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

Stroke outcome in clinical trial patients deriving from different countries

<p><b>Background and Purpose:</b> Stroke incidence and outcome vary widely within and across geographical locations. We examined whether differences in index stroke severity, stroke risk factors, mortality, and stroke outcome across geographical locations remain after adjusting for case mix.</p> <p><b>Methods:</b> We analyzed 3284 patients from the Virtual International Stroke Trials Archive (VISTA). We used logistic regression to examine the incidence of mild index stroke, functional, and neurological outcomes after accounting for age, medical history, year of trial recruitment, and initial stroke severity in the functional and neurological outcome analyses. We examined mortality between geographical regions using a Cox proportional hazards model, accounting for age, initial stroke severity, medical history, and year of trial recruitment.</p> <p><b>Results</b> Patients enrolled in the USA and Canada had the most severe index strokes. Those recruited in Austria and Switzerland had the best functional and neurological outcomes at 90 days (P<0.05), whereas those enrolled in Germany had the worst functional outcome at 90 days (P=0.013). Patients enrolled in Austria, Switzerland, Belgium, Netherlands, Finland, Germany, Greece, Israel, Spain, and Portugal had a significantly better survival rate when compared with those enrolled in USA and Canada. Patients enrolled in trials after 1998 had more severe index strokes, with no significant difference in outcome compared with those enrolled before 1998.</p> <p><b>Conclusion:</b> We identified regional variations in index stroke severity, outcome, and mortality for patients enrolled in ischemic stroke clinical trials over the past 13 years that were not fully explained by case mix. Index stroke severity was greater in patients enrolled after 1998, with no significant improvement in outcomes compared to those enrolled before 1998.</p&gt

Patient-Reported Satisfaction and Study Drug Discontinuation: Post-Hoc Analysis of Findings from ROCKET AF.

IntroductionPatient-reported outcomes (PROs) and satisfaction endpoints are increasingly important in clinical trials and may be associated with treatment adherence. In this post hoc substudy from ROCKET AF, we examined whether patient-reported satisfaction was associated with study drug discontinuation.MethodsROCKET AF (n = 14,264) compared rivaroxaban with warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. We analyzed treatment satisfaction scores: the Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). We compared satisfaction with study drug between the two treatment arms, and examined the association between satisfaction and patient-driven study drug discontinuation (stopping study drug due to withdrawal of consent, noncompliance, or loss to follow-up).ResultsA total of 1577 (11%) patients participated in the Patient Satisfaction substudy; 1181 (8.3%) completed both the ACTS and TSQM II 4 weeks after starting study drug. Patients receiving rivaroxaban did not experience significant differences in satisfaction compared with those receiving warfarin. During a median follow-up of 1.6 years, 448 premature study drug discontinuations occurred (213 rivaroxaban group; 235 warfarin group), of which 116 (26%) were patient-driven (52 [24%] rivaroxaban group; 64 [27%] warfarin group). No significant differences were observed between satisfaction level and rates of patient-driven study drug discontinuation.ConclusionsStudy drug satisfaction did not predict rate of study drug discontinuation. No significant difference was observed between satisfaction with warfarin and rivaroxaban, as expected given the double-blind trial design. Although these results are negative, the importance of PRO data will only increase, and these analyses may inform future studies that explore the relationship between drug-satisfaction PROs, adherence, and clinical outcomes. CLINICALTRIALS.GOV: NCT00403767.FundingThe ROCKET AF trial was funded by Johnson & Johnson and Bayer

The Virtual International Stroke Trials Archive

BACKGROUND AND PURPOSE: Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses. METHODS: Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing. RESULTS: Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on \u3e15,000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 69+/-12 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials. CONCLUSIONS: This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning

European Stroke Science Workshop

The European Stroke Organisation held its first European Stroke Science Workshop in Garmisch-Partenkirchen, Germany (December 15-17, 2011). Stroke experts based in Europe were invited to present and discuss their current research. The scope of the workshop was to review the most recent findings of selected topics in stroke, to exchange ideas, to stimulate new research, and to enhance collaboration between European stroke research groups. Seven scientific sessions were held, each starting with a keynote lecture to review the state of the art of the given topic, followed by 4 or 5 short presentations by experts. They were asked to limit their presentations to 10 slides containing only recent information. The meeting was organized by the executive committee of the European Stroke Organisation (Heinrich Mattle, chairman, Michael Brainin, Angel Chamorro, Werner Hacke, Didier Leys) and supported by the European Stroke Conference (Michael Hennerici). The following sections summarize the content of the workshop. Copyright (c) 2012 S. Karger AG, Base

International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world. We aimed to provide comprehensive data on international patterns of AF stroke prevention treatment. METHODS: Demographics, comorbidities, and stroke risk of the patients in the GARFIELD-AF (n=51,270), ORBIT-AF I (n=10,132), and ORBIT-AF II (n=11,602) registries were compared (overall N=73,004 from 35 countries). Stroke prevention therapies were assessed among patients with new-onset AF (≤6 weeks). RESULTS: Patients from GARFIELD-AF were less likely to be white (63% vs 89% for ORBIT-AF I and 86% for ORBIT-AF II) or have coronary artery disease (19% vs 36% and 27%), but had similar stroke risk (85% CHA2DS2-VASc ≥2 vs 91% and 85%) and lower bleeding risk (11% with HAS-BLED ≥3 vs 24% and 15%). Oral anticoagulant use was 46% and 57% for patients with a CHA2DS2-VASc=0 and 69% and 87% for CHA2DS2-VASc ≥2 in GARFIELD-AF and ORBIT-AF II, respectively, but with substantial geographic heterogeneity in use of oral anticoagulant (range: 31%-93% [GARFIELD-AF] and 66%-100% [ORBIT-AF II]). Among patients with new-onset AF, non-vitamin K antagonist oral anticoagulant use increased over time to 43% in 2016 for GARFIELD-AF and 71% for ORBIT-AF II, whereas use of antiplatelet monotherapy decreased from 36% to 17% (GARFIELD-AF) and 18% to 8% (ORBIT-AF I and II). CONCLUSIONS: Among new-onset AF patients, non-vitamin K antagonist oral anticoagulant use has increased and antiplatelet monotherapy has decreased. However, anticoagulation is used frequently in low-risk patients and inconsistently in those at high risk of stroke. Significant geographic variability in anticoagulation persists and represents an opportunity for improvement

Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy:data from the ROCKET AF clinical trial

Background: Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial. Methods and Results: TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i‐TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i‐TTR was 55.2% (SD 21.3%) and the median i‐TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR 3 was 15.7%. While multiple clinical features were associated with i‐TTR, dominant determinants were previous warfarin use (mean i‐TTR of 61.1% for warfarin‐experienced versus 47.4% in VKA‐naïve patients) and geographic region where patients were managed (mean i‐TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i‐TTRs had INR distributions shifted toward lower INR values and had longer inter‐INR test intervals. Conclusions: Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i‐TTR in global studies of warfarin. Regional differences in mean i‐TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing

Mechanical thrombectomy in acute ischemic stroke : Consensus statement by ESO-Karolinska Stroke Update 2014/2015, supported by ESO, ESMINT, ESNR and EAN

The original version of this consensus statement on mechanical thrombectomy was approved at the European Stroke Organisation (ESO)-Karolinska Stroke Update conference in Stockholm, 16-18 November 2014. The statement has later, during 2015, been updated with new clinical trials data in accordance with a decision made at the conference. Revisions have been made at a face-to-face meeting during the ESO Winter School in Berne in February, through email exchanges and the final version has then been approved by each society. The recommendations are identical to the original version with evidence level upgraded by 20 February 2015 and confirmed by 15 May 2015. The purpose of the ESO-Karolinska Stroke Update meetings is to provide updates on recent stroke therapy research and to discuss how the results may be implemented into clinical routine. Selected topics are discussed at consensus sessions, for which a consensus statement is prepared and discussed by the participants at the meeting. The statements are advisory to the ESO guidelines committee. This consensus statement includes recommendations on mechanical thrombectomy after acute stroke. The statement is supported by ESO, European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), and European Academy of Neurology (EAN).Peer reviewe

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe