Anand Dixit

Endovascular therapy for acute ischaemic stroke: the Pragmatic Ischaemic Stroke Thrombectomy Evaluation (PISTE) randomised, controlled trial

Objective The Pragmatic Ischaemic Thrombectomy Evaluation (PISTE) trial was a multicentre, randomised, controlled clinical trial comparing intravenous thrombolysis (IVT) alone with IVT and adjunctive intra-arterial mechanical thrombectomy (MT) in patients who had acute ischaemic stroke with large artery occlusive anterior circulation stroke confirmed on CT angiography (CTA). Design Eligible patients had IVT started within 4.5 hours of stroke symptom onset. Those randomised to additional MT underwent thrombectomy using any Conformité Européene (CE)-marked device, with target interval times for IVT start to arterial puncture of <90 min. The primary outcome was the proportion of patients achieving independence defined by a modified Rankin Scale (mRS) score of 0–2 at day 90. Results Ten UK centres enrolled 65 patients between April 2013 and April 2015. Median National Institutes of Health Stroke Scale score was 16 (IQR 13–21). Median stroke onset to IVT start was 120 min. In the intention-to-treat analysis, there was no significant difference in disability-free survival at day 90 with MT (absolute difference 11%, adjusted OR 2.12, 95% CI 0.65 to 6.94, p=0.20). Secondary analyses showed significantly greater likelihood of full neurological recovery (mRS 0–1) at day 90 (OR 7.6, 95% CI 1.6 to 37.2, p=0.010). In the per-protocol population (n=58), the primary and most secondary clinical outcomes significantly favoured MT (absolute difference in mRS 0–2 of 22% and adjusted OR 4.9, 95% CI 1.2 to 19.7, p=0.021). Conclusions The trial did not find a significant difference between treatment groups for the primary end point. However, the effect size was consistent with published data and across primary and secondary end points. Proceeding as fast as possible to MT after CTA confirmation of large artery occlusion on a background of intravenous alteplase is safe, improves excellent clinical outcomes and, in the per-protocol population, improves disability-free survival. Trial registration number NCT01745692; Results.

Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke

Background and Purpose— Recent animal studies demonstrate that vagus nerve stimulation (VNS) paired with movement induces movement-specific plasticity in motor cortex and improves forelimb function after stroke. We conducted a randomized controlled clinical pilot study of VNS paired with rehabilitation on upper-limb function after ischemic stroke. Methods— Twenty-one participants with ischemic stroke >6 months before and moderate to severe upper-limb impairment were randomized to VNS plus rehabilitation or rehabilitation alone. Rehabilitation consisted of three 2-hour sessions per week for 6 weeks, each involving >400 movement trials. In the VNS group, movements were paired with 0.5-second VNS. The primary objective was to assess safety and feasibility. Secondary end points included change in upper-limb measures (including the Fugl–Meyer Assessment-Upper Extremity). Results— Nine participants were randomized to VNS plus rehabilitation and 11 to rehabilitation alone. There were no serious adverse device effects. One patient had transient vocal cord palsy and dysphagia after implantation. Five had minor adverse device effects including nausea and taste disturbance on the evening of therapy. In the intention-to-treat analysis, the change in Fugl–Meyer Assessment-Upper Extremity scores was not significantly different (between-group difference, 5.7 points; 95% confidence interval, −0.4 to 11.8). In the per-protocol analysis, there was a significant difference in change in Fugl–Meyer Assessment-Upper Extremity score (between-group difference, 6.5 points; 95% confidence interval, 0.4 to 12.6). Conclusions— This study suggests that VNS paired with rehabilitation is feasible and has not raised safety concerns. Additional studies of VNS in adults with chronic stroke will now be performed. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT01669161.

The SOAR (Stroke subtype, Oxford Community Stroke Project classification, Age, prestroke modified Rankin) score strongly predicts early outcomes in acute stroke

Background Previous prognostic scoring systems in predicting stroke mortality are complex, require multiple measures that vary with time and failed to produce a simple scoring system. Aims/Hypothesis The study aims to derive and internally validate a stroke prognostic scoring system to predict early mortality and hospital length of stay. Methods Data from a UK multicenter stroke register were examined (1997–2010). Using a prior hypothesis based on our and others observations, we selected five patient-related factors (age, gender, stroke subtype, clinical classification, and prestroke disability) as candidate prognostic indicators. An 8-point score was derived based on multiple logistic regression model using four out of five variables. Performance of the model was assessed by plotting the estimated probability of in-hospital death against the actual probability by testing for overfitting (calibration) and area under the curve methods (discrimination). Results The total sample consisted of 12 355 acute stroke patients (ischemic stroke 91·0%). The score predicted both in-patient and seven-day mortality. The crude in-patient mortality were 1·57%, 4·02%, 10·65%, 21·41%, 46·60%, 62·72%, and 75·81% for those who scored 0, 1, 2, 3, 4, 5, and 6, respectively. The calibration of the model revealed no evidence of overfitting (estimated overfitting 0·001). The area under the curve values for both in-hospital and seven-day mortality were 0·79. The score predicted length of stay with a higher score was associated with longer median length of stay in those discharged alive and shorter median length of stay in those who died (P for both <0·001). Conclusions A simple 8-point clinical score is highly predictive of acute stroke mortality and length of hospital stay. It could be used as prognostic tool in service planning and also to risk-stratify patients to use these outcomes as markers of stroke care quality across institutions.

The influence of bolus to infusion delays on plasma tissue plasminogen activator levels

Background Estimates of neuronal loss in acute ischemic stroke show that the typical patient may lose 1·9 million neurons each minute that treatment is delayed. Consequently, significant emphasis has been placed on early evaluation and thrombolysis with tissue plasminogen activator (TPA), the only approved thrombolytic therapy. TPA should be administered as a bolus followed by an immediate infusion because of its short half life. However, in the real life clinical situation, delays in starting the infusion after the bolus can occur. Similarly, once infusion has started, interruptions in the infusion of TPA can also occur. These scenarios may result in lower serum concentrations which could decrease the effectiveness of thrombolysis. We sought to simulate, the influence of bolus infusion delays and also the influence of different intervals of interruptions in the infusion of TPA on serum TPA concentrations. Methods We simulated the effect of multiple intervals of delay after the bolus on serum TPA concentrations using known pharmacokinetics parameters of TPA. The effect of different intervals of interruptions in the infusion of TPA was also determined. The effect of rebolusing with TPA on serum concentrations in the event of significant bolus to infusion delays or significant infusion interruption was also simulated. Results Our data show that delays in starting the infusion may have significant effects on serum TPA concentrations. After the initial bolus, there is a rapid decrease in serum TPA concentrations unless the infusion is started immediately. Greater than 5 min delays in starting the infusion results in a slow gradual increase in serum TPA levels and levels stay well below the target concentrations for significant periods of time. Similarly, interruptions in the infusion of TPA lasting longer than 5 min can also significantly influence TPA levels. Rebolusing with TPA in these scenarios rapidly restores TPA levels to target concentrations. Conclusion Because of its short half life, TPA should be administered as a bolus followed by an immediate infusion. Bolus to infusion delays or interruptions in the infusion of TPA after the bolus may significantly impact serum TPA levels and may reduce the efficacy of thrombolysis. Protocols or administration regimens should be employed to prevent delays or interruptions in the infusion. When delays do occur, rebolusing of TPA may be needed to rapidly restore TPA to target levels.

Smoking cessation and outcome after ischemic stroke or TIA

Objective: To assess whether smoking cessation after an ischemic stroke or TIA improves outcomes compared to continued smoking. Methods: We conducted a prospective observational cohort study of 3,876 nondiabetic men and women enrolled in the Insulin Resistance Intervention After Stroke (IRIS) trial who were randomized to pioglitazone or placebo within 180 days of a qualifying stroke or TIA and followed up for a median of 4.8 years. A tobacco use history was obtained at baseline and updated during annual interviews. The primary outcome, which was not prespecified in the IRIS protocol, was recurrent stroke, myocardial infarction (MI), or death. Cox regression models were used to assess the differences in stroke, MI, and death after 4.8 years, with correction for adjustment variables prespecified in the IRIS trial: age, sex, stroke (vs TIA) as index event, history of stroke, history of hypertension, history of coronary artery disease, and systolic and diastolic blood pressures. Results: At the time of their index event, 1,072 (28%) patients were current smokers. By the time of randomization, 450 (42%) patients had quit smoking. Among quitters, the 5-year risk of stroke, MI, or death was 15.7% compared to 22.6% for patients who continued to smoke (adjusted hazard ratio 0.66, 95% confidence interval 0.48–0.90). Conclusion: Cessation of cigarette smoking after an ischemic stroke or TIA was associated with significant health benefits over 4.8 years in the IRIS trial cohort.

Bolus-Infusion Delays of Alteplase during Thrombolysis in Acute Ischaemic Stroke and Functional Outcome at 3 Months

Background. The efficacy of alteplase in acute ischaemic stroke (AIS) is highly time dependent. Hence, alteplase is administered as soon as possible with a bolus followed by an infusion. Delays between bolus and infusion may occur, but the extent of these delays and the impact on outcome are unclear. Aims. We investigated the extent of bolus-infusion delays and the relationship between delays and stroke outcome. Method. We reviewed medical records of 276 patients who received alteplase for AIS at our centre between April, 2008, and June, 2013. Complete demographic and clinical data including 3-month modified Rankin Score (mRS) from 229 patients were analysed comparing delays of 0–8 and >8 minutes. Results. Overall mean (SD) bolus-infusion delay was 9 (7) minutes. Baseline characteristics were similar apart from more severe strokes in delays >8 minutes. Three-month outcomes were not significantly different although delays >8 minutes had lower functional independence rate (mRS 0-1: 23.1% versus 28.1%; adjusted OR 1.2 (95% CI 0.6 to 2.4, P = 0.68)) and higher mortality rate (18% versus 11%, OR 1.0, 95% CI 0.6 to 1.7, P = 0.95). Conclusions. In this single centre series, bolus-infusion delays of alteplase in AIS were common and no effect of bolus-infusion delays on independence and mortality was found.