Rachael L. Fulton

Contemporary Outcome Measures in Acute Stroke Research Choice of Primary Outcome Measure

Background and Purpose— The diversity of available outcome measures for acute stroke trials is challenging and implies that the scales may be imperfect. To assist researchers planning trials and to aid interpretation, this article reviews and makes recommendations on the available choices of scales. The aim is to identify an approach that will be universally accepted and that should be included in most acute trials, without seeking to restrict options for special circumstances. Methods— The article considers outcome measures that have been widely used or are currently advised. It examines desirable properties for outcome measures such as validity, relevance, responsiveness, statistical properties, availability of training, cultural and language issues, resistance to comorbidity, as well as potential weaknesses. Tracking and agreement among outcomes are covered. Results— Typical ranges of scores for the common scales are described, along with their statistical properties, which in turn influence optimal analytic techniques. The timing of recovery on scores and usual practice in trial design are considered. Conclusions— The preferred outcome measure for acute trials is the modified Rankin Scale, assessed at 3 months after stroke onset or later. The interview should be conducted by a certified rater and should involve both the patient and any relevant caregiver. Incremental benefits at any level of the modified Rankin Scale may be acceptable. The modified Rankin Scale is imperfect but should be retained in its present form for comparability with existing treatment comparisons. No second measure should be required, but correlations with supporting scales may be used to confirm consistency in direction of effects on other measures.

Seven-Day NIHSS Is a Sensitive Outcome Measure for Exploratory Clinical Trials in Acute Stroke Evidence From the Virtual International Stroke Trials Archive

Background and Purpose— Clinical trials in stroke typically measure outcome after 90 days. Earlier outcome assessment would reduce costs and may increase power. We aimed to compare the sensitivity of 4 end points (modified Rankin Scale [mRS] at 30 and 90 days, and National Institutes of Health Stroke Scale (NIHSS) at 7 and 90 days, analyzed as ordinal measures) to detect the established treatment effect of recombinant tissue-type plasminogen activator (rtPA). Methods— Within the Virtual International Stroke Trials Archive, we compared rtPA–treated patients with untreated control subjects using a multiple resampling approach. From our total sample we drew 10 000 random samples of unique patients, constraining the sample sizes in treated and untreated groups to be equal. In each of these samples we tested for the treatment effect of rtPA by each of the 4 studied end points. The percentage of samples yielding significant results approximates the power of each end point at a given sample size. This process was repeated across a range of sample sizes, to determine the relationship between sample size and power for each of the 4 end points. Results— For our 4 end points of mRS at 30 and 90 days, and NIHSS at 7 and 90 days the smallest sample sizes required to generate statistical power >80% were 620, 480, 370, and 420, respectively, making 7-day NIHSS the most sensitive end point. These results were supported by dichotomized analyses. Conclusions— Seven-day NIHSS score appears a sensitive end point that should be validated in randomized trial datasets for use in exploratory stroke trials.

Transcranial Laser Therapy in Acute Stroke Treatment Results of Neurothera Effectiveness and Safety Trial 3, a Phase III Clinical End Point Device Trial

Background and Purpose— On the basis of phase II trials, we considered that transcranial laser therapy could have neuroprotective effects in patients with acute ischemic stroke. Methods— We studied transcranial laser therapy in a double-blind, sham-controlled randomized clinical trial intended to enroll 1000 patients with acute ischemic stroke treated ⩽24 hours after stroke onset and who did not undergo thrombolytic therapy. The primary efficacy measure was the 90-day functional outcome as assessed by the modified Rankin Scale, with hierarchical Bayesian analysis incorporating relevant previous data. Interim analyses were planned after 300 and 600 patients included. Results— The study was terminated on recommendation by the Data Monitoring Committee after a futility analysis of 566 completed patients found no difference in the primary end point (transcranial laser therapy 140/282 [49.6%] versus sham 140/284 [49.3%] for good functional outcome; modified Rankin Scale, 0–2). The results remained stable after inclusion of all 630 randomized patients (adjusted odds ratio, 1.024; 95% confidence interval, 0.705–1.488). Conclusions— Once the results of the interim futility analysis became available, all study support was immediately withdrawn by the capital firms behind PhotoThera, and the company was dissolved. Proper termination of the trial was difficult but was finally achieved through special efforts by former employees of PhotoThera, the CRO Parexel and members of the steering and the safety committees. We conclude that transcranial laser therapy does not have a measurable neuroprotective effect in patients with acute ischemic stroke when applied within 24 hours after stroke onset. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01120301.

Risk of Stroke in Chronic Heart Failure Patients Without Atrial Fibrillation Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials

Introduction: The contemporary incidence of stroke in patients with heart failure (HF) but not in atrial fibrillation (AF) is uncertain. Furthermore, there may be a subset of such patients with a risk of stroke sufficient to justify anticoagulant prophylaxis. We report the incidence of stroke in HF patients with and without AF. We also describe predictors of stroke in patients without AF. These identify subjects with a risk of stroke as high as in patients with AF and who might merit anticoagulation. Methods: We determined the incidence of stroke in HF patients in the Controlled Rosuvastatin in Multinational Trial Heart Failure trial (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiac- Heart Failure trial (GISSI-HF). Multivariable (MV) Cox regression models for stroke in patients without AF were built using 10 routine clinical and laboratory variables derived from univariable analysis of 25 baseline variables and variables identified from review of prior studies of stroke predictors. Results: A total of 9,585 patients were included. Of these, 6,054 had no AF. The median overall follow-up time was 3.10 (IQR: 2.38-3.82) years and 371 patients experienced a stroke (rate 13.1 per 1000 patient-years). The stroke rates in patients with and without AF were, 16.8 per 1000 patient-years and 11.1 per 1000 patient-years, respectively. In MV analysis, age, body mass index, NYHA class, insulin-treated diabetes, and history of previous stroke were the only independent predictors of stroke. Using the risk score formulated from this model, patients in the upper tertile had a rate of stroke that exceeded that of the patients with AF (19.3 per 1000 patient-years). Conclusions: In a large contemporary HF population, we found that a third of patients without AF have a risk of stroke that is at least as great as in HF patients with AF. This high-risk subset can be identified using simple clinical variables. A clinical trial of prophylactic anticoagulation is merited in these patients.Background— Our aim was to describe the incidence and predictors of stroke in patients who have heart failure without atrial fibrillation (AF). Methods and Results— We pooled 2 contemporary heart failure trials, the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca-Heart Failure trial (GISSI-HF). Of the 9585 total patients, 6054 did not have AF. Stroke occurred in 165 patients (4.7%) with AF and in 206 patients (3.4%) without AF (rates 16.8/1000 patient-years and 11.1/1000 patient-years, respectively). Using Cox proportional-hazards models, we identified the following independent predictors of stroke in patients without AF (ranked by &khgr;2 value): age (hazard ratio, 1.34; 95% confidence interval, 1.18–1.63 per 10 years), New York Heart Association class (1.60, 1.21–2.12 class III/IV versus II), diabetes mellitus treated with insulin (1.87, 1.22–2.88), body mass index (0.74, 0.60–0.91 per 5 kg/m2 up to 30), and previous stroke (1.81, 1.19–2.74). N-terminal pro B-type natriuretic peptide (available in 2632 patients) was also an independent predictor of stroke (hazard ratio, 1.31; 1.11–1.57 per log unit) when added to this model. With the use of a risk score formulated from these predictors, we found that patients in the upper third of risk had a rate of stroke that approximated the risk in patients with AF. Conclusions— A small number of demographic and clinical variables identified a subset of patients who have heart failure without AF at a high risk of stroke.

Risk of Stroke in Chronic Heart Failure Patients without Atrial Fibrillation: Analysis of the CORONA and GISSI-HF Trials

Introduction: The contemporary incidence of stroke in patients with heart failure (HF) but not in atrial fibrillation (AF) is uncertain. Furthermore, there may be a subset of such patients with a risk of stroke sufficient to justify anticoagulant prophylaxis. We report the incidence of stroke in HF patients with and without AF. We also describe predictors of stroke in patients without AF. These identify subjects with a risk of stroke as high as in patients with AF and who might merit anticoagulation. Methods: We determined the incidence of stroke in HF patients in the Controlled Rosuvastatin in Multinational Trial Heart Failure trial (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiac- Heart Failure trial (GISSI-HF). Multivariable (MV) Cox regression models for stroke in patients without AF were built using 10 routine clinical and laboratory variables derived from univariable analysis of 25 baseline variables and variables identified from review of prior studies of stroke predictors. Results: A total of 9,585 patients were included. Of these, 6,054 had no AF. The median overall follow-up time was 3.10 (IQR: 2.38-3.82) years and 371 patients experienced a stroke (rate 13.1 per 1000 patient-years). The stroke rates in patients with and without AF were, 16.8 per 1000 patient-years and 11.1 per 1000 patient-years, respectively. In MV analysis, age, body mass index, NYHA class, insulin-treated diabetes, and history of previous stroke were the only independent predictors of stroke. Using the risk score formulated from this model, patients in the upper tertile had a rate of stroke that exceeded that of the patients with AF (19.3 per 1000 patient-years). Conclusions: In a large contemporary HF population, we found that a third of patients without AF have a risk of stroke that is at least as great as in HF patients with AF. This high-risk subset can be identified using simple clinical variables. A clinical trial of prophylactic anticoagulation is merited in these patients.Background— Our aim was to describe the incidence and predictors of stroke in patients who have heart failure without atrial fibrillation (AF). Methods and Results— We pooled 2 contemporary heart failure trials, the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca-Heart Failure trial (GISSI-HF). Of the 9585 total patients, 6054 did not have AF. Stroke occurred in 165 patients (4.7%) with AF and in 206 patients (3.4%) without AF (rates 16.8/1000 patient-years and 11.1/1000 patient-years, respectively). Using Cox proportional-hazards models, we identified the following independent predictors of stroke in patients without AF (ranked by &khgr;2 value): age (hazard ratio, 1.34; 95% confidence interval, 1.18–1.63 per 10 years), New York Heart Association class (1.60, 1.21–2.12 class III/IV versus II), diabetes mellitus treated with insulin (1.87, 1.22–2.88), body mass index (0.74, 0.60–0.91 per 5 kg/m2 up to 30), and previous stroke (1.81, 1.19–2.74). N-terminal pro B-type natriuretic peptide (available in 2632 patients) was also an independent predictor of stroke (hazard ratio, 1.31; 1.11–1.57 per log unit) when added to this model. With the use of a risk score formulated from these predictors, we found that patients in the upper third of risk had a rate of stroke that approximated the risk in patients with AF. Conclusions— A small number of demographic and clinical variables identified a subset of patients who have heart failure without AF at a high risk of stroke.

Allopurinol Initiation and Change in Blood Pressure in Older Adults With Hypertension

Hypertension is a key risk factor for cardiovascular disease, and new treatments are needed. Uric acid reduction lowers blood pressure (BP) in adolescents, suggesting a direct pathophysiological role in the development of hypertension. Whether the same relationship is present in older adults is unknown. We explored change in BP after allopurinol initiation using data from the UK Clinical Practice Research Datalink. Data were extracted for patients with hypertension aged >65 years who were prescribed allopurinol with pretreatment and during treatment BP readings. Data from comparable controls were extracted. The change in BP in patients with stable BP medication was the primary outcome and was compared between groups. Regression analysis was used to adjust for potential confounding factors, and a propensity-matched sample was generated. Three hundred sixty-five patients who received allopurinol and 6678 controls were included. BP fell in the allopurinol group compared with controls (between-group difference in systolic and diastolic BP: 2.1 mm Hg; 95% confidence interval, −0.6 to 4.8; and 1.7 mm Hg; 95% confidence interval, 0.4–3.1, respectively). Allopurinol use was independently associated with a fall in both systolic and diastolic BP on regression analysis (P<0.001). Results were consistent in the propensity-matched sample. There was a trend toward greater fall in BP in the high-dose allopurinol group, but change in BP was not related to baseline uric acid level. Allopurinol use is associated with a small fall in BP in adults. Further studies of the effect of high-dose allopurinol in adults with hypertension are needed.

Risk Factors of Ischemic Stroke and Subsequent Outcome in Patients Receiving Hemodialysis

Background and Purpose— End-stage renal disease (ESRD) requiring hemodialysis carries up to a 10-fold greater risk of stroke than normal renal function. Knowledge on risk factors and management strategies derived from the general population may not be applicable to those with ESRD. We studied a large ESRD population to identify risk factors and outcomes for stroke. Methods— All adult patients receiving hemodialysis for ESRD from January 1, 2007, to December 31, 2012, were extracted from the electronic patient record. Variables associated with stroke were identified by survival analysis; demographic, clinical, imaging, and dialysis-related variables were assessed, and case-fatality was determined. Follow-up was until December 31, 2013. Results— A total of 1382 patients were identified (mean age, 60.5 years; 58.5% men). The prevalence of atrial fibrillation was 21.2%, and 59.4% were incident hemodialysis patients. One hundred and sixty patients (11.6%) experienced a stroke during 3471 patient-years of follow-up (95% ischemic). Stroke incidence was 41.5/1000 patient-years in prevalent and 50.1/1000 patient-years in incident hemodialysis patients. Factors associated with stroke on regression analysis were prior stroke, diabetes mellitus, and age at starting renal replacement therapy. Atrial fibrillation was not significantly associated with stroke, and warfarin did not affect stroke risk in warfarin-treated patients. Fatality was 18.8% at 7 days, 26.9% at 28 days, and 56.3% at 365 days after stroke. Conclusions— Incidence of stroke is high in patients with ESRD on hemodialysis with high case-fatality. Incident hemodialysis patients had the highest stroke incidence. Many, but not all, important risk factors commonly associated with stroke in the general population were not associated with stroke in patients receiving hemodialysis.

Association of improved outcome in acute ischaemic stroke patients with atrial fibrillation who receive early antithrombotic therapy: analysis from VISTA.

Ischaemic stroke patients with atrial fibrillation (AF) are at risk of early recurrent stroke (RS). However, antithrombotics commenced at the acute stage may exacerbate haemorrhagic transformation, provoking symptomatic intracerebral haemorrhage (SICH). The relevance of antithrombotics on the patterns and outcome of the cohort was investigated.

Impact of Atrial Fibrillation on Outcome in Thrombolyzed Patients With Stroke: Evidence From the Virtual International Stroke Trials Archive (VISTA)

Background and Purpose— Atrial fibrillation has been considered a risk factor for poor outcome from acute stroke and may influence response to thrombolysis, although supporting data are limited due to potential confounding with age and stroke severity. Method— We assessed the association of atrial fibrillation and thrombolysis exposure with the modified Rankin Scale score distribution at 90 days among patients registered in a trials archive. We used an age and baseline National Institutes of Health Stroke Scale-adjusted Cochran-Mantel-Haenszel test to test significance (P) followed by proportional odds logistic regression analysis to estimate the ORs for improved modified Rankin Scale score. Results— Data were available for 7091 patients, of whom 3027 were thrombolyzed. A total of 1631 patients had a history of atrial fibrillation, of whom 639 were thrombolyzed. Among patients with atrial fibrillation, baseline severity was greater (median baseline National Institutes of Health Stroke Scale, 14 versus 12; P<0.001) and age was higher (mean age, 74.0 versus 66.5; P<0.001). An association of treatment with outcome was seen independently and was of similar magnitude within patients with atrial fibrillation (OR, 1.44; 95% CI, 1.12–1.73; P<0.001) and without atrial fibrillation (OR, 1.53; 95% CI, 1.39–1.69; P<0.001). No association of atrial fibrillation and overall stroke outcome could be found (OR, 0.93; 95% CI, 0.84–1.03; P=0.409). Conclusion— In this nonrandomized comparison, presence of atrial fibrillation had no independent impact on stroke outcome and compared with untreated comparators, the patients who received thrombolysis experienced an advantage in outcomes that was of equal magnitude whether in the presence or absence of atrial fibrillation.

A Case Study in Model-driven Synthetic Biology

We report on a case study in synthetic biology, demonstrating the model-driven design of a self-powering electrochemical biosensor. An essential result of the design process is a general template of a biosensor, which can be instantiated to be adapted to specific pollutants. This template represents a gene expression network extended by metabolic activity. We illustrate the model-based analysis of this template using qualitative, stochastic and continuous Petri nets and related analysis techniques, contributing to a reliable and robust design.