Comparison of nonparametric estimators of the expected number of recurrent events.

We compare the performance of nonparametric estimators for the mean number of recurrent events and provide a systematic overview for different recurrent event settings. The mean number of recurrent events is an easily interpreted marginal feature often used for treatment comparisons in clinical trials. Incomplete observations, dependencies between successive events, terminating events acting as competing risk, or gaps between at risk periods complicate the estimation. We use survival multistate models to represent different complex recurrent event situations, profiting from recent advances in nonparametric estimation for non-Markov multistate models, and explain several estimators by using multistate intensity processes, including the common Nelson-Aalen-type estimators with and without competing mortality. In addition to building on estimation of state occupation probabilities in non-Markov models, we consider a simple extension of the Nelson-Aalen estimator by allowing for dependence on the number of prior recurrent events. We pay particular attention to the assumptions required for the censoring mechanism, one issue being that some settings require the censoring process to be entirely unrelated while others allow for state-dependent or event-driven censoring. We conducted extensive simulation studies to compare the estimators in various complex situations with recurrent events. Our practical example deals with recurrent chronic obstructive pulmonary disease exacerbations in a clinical study, which will also be used to illustrate two-sample-inference using resampling.

Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA-REG OUTCOME trial.

AIMS: In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of death from heart failure (HF) or hospitalization for heart failure (HHF) versus placebo in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease. We evaluated post hoc the degree to which covariates mediated the effects of empagliflozin on HHF or HF death. METHODS AND RESULTS: A mediator had to fulfil the following criteria: (i) affected by active treatment, (ii) associated with the outcome, and finally (iii) adjustment for it results in a reduced treatment effect compared with unadjusted analysis. Potential mediators were calculated as change from baseline or updated mean and evaluated in univariable analyses as time-dependent covariates in Cox regression of time to HHF or HF death; those with the largest mediating effects were then included in a multivariable analysis. Increases in heart rate, log urine albumin-to-creatinine ratio (UACR), waist circumference, and uric acid were associated with increased risk of HHF or HF death; increases in high-density lipoprotein cholesterol, estimated glomerular filtration rate, haematocrit, haemoglobin, and albumin were associated with reduced risk of HHF or HF death. In univariable analyses, change from baseline in haematocrit, haemoglobin, albumin, uric acid, and logUACR mediated 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin versus placebo, respectively. Multivariable analysis including haemoglobin, logUACR, and uric acid mediated 85% of risk reduction with similar results when updated means were evaluated. CONCLUSIONS: Changes in haematocrit and haemoglobin were the most important mediators of the reduction in HHF and death from HF in patients with T2DM and established CV disease treated with empagliflozin. Albumin, uric acid, and logUACR had smaller mediating effects in this population.

Generic and specific recurrent neural network models: Applications for large and small scale biopharmaceutical upstream processes.

The calculation of temporally varying upstream process outcomes is a challenging task. Over the last years, several parametric, semi-parametric as well as non-parametric approaches were developed to provide reliable estimates for key process parameters. We present generic and product-specific recurrent neural network (RNN) models for the computation and study of growth and metabolite-related upstream process parameters as well as their temporal evolution. Our approach can be used for the control and study of single product-specific large-scale manufacturing runs as well as generic small-scale evaluations for combined processes and products at development stage. The computational results for the product titer as well as various major upstream outcomes in addition to relevant process parameters show a high degree of accuracy when compared to experimental data and, accordingly, a reasonable predictive capability of the RNN models. The calculated values for the root-mean squared errors of prediction are significantly smaller than the experimental standard deviation for the considered process run ensembles, which highlights the broad applicability of our approach. As a specific benefit for platform processes, the generic RNN model is also used to simulate process outcomes for different temperatures in good agreement with experimental results. The high level of accuracy and the straightforward usage of the approach without sophisticated parameterization and recalibration procedures highlight the benefits of the RNN models, which can be regarded as promising alternatives to existing parametric and semi-parametric methods.

Validation Is Not Verification: Precise Terminology and Scientific Methods in Bioprocess Modeling.

Advanced statistical approaches and new modeling procedures for biopharmaceutical development and manufacturing have received increasing attention. With this forum article, we would like to highlight the need for a consistent terminology and the necessity for appropriate model validation strategies.

Asymptotic properties of the two one-sided t-tests - new insights and the Schuirmann-constant.

The two one-sided t-tests (TOST) method is the most popular statistical equivalence test with many areas of application, i.e., in the pharmaceutical industry. Proper sample size calculation is needed in order to show equivalence with a certain power. Here, the crucial problem of choosing a suitable mean-difference in TOST sample size calculations is addressed. As an alternative concept, it is assumed that the mean-difference follows an a-priori distribution. Special interest is given to the uniform and some centered triangle a-priori distributions. Using a newly developed asymptotical theory a helpful analogy principle is found: every a-priori distribution corresponds to a point mean-difference, which we call its Schuirmann-constant. This constant does not depend on the standard deviation and aims to support the investigator in finding a well-considered mean-difference for proper sample size calculations in complex data situations. In addition to the proposed concept, we demonstrate that well-known sample size approximation formulas in the literature are in fact biased and state their unbiased corrections as well. Moreover, an R package is provided for a right away application of our newly developed concepts.

Artificial neural networks for the prediction of solvation energies based on experimental and computational data.

The knowledge of thermodynamic properties for novel electrolyte formulations is of fundamental interest for industrial applications as well as academic research. Herewith, we present an artificial neural networks (ANN) approach for the prediction of solvation energies and entropies for distinct ion pairs in various protic and aprotic solvents. The considered feed-forward ANN is trained either by experimental data or computational results from conceptual density functional theory calculations. The proposed concept of mapping computed values to experimental data lowers the amount of time-consuming and costly experiments and helps to overcome certain limitations. Our findings reveal high correlation coefficients between predicted and experimental values which demonstrate the validity of our approach.

Action limit outlier test: a novel approach for the identification of outliers in bioassay dose-response curves.

Aim/Materials & methods: Guidelines like United States Pharmacopeia 1032 [1] and pharm.Eur. [2] acknowledge that cell-based bioassays are complex methods and thus prone to outliers. However, investigations into root causes of outliers are often inconclusive. We have established a procedure (including quality control and documentation) implemented in a freely available software application which includes not only the experience of the analyst but also information of historical data. Results: This action limit outlier test is unique to our knowledge. Action limit outlier test allows the determination of outliers efficiently which lead to a significant reduction of false positives in comparison with the traditional outlier test ROUT [3] or Rosner [4] alone as shown by our simulated data (58 and 44% reduction of false positives for ROUT and Rosner, respectively).

Alteplase for Acute Ischemic Stroke in Patients Aged >80 Years: Pooled Analyses of Individual Patient Data.

BACKGROUND/PURPOSE: Expert guidelines specify no upper age limit for alteplase for thrombolysis of acute ischemic stroke (AIS) but, until recently, European regulatory criteria restricted its use to patients aged 18 to 80 years. We performed pooled analyses of randomized controlled trial (RCT) and registry data to evaluate the benefit-risk profile of alteplase for AIS among patients aged >80 years to support a regulatory application to lift the upper age restriction. METHODS: Individual patient data were evaluated from 7 randomized trials of alteplase (0.9 mg/kg) versus placebo or open control for AIS, and the European SITS-UTMOST registry database. Clinical outcomes, including good functional outcome (score 0-1, modified Rankin Scale day 90 or Oxford Handicap Score day 180), were evaluated in the full RCT and registry populations, and specified age-based subgroups (≤80 or >80 years) who met existing European regulatory criteria for alteplase, excluding upper age restriction. RESULTS: Regardless of treatment allocation, 90-day mortality was lower among RCT patients aged ≤80 versus >80 years who otherwise met existing European regulatory criteria (246/2405 [10.2%] versus 307/1028 [29.9%], respectively). Among patients aged >80 years, alteplase versus placebo was associated with a higher proportion of good stroke outcome (modified Rankin Scale score 0-1; 99/518 [19.1%] versus 67/510 [13.1%]; P=0.0109) and similar 90-day mortality (153/518 [29.5%] versus 154/510 [30.2%]; P=0.8382). The odds of a good stroke outcome following alteplase allocation in the full RCT population were independent of age (P=0.7383). Good stroke outcome was reported for almost half (4821/11 169 [43.2%]) of the patients who received alteplase in routine practice. Outcomes in routine practice supported those achieved in RCTs. CONCLUSIONS: Alteplase for AIS has a positive benefit-risk profile among patients aged >80 years when administered according to other regulatory criteria. Alteplase for AIS should be evaluated on an individual benefit-risk basis.

Towards a Digital Bioprocess Replica: Computational Approaches in Biopharmaceutical Development and Manufacturing.

Quantitative unit operation models for the optimization and refinement of modern late-stage biopharmaceutical drug manufacturing processes have recently attracted increasing attention. The supplementary benefits of these models include increased process robustness and control in combination with a more stringent design of the bioprocess due to a reduced number of exploratory experiments. In addition to unit operations, further efforts also focus on digital bioprocess replicas, which are straightforward combinations of unit operation and process models from inoculum to the fill and finish phase. In this review, we shed more light on digital bioprocess replicas in addition to standard unit operation models and discuss their strengths and weaknesses. We comment on the current usage of these approaches for late stage processes and outline the associated benefits, challenges and limitations.

Extending the time window for intravenous thrombolysis in acute ischemic stroke using magnetic resonance imaging-based patient selection.

BACKGROUND: Intravenous thrombolysis with alteplase within a time window up to 4.5 h is the only approved pharmacological treatment for acute ischemic stroke. We studied whether acute ischemic stroke patients with penumbral tissue identified on magnetic resonance imaging 4.5-9 h after symptom onset benefit from intravenous thrombolysis compared to placebo. METHODS: Acute ischemic stroke patients with salvageable brain tissue identified on a magnetic resonance imaging were randomly assigned to receive standard dose alteplase or placebo. The primary end point was disability at 90 days assessed by the modified Rankin scale, which has a range of 0-6 (with 0 indicating no symptoms at all and 6 indicating death). Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events. RESULTS: The trial was stopped early for slow recruitment after the enrollment of 119 (61 alteplase, 58 placebo) of 264 patients planned. Median time to intravenous thrombolysis was 7 h 42 min. The primary endpoint showed no significant difference in the modified Rankin scale distribution at day 90 (odds ratio alteplase versus placebo, 1.20; 95% CI, 0.63-2.27, P = 0.58). One symptomatic intracranial hemorrhage occurred in the alteplase group. Mortality at 90 days did not differ significantly between the two groups (11.5 and 6.8%, respectively; P = 0.53). CONCLUSIONS: Intravenous alteplase administered between 4.5 and 9 h after the onset of symptoms in patients with salvageable tissue did not result in a significant benefit over placebo. (Supported by Boehringer Ingelheim, Germany; ISRCTN 71616222).

How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial.

OBJECTIVE: In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving 7,020 patients with type 2 diabetes and established cardiovascular (CV) disease, empagliflozin given in addition to standard of care reduced the risk of CV death by 38% versus placebo (hazard ratio [HR] 0.62 [95% CI 0.49, 0.77]). This exploratory mediation analysis assesses the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin. RESEARCH DESIGN AND METHODS: Effects of potential mediators, identified post hoc, on the HR for CV death with empagliflozin versus placebo were analyzed by Cox regression models, with treatment group adjusted for the baseline value of the variable and its change from baseline or updated mean (i.e., considering all prior values), each as a time-dependent covariate. HRs were compared with a model without adjustment for covariates. Multivariable analyses also were performed. RESULTS: Changes in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA1c. In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin:creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death. CONCLUSIONS: In this exploratory analysis from the EMPA-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo.

Effects of alteplase for acute stroke according to criteria defining the European Union and United States marketing authorizations: Individual-patient-data meta-analysis of randomized trials.

Background The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke differs between the Europe Union and United States. Aims We compared the effects of alteplase in cohorts defined by the current Europe Union or United States marketing approval labels, and by hypothetical revisions of the labels that would remove the Europe Union upper age limit or extend the United States treatment time window to 4.5 h. Methods We assessed outcomes in an individual-patient-data meta-analysis of eight randomized trials of intravenous alteplase (0.9 mg/kg) versus control for acute ischemic stroke. Outcomes included: excellent outcome (modified Rankin score 0-1) at 3-6 months, the distribution of modified Rankin score, symptomatic intracerebral hemorrhage, and 90-day mortality. Results Alteplase increased the odds of modified Rankin score 0-1 among 2449/6136 (40%) patients who met the current European Union label and 3491 (57%) patients who met the age-revised label (odds ratio 1.42, 95% CI 1.21-1.68 and 1.43, 1.23-1.65, respectively), but not in those outside the age-revised label (1.06, 0.90-1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76-1.25 and 1.01, 0.86-1.19, respectively) but mortality remained higher outside the age-revised label (1.19, 0.99-1.42). Similarly, alteplase increased the odds of modified Rankin score 0-1 among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-h revised approval (odds ratio 1.55, 1.19-2.01 and 1.37, 1.17-1.59, respectively), but not for those outside the 4.5-h revised approval (1.14, 0.97-1.34). By 90 days, no increased mortality remained for the current and 4.5-h revised label cohorts (hazard ratios 0.99, 0.77-1.26 and 1.02, 0.87-1.20, respectively) but mortality remained higher outside the 4.5-h revised approval (1.17, 0.98-1.41). Conclusions An age-revised European Union label or 4.5-h-revised United States label would each increase the number of patients deriving net benefit from alteplase by 90 days after acute ischemic stroke, without excess mortality.

Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes: A Pooled Analysis of 9 Trials.

BACKGROUND: Thrombolytic therapy with intravenous alteplase within 4.5 hours of ischemic stroke onset increases the overall likelihood of an excellent outcome (no, or nondisabling, symptoms). Any improvement in functional outcome distribution has value, and herein we provide an assessment of the effect of alteplase on the distribution of the functional level by treatment delay, age, and stroke severity. METHODS: Prespecified pooled analysis of 6756 patients from 9 randomized trials comparing alteplase versus placebo/open control. Ordinal logistic regression models assessed treatment differences after adjustment for treatment delay, age, stroke severity, and relevant interaction term(s). RESULTS: Treatment with alteplase was beneficial for a delay in treatment extending to 4.5 hours after stroke onset, with a greater benefit with earlier treatment. Neither age nor stroke severity significantly influenced the slope of the relationship between benefit and time to treatment initiation. For the observed case mix of patients treated within 4.5 hours of stroke onset (mean 3 hours and 20 minutes), the net absolute benefit from alteplase (ie, the difference between those who would do better if given alteplase and those who would do worse) was 55 patients per 1000 treated (95% confidence interval, 13-91; P=0.004). CONCLUSIONS: Treatment with intravenous alteplase initiated within 4.5 hours of stroke onset increases the chance of achieving an improved level of function for all patients across the age spectrum, including the over 80s and across all severities of stroke studied (top versus bottom fifth means: 22 versus 4); the earlier that treatment is initiated, the greater the benefit.

Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis.

BACKGROUND: Randomised trials have shown that alteplase improves the odds of a good outcome when delivered within 4·5 h of acute ischaemic stroke. However, alteplase also increases the risk of intracerebral haemorrhage; we aimed to determine the proportional and absolute effects of alteplase on the risks of intracerebral haemorrhage, mortality, and functional impairment in different types of patients. METHODS: We used individual patient data from the Stroke Thrombolysis Trialists' (STT) meta-analysis of randomised trials of alteplase versus placebo (or untreated control) in patients with acute ischaemic stroke. We prespecified assessment of three classifications of intracerebral haemorrhage: type 2 parenchymal haemorrhage within 7 days; Safe Implementation of Thrombolysis in Stroke Monitoring Study's (SITS-MOST) haemorrhage within 24-36 h (type 2 parenchymal haemorrhage with a deterioration of at least 4 points on National Institutes of Health Stroke Scale [NIHSS]); and fatal intracerebral haemorrhage within 7 days. We used logistic regression, stratified by trial, to model the log odds of intracerebral haemorrhage on allocation to alteplase, treatment delay, age, and stroke severity. We did exploratory analyses to assess mortality after intracerebral haemorrhage and examine the absolute risks of intracerebral haemorrhage in the context of functional outcome at 90-180 days. FINDINGS: Data were available from 6756 participants in the nine trials of intravenous alteplase versus control. Alteplase increased the odds of type 2 parenchymal haemorrhage (occurring in 231 [6·8%] of 3391 patients allocated alteplase vs 44 [1·3%] of 3365 patients allocated control; odds ratio [OR] 5·55 [95% CI 4·01-7·70]; absolute excess 5·5% [4·6-6·4]); of SITS-MOST haemorrhage (124 [3·7%] of 3391 vs 19 [0·6%] of 3365; OR 6·67 [4·11-10·84]; absolute excess 3·1% [2·4-3·8]); and of fatal intracerebral haemorrhage (91 [2·7%] of 3391 vs 13 [0·4%] of 3365; OR 7·14 [3·98-12·79]; absolute excess 2·3% [1·7-2·9]). However defined, the proportional increase in intracerebral haemorrhage was similar irrespective of treatment delay, age, or baseline stroke severity, but the absolute excess risk of intracerebral haemorrhage increased with increasing stroke severity: for SITS-MOST intracerebral haemorrhage the absolute excess risk ranged from 1·5% (0·8-2·6%) for strokes with NIHSS 0-4 to 3·7% (2·1-6·3%) for NIHSS 22 or more (p=0·0101). For patients treated within 4·5 h, the absolute increase in the proportion (6·8% [4·0% to 9·5%]) achieving a modified Rankin Scale of 0 or 1 (excellent outcome) exceeded the absolute increase in risk of fatal intracerebral haemorrhage (2·2% [1·5% to 3·0%]) and the increased risk of any death within 90 days (0·9% [-1·4% to 3·2%]). INTERPRETATION: Among patients given alteplase, the net outcome is predicted both by time to treatment (with faster time increasing the proportion achieving an excellent outcome) and stroke severity (with a more severe stroke increasing the absolute risk of intracerebral haemorrhage). Although, within 4·5 h of stroke, the probability of achieving an excellent outcome with alteplase treatment exceeds the risk of death, early treatment is especially important for patients with severe stroke. FUNDING: UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

European Cooperative Acute Stroke Study-4: Extending the time for thrombolysis in emergency neurological deficits ECASS-4: ExTEND.

RATIONALE AND HYPOTHESIS: Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is an effective and approved therapy for acute ischemic stroke within 4.5 h of onset except for USA, Canada, Croatia, and Moldovia with a current 3 h label. We hypothesized that ischemic stroke patients selected with significant penumbral mismatch on magnetic resonance imaging (MRI) at 4.5-9 h after onset of stroke will have improved clinical outcomes when given intravenous rt-PA (alteplase) compared to placebo. STUDY DESIGN: ECASS-4: ExTEND is an investigator driven, phase 3, randomized, multi-center, double-blind, placebo-controlled study. Ischemic stroke patients presenting within 4.5 and 9 h of stroke onset, who fulfil clinical requirements (National Institutes of Health Stroke Score (NIHSS) 4-26 and pre-stroke modified Rankin Scale (mRS) 0-1) will undergo MRI. Patients who meet imaging criteria (infarct core volume <100 ml, perfusion lesion: infarct core mismatch ratio >1.2 and perfusion lesion minimum volume of 20 ml) additionally will be randomized to either rt-PA or placebo. STUDY OUTCOME: The primary outcome measure will be the categorical shift in the mRS at day 90. Clinical secondary outcomes will be disability at day 90 dichotomized as favorable outcome mRS 0-1 at day 90. Tertiary endpoints include reduction in the NIHSS by 11 or more points or reaching 0-1 at day 90, reperfusion and recanalization at 24 h post stroke as well as depression, life quality, and cognitive impairment at day 90. Safety endpoints will include symptomatic intracranial hemorrhage (ICH) and death.

Online Tool to Improve Stratification of Adverse Events in Stroke Clinical Trials.

BACKGROUND AND PURPOSE: Knowing characteristic adverse events (AEs) and their incidence among patients participating in acute stroke trials may assist interpretation of future studies. We aimed to develop an online tool to inform stroke trial safety. METHODS: We identified relevant AEs from patients within the Virtual International Stroke Trials Archive (VISTA), using receiver operating characteristic principles. We modeled their incidence on patient age, baseline National Institutes of Health Stroke Scale, and comorbidities using binary logistic regression. Models with an R(2) >5% were deemed powerful enough to predict expected AE incidences and were included. The calculator was developed using programs R and Visual Studios. RESULTS: Forty-eight of the most common AEs were identified and incorporated into the IschAEmic Stroke Calculator. The calculator, publicly available at http://www.vistacollaboration.org calculates the expected incidence of AEs or groups of AEs in a trial cohort and where possible compares them with the observed incidence. CONCLUSIONS: The IschAEmic Stroke Calculator is an open access resource to support safety interpretation within acute stroke trials. Prediction of AEs with higher likelihood of occurrence may direct preventive clinical measures.

The SITS-UTMOST: A registry-based prospective study in Europe investigating the impact of regulatory approval of intravenous Actilyse in the extended time window (3-4.5 h) in acute ischaemic stroke.

INTRODUCTION: The SITS-UTMOST (Safe Implementation of Thrombolysis in Upper Time window Monitoring Study) was a registry-based prospective study of intravenous alteplase used in the extended time window (3-4.5 h) in acute ischaemic stroke to evaluate the impact of the approval of the extended time window on routine clinical practice. PATIENTS AND METHODS: Inclusion of at least 1000 patients treated within 3-4.5 h according to the licensed criteria and actively registered in the SITS-International Stroke Thrombolysis Registry was planned. Prospective data collection started 2 May 2012 and ended 2 November 2014. A historical cohort was identified for 2 years preceding May 2012. Clinical management and outcome were contrasted between patients treated within 3 h versus 3-4.5 h in the prospective cohort and between historical and prospective cohorts for the 3 h time window. Outcomes were functional independency (modified Rankin scale, mRS) 0-2, favourable outcome (mRS 0-1), and death at 3 months and symptomatic intracerebral haemorrhage (SICH) per SITS. RESULTS: 4157 patients from 81 centres in 12 EU countries were entered prospectively (N = 1118 in the 3-4.5 h, N = 3039 in the 0-3 h time window) and 3454 retrospective patients in the 0-3 h time window who met the marketing approval conditions. In the prospective cohort, median arrival to treatment time was longer in the 3-4.5 h than 3 h window (79 vs. 55 min). Within the 3 h time window, treatment delays were shorter for prospective than historical patients (55 vs. 63). There was no significant difference between the 3-4.5 h versus 3 h prospective cohort with regard to percentage of reported SICH (1.6 vs. 1.7), death (11.6 vs. 11.1), functional independency (66 vs. 65) at 3 months or favourable outcome (51 vs. 50). DISCUSSION: Main weakness is the observational design of the study. CONCLUSION: This study neither identified negative impact on treatment delay, nor on outcome, following extension of the approved time window to 4.5 h for use of alteplase in stroke.

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.

BACKGROUND: The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known. METHODS: We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. RESULTS: A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events. CONCLUSIONS: Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).

Development and validation of a simplified Stroke-Thrombolytic Predictive Instrument.

OBJECTIVES: The Stroke-Thrombolytic Predictive Instrument (Stroke-TPI) predicts the probability of good and bad outcomes with and without recombinant tissue plasminogen activator (rtPA). We sought to rebuild and externally validate a simpler Stroke-TPI to support implementation in routine clinical care. METHODS: Using the original derivation cohort of 1,983 patients from a combined database of randomized clinical trials (NINDS [National Institute of Neurological Disorders and Stroke] 1 and 2; ATLANTIS [Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke] A and B; and ECASS [European Cooperative Acute Stroke Study] II), we simplified the Stroke-TPI by reducing variables and interaction terms and by exploring simpler (3- and 8-item) stroke severity scores. External validation was performed in the ECASS III trial (n = 821). RESULTS: The following 6 variables were most predictive of good outcomes: age, systolic blood pressure, diabetes, stroke severity, symptom onset to treatment time, and rtPA therapy. Treatment effect modifiers included onset to treatment time and systolic blood pressure. For the models predicting a bad outcome (modified Rankin Scale [mRS] score ≥5), significant variables included age, stroke severity, and serum glucose. rtPA therapy did not change the risk of a poor outcome. Compared with models using the full NIH Stroke Scale, models using the 3-item severity score showed similar discrimination and excellent calibration. External validation on ECASS III showed similar performance (C statistics 0.75 [mRS score ≤1] and 0.80 [mRS score ≤2]). CONCLUSION: A simpler model using a 3-item stroke severity score, instead of the 15-item NIH Stroke Scale, has similar prognostic value and may be easier to use in routine care. Future studies are needed to test whether it can improve process and clinical outcomes.