Minimal sufficient balance randomization for sequential randomized controlled trial designs: results from the ESCAPE trial.

BACKGROUND: We describe the implementation of minimal sufficient balance randomization, a covariate-adaptive randomization technique, used for the "Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times" (ESCAPE) trial. METHODS: The ESCAPE trial is a prospective, multicenter, randomized clinical trial that enrolled subjects with the following main inclusion criteria: less than 12 h from symptom onset, age 18 years or older, baseline NIHSS score > 5, ASPECTS score > 5 and computed tomography angiography (CTA) evidence of carotid T/L or M1-segment middle cerebral artery (MCA) occlusion, and at least moderate collaterals by CTA. Patients were randomized using a real-time, dynamic, Internet-based, minimal sufficient balance randomization method that balanced the study arms with respect to baseline covariates including age, sex, baseline NIHSS score, site of arterial occlusion, baseline ASPECTS score and treatment with intravenously administered alteplase. RESULTS: Permutation-based tests of group differences confirmed group balance across several baseline covariates including sex (p = 1.00), baseline NIHSS score (p = 0.95), site of arterial occlusion (p = 1.00), baseline ASPECTS score (p = 0.28), treatment with intravenously administered alteplase (p = 0.31), and age (p = 0.67). CONCLUSION: Results from the ESCAPE trial demonstrate the feasibility and the benefit of this covariate adaptive randomization scheme in small-sample trials and for data monitoring endeavors. TRIAL REGISTRATION: ESCAPE trial - NCT01778335 - at www.clinicaltrials.gov . Registered on 29 January 2013.

Elevated troponin in patients with acute stroke - Is it a true heart attack?

Although the prognostic value of a positive troponin in an acute stroke patient is still uncertain, it is a commonly encountered clinical situation given that Ischemic Heart Disease (IHD) and cerebrovascular disease (CVD) frequently co-exist in the same patient and share similar risk factors. Our objectives in this review are to (1) identify the biologic relationship between acute cerebrovascular stroke and elevated troponin levels, (2) determine the pathophysiologic differences between positive troponin in the setting of acute stroke versus acute myocardial infarction (AMI), and (3) examine whether positive troponin in the setting of acute stroke has prognostic significance. We also will provide an insight analysis of some of the available studies and will provide guidance for a management approach based on the available data according to the current guidelines.

Methods to improve patient recruitment and retention in stroke trials.

BACKGROUND: The success of randomized-controlled stroke trials is dependent on the recruitment and retention of a sufficient number of patients, but fewer than half of all trials meet their target number of patients. METHODS: We performed a search and review of the literature, and conducted a survey and workshop among 56 European stroke trialists, to identify barriers, suggest methods to improve recruitment and retention, and make a priority list of interventions that merit further evaluation. RESULTS: The survey and workshop identified a number of barriers to patient recruitment and retention, from patients' incapacity to consent, to handicaps that prevent patients from participation in trial-specific follow-up. Methods to improve recruitment and retention may include simple interventions with individual participants, funding of research networks, and reimbursement of new treatments by health services only when delivered within clinical trials. The literature review revealed that few methods have been formally evaluated. The top five priorities for evaluation identified in the workshop were as follows: short and illustrated patient information leaflets, nonwritten consent, reimbursement for new interventions only within a study, and monetary incentives to institutions taking part in research (for recruitment); and involvement of patient groups, remote and central follow-up, use of mobile devices, and reminders to patients about their consent to participate (for retention). CONCLUSIONS: Many interventions have been used with the aim of improving recruitment and retention of patients in stroke studies, but only a minority has been evaluated. We have identified methods that could be tested, and propose that such evaluations may be nested within on-going clinical trials.

Phone and Video-Based Modalities of Central Blinded Adjudication of Modified Rankin Scores in an Endovascular Stroke Trial.

BACKGROUND AND PURPOSE: The standard outcome measure in stroke research is modified Rankin scale (mRS) evaluated by local blinded investigators. We aimed to assess feasibility and reliability of 2 central adjudication methods of mRS in the setting of a randomized endovascular stroke trial. METHODS: This is a secondary analysis derived from the Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset (REVASCAT) trial cohort. Primary outcome was distribution of mRS at 90 days. Local evaluation was done by certified investigators masked to treatment assignment using structured face-to-face interviews. In addition, central assessment was performed by 2 independent raters via structured phone interview (n=120) and via video recordings of the face-to-face interviews with local investigators (n=106). Interrater agreement was evaluated using kappa and discordance statistics. Sensitivity analyses for the primary end point using different adjudication approaches were performed. Correlation between mRS obtained with each modality and 24-hour follow-up infarct volumes was studied. RESULTS: Using local evaluation as the reference, higher agreement rates were noted with central video than with central phone evaluations (kw 0.92 [0.88-0.96] versus 0.77 [0.72-0.83]). Discrepancies in mRS scoring between local and central raters (phone- and video-based) were similar in both treatment allocation arms. Sensitivity analyses showed benefit of endovascular treatment irrespective of adjudication method, but higher odds ratios were observed with local evaluations. Final infarct volume was similarly correlated with mRS across all 3 evaluation modalities. CONCLUSIONS: Central adjudication of mRS is feasible, reducing interrater variability and avoiding potential problems related to lack of blinding. Our findings may have implications in the planning of future randomized acute stroke trials, especially in those including nonpharmacological interventions. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379.

Comparison of statistical and operational properties of subject randomization procedures for large multicenter clinical trial treating medical emergencies.

Large multicenter acute stroke trials demand a randomization procedure with a high level of treatment allocation randomness, an effective control on overall and within-site imbalances, and a minimized time delay of study treatment caused by the randomization procedure. Driven by the randomization algorithm design of A Study of the Efficacy and Safety of Activase (Alteplase) in Patients with Mild Stroke (PRISMS) (NCT02072226), this paper compares operational and statistical properties of different randomization algorithms in local, central, and step-forward randomization settings. Results show that the step-forward randomization with block urn design provides better performances over others. If the concern on the potential time delay is not serious and a central randomization system is available, the minimization method with an imbalance control threshold and a biased coin probability could be a better choice.

Statistical analysis plan for the 'Efficacy of Nitric Oxide in Stroke' (ENOS) trial.

High blood pressure is common during the acute phase of stroke and is associated with a poor outcome. However, the management of high blood pressure remains unclear. The 'Efficacy of Nitric Oxide in Stroke' trial tested whether transdermal glyceryl trinitrate, a nitric oxide donor that lowers blood pressure, is safe and effective in improving outcome after acute stroke. Efficacy of Nitric Oxide in Stroke is an international multicenter, prospective, randomized, single-blind, blinded endpoint trial, with funding from the U.K. Medical Research Council. Patients with acute ischemic stroke or intracerebral hemorrhage and systolic blood pressure 140-220 mmHg were randomized to glyceryl trinitrate or no glyceryl trinitrate and, where relevant, to continue or stop prestroke antihypertensive therapy. The primary outcome is shift in modified Rankin Scale at three-months. Patients or relatives gave written informed (proxy) consent, and all sites had research ethics approval. Analyses will be done by intention to treat. This paper and attachment describe the trial's statistical analysis plan, developed prior to unblinding of date. The statistical analysis plan contains design and methods for analyses, and unpopulated tables and figures for the two primary publications and some secondary publications. The database will be locked in late February 2014 in preparation for presentation of the results in May 2014. The data from the trial will improve the precision of the estimates of the overall treatment effects (efficacy and safety) of results from completed trials of blood pressure management in acute stroke, and provide the first large-scale randomized evidence on transdermal glyceryl trinitrate, and of continuing (vs. stopping) prestroke antihypertensive medications, in acute stroke.

Acute combined revascularization in acute ischemic stroke with intracranial arterial occlusion: self-expanding solitaire stent during intravenous thrombolysis.

PURPOSE: To investigate the safety and efficacy of the self-expanding Solitaire stent used during intravenous thrombolysis (IVT) for intracranial arterial occlusion (IAO) in acute ischemic stroke (AIS). MATERIALS AND METHODS: Consecutive nonselected patients with AIS with IAO documented on computed tomographic angiography or magnetic resonance angiography and treated with IVT were included in this prospective study. Stent intervention was initiated and performed during administration of IVT without waiting for any clinical or radiologic signs of potential recanalization. Stroke severity was assessed by National Institutes of Health Stroke Scale (NIHSS), and 90-day clinical outcome was assessed by modified Rankin scale (mRS), with a good outcome defined as an mRS score of 0-2. Recanalization was rated by thrombolysis in cerebral infarction (TICI) scale. RESULTS: Fifty patients (mean age, 66.8 y ± 14.6) had a baseline median NIHSS score of 18.0. Overall recanalization was achieved in 94% of patients, and complete recanalization (ie, TICI 3 flow) was achieved in 72% of patients. The mean time from stroke onset to maximal recanalization was 244.2 minutes ± 87.9, with a median of 232.5 minutes. The average number of device passes was 1.5, with a mean procedure time to maximal recanalization of 49.5 minutes ± 13.0. Symptomatic intracerebral hemorrhage occurred in 6% of patients. The median mRS score at 90 days was 1, and 60% of patients had a good outcome (ie, mRS score 0-2). The overall 3-month mortality rate was 14%. CONCLUSIONS: Combined revascularization with the Solitaire stent during IVT appears to be safe and effective in the treatment of acute IAO.

Efficacy of peripheral interventional radiologists performing endovascular stroke therapy guided by CT perfusion triage of patients.

PURPOSE: To assess safety and efficacy of intraarterial mechanical thrombectomy for treatment of ischemic stroke in a community hospital by peripheral interventional radiologists employing computed tomography (CT) perfusion imaging for patient selection. MATERIALS AND METHODS: Forty patients, 11 men (27.5%) and 29 women (72.5%), were treated between February 2008 and October 2011. Eligible patients had a National Institutes of Health Stroke Scale (NIHSS) score greater than 8 and diagnosis of large-vessel ischemic stroke by head CT angiogram, and met previously reported CT perfusion imaging triage criteria. RESULTS: The baseline NIHSS score was 18.0 ± 7.9 (range, 8-35). Sixteen patients (40%) had a baseline NIHSS score greater than 20. Symptom onset was unknown in five patients. Symptom onset to device time in the remaining 35 patients was 254.8 minutes ± 150.9 (range, 75-775 min). A total of 65% of patients showed thrombolysis in cerebral infarction (TICI) 2a, 2b, or 3 flow following the procedure. Symptomatic intracranial hemorrhage was seen in four patients (10.0%). At 90 days, 32 patients (80%) were alive and eight (20%) had died. The modified Rankin scale (mRS) score at 90 days was no more than 2 in 20 patients (50.0%). The mean mRS score at 90 days was 2.9 ± 2.0 (range, 0-6). NIHSS score at 90 days was 5.1 ± 6.1 (range, 0-24). In patients with successful recanalization (ie, TICI 2 or 3 flow), a good clinical outcome (ie, mRS score ≤ 2) was achieved in 65.3% of patients (mean, 2.4 ± 1.9; range, 0-6), and 90-day mortality rate was 15.4%, compared with 28.6% in patients with TICI 0/1 flow. CONCLUSIONS: Peripheral interventional radiologists who use CT perfusion imaging for patient triage can have good neurologic outcomes and provide sustainable, safe, and complete around-the-clock coverage for endovascular stroke treatment.