among the patients in our analysis, 48.9% (n = 19 692) were men and 27.7% (n = 11 107) were current smokers; 1312 patients (3.3%) had a history of myocardial infarction, 464 (1.1%) had a history of stroke, and 1420 (3.5%) had a history of diabetes mellitus. We could not include data on 31 995 1-year periods of follow-up (18.7%) in assessing a possible relation between fatal events and diastolic blood pressure because of missing blood pressure measurements. Overall, our analysis comprised data on 1655 deaths (56% of which were caused by cardiovascular events) during 126 908 total patient-years of follow-up. Table 1. Patient Events in Each Study Recorded during Follow-up between 1 Year after Study Inclusion and End of Study Follow-up One year after study entry, mean diastolic blood pressure in each trial was significantly lower in the active treatment group than in the control group; the mean 1-year difference in diastolic blood pressure between treatmen

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.

Abstract 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 outcome 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 individuals risk of cardiovascular disease, including stroke and coronary heart disease. It is useful for physicians when determining an individuals need for antihypertensive treatment and other management strategies for cardiovascular risk. What is already known on this topic Many other factors are known to affect the risk of cardiovascular disease in patients with raised blood pressure A patients overall risk should be taken into account when determining their need for antihypertensive drugs and other strategies for improving cardiovascular health What this study adds A new score uses 11 risk factors to quantify an adults risk of death from cardiovascular disease, including stroke and coronary heart disease The score is based on a large cohort of participants in controlled trials of antihypertensive drugs An individuals risk can be readily assessed as high or low compared with others of the same age and sex The website http://www.riskscore.org.uk/ is available for users of the risk score

Effect of Antihypertensive Treatment in Patients Having Already Suffered From Stroke: Gathering the Evidence

BACKGROUND AND PURPOSE Drug treatment of high blood pressure has been shown to reduce the associated cardiovascular risk. Stroke represents the type of event more strongly linked with high blood pressure, responsible for a high rate of death or invalidity, and with the highest proportion of events that can be avoided by treatment. Hypertensive patients with a history of cerebrovascular accident are at particularly high risk of recurrence. Specific trials of blood pressure lowering drugs in stroke survivors showed inconclusive results in the past. METHODS We performed a meta-analysis using all available randomized controlled clinical trials assessing the effect of blood pressure lowering drugs on clinical outcomes (recurrence of stroke, coronary events, cause-specific, and overall mortality) in patients with prior stroke or transient ischemic attack. RESULTS We identified 9 trials, including a total of 6752 patients: 2 trials included 551 hypertensive stroke survivors; 6 trials of hypertensive patients included a small proportion of stroke survivors (536 patients); 1 trial included stroke survivors, whether hypertensive or not (5665 patients). The recurrence of stroke, fatal and nonfatal, was significantly reduced in active groups compared with control groups consistently across the different sources of data (relative risk of 0.72, 95% confidence interval: 0.61 to 0.85). There was no evidence that this intervention induced serious adverse effect. CONCLUSIONS Blood pressure lowering drug interventions reduced the risk of stroke recurrence in stroke survivors. Available data did not allow to verify whether such benefit depends on initial blood pressure level. More data are needed before considering antihypertensive therapy in normotensive patients at high cerebrovascular risk.

Amiodarone Interaction With β-Blockers Analysis of the Merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) Databases

Background—Investigations with in vitro and animal models suggest an interaction between amiodarone and β-blockers. The objective of this work was to explore if an interaction with β-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: β-blockers and amiodarone used, β-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 β-blockers and amiodarone than for t...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.

Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials

Objective To determine how length of anticoagulation and clinical presentation of venous thromboembolism influence the risk of recurrence after anticoagulant treatment is stopped and to identify the shortest length of anticoagulation that reduces the risk of recurrence to its lowest level. Design Pooled analysis of individual participants’ data from seven randomised trials. Setting Outpatient anticoagulant clinics in academic centres. Population 2925 men or women with a first venous thromboembolism who did not have cancer and received different durations of anticoagulant treatment. Main outcome measure First recurrent venous thromboembolism after stopping anticoagulant treatment during up to 24 months of follow-up. Results Recurrence was lower after isolated distal deep vein thrombosis than after proximal deep vein thrombosis (hazard ratio 0.49, 95% confidence interval 0.34 to 0.71), similar after pulmonary embolism and proximal deep vein thrombosis (1.19, 0.87 to 1.63), and lower after thrombosis provoked by a temporary risk factor than after unprovoked thrombosis (0.55, 0.41 to 0.74). Recurrence was higher if anticoagulation was stopped at 1.0 or 1.5 months compared with at 3 months or later (hazard ratio 1.52, 1.14 to 2.02) and similar if treatment was stopped at 3 months compared with at 6 months or later (1.19, 0.86 to 1.65). High rates of recurrence associated with shorter durations of anticoagulation were confined to the first 6 months after stopping treatment. Conclusion Three months of treatment achieves a similar risk of recurrent venous thromboembolism after stopping anticoagulation to a longer course of treatment. Unprovoked proximal deep vein thrombosis and pulmonary embolism have a high risk of recurrence whenever treatment is stopped.

Hemorrhagic Transformation in Acute Ischemic Stroke The MAST-E Study

BACKGROUND AND PURPOSE Hemorrhagic transformation (HT) is the most critical complication of thrombolytics in clinical trials in acute stroke. The aim of this study was to determine the rates and the predictors of HT in the Multicenter Acute Stroke Trial-Europe (MAST-E) study. METHODS We performed a post hoc analysis of MAST-E data designed to assess the safety and efficacy of streptokinase administered intravenously within 6 hours of stroke onset. HT included all intracerebral hemorrhages and symptomatic hemorrhages (SHT) associated with clinical worsening. The predictors of HT and SHT were determined using multivariate modeling. RESULTS Among the 310 patients included, 159 patients had HT and 37 SHT (97 and 33 in the streptokinase group and 62 and 4 in the placebo group, respectively). Patients with SHT had significantly more atrial fibrillation, diabetes mellitus, no heparin use, streptokinase treatment, and early CT signs. In the multivariate analysis, HT was predicted by early CT signs and streptokinase treatment. SHT was predicted by diabetes mellitus, early CT signs, streptokinase treatment, and the interaction between streptokinase treatment and decreased level of consciousness. Among the streptokinase-treated patients, the same predictors remained. CONCLUSIONS The relative risks of HT after streptokinase were in the same range in MAST-E as in other streptokinase and tPA trials. Early CT signs were strong predictors of both HT and SHT, stressing that these patients are at high risk of bleeding. In our study, the predictors of HT and SHT were similar to those of tPA trials in acute stroke.

Pulsatile blood pressure component as predictor of mortality in hypertension: a meta-analysis of clinical trial control groups

Objective Although current guidelines rest exclusively on the measurement of systolic and diastolic blood pressures, the arterial pressure wave is more precisely described as consisting of a pulsatile (pulse pressure) and a steady (mean pressure) component. This study explored the independent roles of pulse pressure and mean pressure as predictors of mortality in a wide range of patients with hypertension. Design and methods This meta-analysis, based on individual patient data, has combined results from the control groups of seven randomized clinical trials conducted in patients with systolo-diastolic or isolated systolic hypertension. The relative hazard rates associated with pulse pressure and mean pressure were calculated using Coxs proportional hazard regression models with stratification for the seven trials and with adjustment for sex, age, smoking and the other pressure. Results A 10 mmHg wider pulse pressure at baseline, which corresponds to approximately one-half of its standard deviation, was independently associated with an increase in risk by 6% for total mortality (P = 0.001), 7% for cardiovascular mortality (P = 0.01), and 7% for fatal coronary accidents (P = 0.03).The corresponding increase in risk of fatal stroke was similar (+6%, P = 0.27) but there were too few strokes to reach statistical significance. In similar analyses, mean pressure was not identified as an independent predictor of these outcomes. Significant interactions of pulse pressure or mean pressure with age suggested that the prognostic power of pulse pressure for fatal stroke was more important at higher age (P = 0.04), whereas the prognostic power of mean pressure for coronary mortality was greatest in the young (P = 0.01). Conclusions In hypertensive patients pulse pressure, not mean pressure, is associated with an increased risk of fatal events. This appears to be true in a broad range of patients with hypertension.

A multicenter, randomized, double-blind, placebo-controlled trial to test efficacy and safety of magnetic resonance imaging-based thrombolysis in wake-up stroke (WAKE-UP).

Rationale In about 20% of acute ischemic stroke patients stroke occurs during sleep. These patients are generally excluded from intravenous thrombolysis. MRI can identify patients within the time-window for thrombolysis (≤4·5 h from symptom onset) by a mismatch between the acute ischemic lesion visible on diffusion weighted imaging (DWI) but not visible on fluid-attenuated inversion recovery (FLAIR) imaging. Aims and hypothesis The study aims to test the efficacy and safety of MRI-guided thrombolysis with tissue plasminogen activator (rtPA) in ischemic stroke patients with unknown time of symptom onset, e.g., waking up with stroke symptoms. We hypothesize that stroke patients with unknown time of symptom onset with a DWI-FLAIR-mismatch pattern on MRI will have improved outcome when treated with rtPA compared to placebo. Design WAKE-UP is an investigator initiated, European, multicentre, randomized, double-blind, placebo-controlled clinical trial. Patients with unknown time of symptom onset who fulfil clinical inclusion criteria (disabling neurological deficit, no contraindications against thrombolysis) will be studied by MRI. Patients with MRI findings of a DWI-FLAIR-mismatch will be randomised to either treatment with rtPA or placebo. Study outcome The primary efficacy endpoint will be favourable outcome defined by modified Rankin Scale 0–1 at day 90. The primary safety outcome measures will be mortality and death or dependency defined by modified Rankin Scale 4–6 at 90 days. Discussion If positive, WAKE-UP is expected to change clinical practice making effective and safe treatment available for a large group of acute stroke patients currently excluded from specific acute therapy.

Cognitive Therapy versus Rogerian Supportive Therapy in Borderline Personality Disorder: Two-Year Follow-Up of a Controlled Pilot Study

Background: To date, there have been no studies comparing cognitive therapy (CT) with Rogerian supportive therapy (RST) in borderline personality disorder. Method: Sixty-five DSM-IV borderline personality disorder outpatients were recruited at 2 centres: Lyon and Marseille. Thirty-three patients were randomly allocated to CT and 32 to RST. The therapists were the same in both groups. Both treatments shared the same duration (1 year) and amount of therapy. Assessment by independent evaluators utilised the Clinical Global Impression (CGI) Scale, the Hamilton Depression Scale, Beck Depression Inventory, Beck Anxiety Inventory, Hopelessness Scale, Young Schema Questionnaire II, Eysenck Impulsivity Venturesomeness Empathy (IVE) Inventory, a self-harming behaviours checklist and scales measuring quality of life and the therapeutic relationship. The response criterion was a score of 3 or less on the CGI, associated with a Hopelessness Scale score of <8. Results: No patient committed suicide during the trial. Fifty-one patients were evaluated at week 24, 38 at week 52 and 21 at week 104. Cognitive therapy retained the patients in therapy for a longer time. The response criterion found no significant between-group differences at any measurement point in the completers. However, at week 24, CT was better than RST on the Hopelessness Scale, IVE scale and regarding the therapeutic relationship. At week 104, the CGI improvement (patient and evaluator) was significantly better in CT than in RST. High baseline depression and impulsivity predicted dropouts. Conclusions: CT retained the patients in therapy longer, showed earlier positive effects on hopelessness and impulsivity, and demonstrated better long-term outcomes on global measures of improvement.