Association of Time to Thrombolysis With Early Reperfusion After Alteplase and Tenecteplase in Patients With Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: Early treatment with intravenous alteplase increases the probability of lytic-induced reperfusion in large vessel occlusion (LVO) patients. The relationship of tenecteplase-induced reperfusion and the timing of thrombolytic administration has not been explored. In this study, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates and assessed their relationship to the time of thrombolytic administration. METHODS: Patients who were initially treated with a thrombolytic within 4.5 hours of symptom onset were pooled from the Royal Melbourne Stroke Registry, EXTEND-IA, EXTEND-IA TNK, and EXTEND-IA TNK part 2 trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at initial angiographic assessment (or repeat CT perfusion/angiography). We compared the treatment effect of tenecteplase and alteplase through fixed-effects Poisson regression modelling. RESULTS: Among 846 patients included in the primary analysis, early reperfusion was observed in 173 (20%) patients (tenecteplase: 98/470 [21%], onset-to-thrombolytic time: 132 minutes [interquartile range (IQR): 99-170], and thrombolytic-to-assessment time: 61 minutes [IQR: 39-96]; alteplase: 75/376 [19%], onset-to-thrombolytic time: 143 minutes [IQR: 105-180], thrombolytic-to-assessment time: 92 minutes [IQR: 63-144]). Earlier onset-to-thrombolytic administration times were associated with an increased probability of thrombolytic-induced reperfusion in patients treated with either tenecteplase (adjusted risk ratio [aRR] 1.05 per 15 minutes [95% confidence interval (CI) 1.00-1.12] or alteplase (aRR 1.06 per 15 minutes [95% CI 1.00-1.13]). Tenecteplase remained associated with higher rates of reperfusion vs alteplase after adjustment for onset-to-thrombolytic time, occlusion site, thrombolytic-to-assessment time, and study as a fixed effect, (adjusted incidence rate ratio: 1.41 [95% CI 1.02-1.93]). No significant treatment-by-time interaction was observed (p = 0.87). DISCUSSION: In patients with LVO presenting within 4.5 hours of symptom onset, earlier thrombolytic administration increased successful reperfusion rates. Compared with alteplase, tenecteplase was associated with a higher probability of lytic-induced reperfusion, independent of onset-to-lytic administration times. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifiers: NCT02388061, NCT03340493. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with LVO receiving a thrombolytic, reperfusion was more likely with tenecteplase than alteplase.

Tenecteplase Improves Reperfusion across Time in Large Vessel Stroke.

OBJECTIVE: Tenecteplase improves reperfusion compared to alteplase in patients with large vessel occlusions. To determine whether this improvement varies across the spectrum of thrombolytic agent to reperfusion assessment times, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates. METHODS: Patients with large vessel occlusion and treatment with thrombolysis were pooled from the Melbourne Stroke Registry, and the EXTEND-IA and EXTEND-IA TNK trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at imaging reassessment. We compared the treatment effect of tenecteplase and alteplase, accounting for thrombolytic to assessment exposure times, via Poisson modeling. We compared 90-day outcomes of patients who achieved reperfusion with a thrombolytic to patients who achieved reperfusion via endovascular therapy using ordinal logistic regression. RESULTS: Among 893 patients included in the primary analysis, thrombolytic-induced reperfusion was observed in 184 (21%) patients. Tenecteplase was associated with higher rates of reperfusion (adjusted incidence rate ratio [aIRR] = 1.50, 95% confidence interval [CI] = 1.09-2.07, p = 0.01). Findings were consistent in patient subgroups with first segment (aIRR = 1.41, 95% CI = 0.93-2.14) and second segment (aIRR = 2.07, 95% CI = 0.98-4.37) middle cerebral artery occlusions. Increased thrombolytic to reperfusion assessment times were associated with reperfusion (tenecteplase: adjusted risk ratio [aRR] = 1.08 per 15 minutes, 95% CI = 1.04-1.13 vs alteplase: aRR = 1.06 per 15 minutes, 95% CI = 1.00-1.13). No significant treatment-by-time interaction was observed (p = 0.87). Reperfusion via thrombolysis was associated with improved 90-day modified Rankin Scale scores (adjusted common odds ratio = 2.15, 95% CI = 1.54-3.01) compared to patients who achieved reperfusion following endovascular therapy. INTERPRETATION: Tenecteplase, compared to alteplase, increases prethrombectomy reperfusion, regardless of the time from administration to reperfusion assessment. Prethrombectomy reperfusion is associated with better clinical outcomes. ANN NEUROL 2023;93:489-499.

Airplane stroke syndrome.

Only 37 cases of stroke during or soon after long-haul flights have been published to our knowledge. In this retrospective observational study, we searched the Royal Melbourne Hospital prospective stroke database and all discharge summaries from 1 September 2003 to 30 September 2014 for flight-related strokes, defined as patients presenting with stroke within 14days of air travel. We hypothesised that a patent foramen ovale (PFO) is an important, but not the only mechanism, of flight-related stroke. We describe the patient, stroke, and flight characteristics. Over the study period, 131 million passengers arrived at Melbourne airport. Our centre admitted 5727 stroke patients, of whom 42 (0.73%) had flight-related strokes. Flight-related stroke patients were younger (median age 65 versus 73, p<0.001), had similar stroke severity, and received intravenous thrombolysis more often than non-flight-related stroke patients. Seven patients had flight-related intracerebral haemorrhage. The aetiology of the ischaemic strokes was cardioembolic in 14/35 (40%), including seven patients with confirmed PFO, one with atrial septal defect, four with atrial fibrillation, one with endocarditis, and one with aortic arch atheroma. Paradoxical embolism was confirmed in six patients. Stroke related to air travel is a rare occurrence, less than one in a million. Although 20% of patients had a PFO, distribution of stroke aetiologies was diverse and was not limited to PFO and paradoxical embolism.

Thrombolysis for acute ischemic stroke: do patients treated out of hours have a worse outcome?

INTRODUCTION: Previous studies on the impact of nonworking hours (NWH) have produced conflicting results. We aimed to compare the time to treatment with thrombolysis between NWH and working hours (WH) at an Australian comprehensive stroke center. MATERIALS AND METHODS: All acute ischemic stroke patients treated with intravenous alteplase (IV-alteplase) from January 2003 to December 2011 at the Royal Melbourne Hospital were included. Data collected included demographics, serial time points (including onset, presentation to emergency department, neuroimaging, and thrombolysis), and clinical outcomes (modified Rankin Scale [mRS] and death) at 3 months. NWH were defined as weekdays 5 PM-8 AM, weekends, and public holidays. Comparisons were made in the door-to-computed tomography (CT) time, the door-to-needle time, mRS, and mortality within 3 months between the NWH group and WH group. RESULTS: We recruited 388 consecutive patients who received IV-alteplase, 226 patients were in NWH and 162 patients in WH. The median age was 71 years (Interquartile range [IQR] = 60-79), 54.1% of patients were male, and the median National Institutes of Health Stroke Scale score was 13 (IQR = 8-18). No significant differences were observed at baseline between the NWH and WH groups except for prior stroke. There was a 15-minute increase in the median door-to-needle time (80 minutes in the NWH group versus 64.5 minutes in the WH group, 95% confidence interval [CI]: 6.36-23.64, P = .001). No significant differences were noted in the median door-to-CT time (95% CI: -1.16 to 9.16, P = .128) and clinical outcomes at 3 months (P > .05). Both the door-to-CT time and the door-to-needle time became shorter over the period of the study (P < .001). CONCLUSIONS: Our study showed that the "NWH effect" increased the door-to-needle time. The patients treated out of hours did not have a worse outcome.

Warfarin-associated intracerebral hemorrhage: volume, anticoagulation intensity and location.

BACKGROUND: Warfarin use increases mortality in patients with intracerebral hemorrhage (ICH). Larger hematoma volume and infratentorial location are both major determinants of poor outcome in ICH. Although warfarin-associated intracerebral hemorrhages have greater volumes, there is uncertainty about the effects of location. We aimed to investigate the influence of warfarin on hematoma volume and location. METHODS: We conducted a retrospective study of all patients hospitalized for ICH at a large stroke center from October 2007 to January 2012. Initial CT scans were used to quantify hematoma volumes using the computer-assisted planimetric analysis. Univariate and multivariable analyses determined the influence of warfarin on hemorrhage location. Median regression analysis was performed to estimate the effects of INR on hematoma volumes. RESULTS: We included 404 consecutive patients with ICH of whom 69 were on warfarin. Patients on warfarin had larger hematoma volumes (median 23.9mL vs. 14.2mL; P=0.046). In patients excessively anticoagulated with warfarin (defined as INR>3.0), compared with those in the therapeutic range, brainstem ICH was more frequent (24.0% vs. 6.1%; P=0.005). Patients with INR>3.0 had increased odds of infratentorial hemorrhage (OR 3.63; 95% CI 1.52-8.64; P=0.004) when compared to non-warfarin ICH patients. After adjustment for hematoma location, there was no significant association between INR and hematoma volume. CONCLUSIONS: Patients with warfarin-associated ICH have a predilection for brainstem ICH. After adjustment for ICH location, no relationship between admission INR and hematoma volume was found.

Helsinki model cut stroke thrombolysis delays to 25 minutes in Melbourne in only 4 months.

OBJECTIVE: To test the transferability of the Helsinki stroke thrombolysis model that achieved a median 20-minute door-to-needle time (DNT) to an Australian health care setting. METHODS: The existing "code stroke" model at the Royal Melbourne Hospital was evaluated and restructured to include key components of the Helsinki model: 1) ambulance prenotification with patient details alerting the stroke team to meet the patient on arrival; 2) patients transferred directly from triage onto the CT table on the ambulance stretcher; and 3) tissue plasminogen activator (tPA) delivered in CT immediately after imaging. We analyzed our prospective, consecutive tPA registry for effects of these protocol changes on our DNT after implementation during business hours (8 am to 5 pm Monday-Friday) from May 2012. RESULTS: There were 48 patients treated with tPA in the 8 months after the protocol change. Compared with 85 patients treated in 2011, the median (interquartile range) DNT was reduced from 61 (43-75) minutes to 46 (24-79) minutes (p = 0.040). All of the effect came from the change in the in-hours DNT, down from 43 (33-59) to 25 (19-48) minutes (p = 0.009), whereas the out-of-hours delays remain unchanged, from 67 (55-82) to 62 (44-95) minutes (p = 0.835). CONCLUSION: We demonstrated rapid transferability of an optimized tPA protocol to a different health care setting. With the cooperation of ambulance, emergency, and stroke teams, we succeeded in the absence of a dedicated neurologic emergency department or electronic patient records, which are features of the Finnish system. The next challenge is providing the same service out-of-hours.

Do patients who take part in stroke research differ from non-participants? Implications for generalizability of results.

BACKGROUND: Stroke is one of the most disabling neurological conditions. Clinical research is vital for expanding knowledge of treatment effectiveness among stroke patients. However, evidence begins to accumulate that stroke patients who take part in research represent only a small proportion of all stroke patients. Research participants may also differ from the broader patient population in ways that could potentially distort treatment effects reported in therapeutic trials. The aims of this study were to estimate the proportion of stroke patients who take part in clinical research studies and to compare demographic and clinical profiles of research participants and non-participants. METHODS: 5,235 consecutive patients admitted to the Stroke Care Unit of the Royal Melbourne Hospital, Melbourne, Australia, for stroke or transient ischaemic attack between January 2004 and December 2011 were studied. The study used cross-sectional design. Information was collected on patients' demographic and socio-economic characteristics, risk factors, and comorbidities. Associations between research participation and patient characteristics were initially assessed using χ(2) or Mann-Whitney tests, followed by a multivariable logistic regression analysis. The logistic regression analysis was carried out using generalised estimating equations approach, to account for patient readmissions during the study period. RESULTS: 558 Stroke Care Unit patients (10.7%) took part in at least one of the 33 clinical research studies during the study period. Transfer from another hospital (OR = 0.35, 95% CI 0.22-0.55), worse premorbid function (OR = 0.61, 95% CI 0.54-0.70), being single (OR = 0.61, 95% CI 0.44-0.84) or widowed (OR = 0.77, 95% CI 0.60-0.99), non-English language (OR = 0.67, 95% CI 0.53-0.85), high socio-economic status (OR = 0.74, 95% CI 0.59-0.93), residence outside Melbourne (OR = 0.75, 95% CI 0.60-0.95), weekend admission (OR = 0.78, 95% CI 0.64-0.94), and a history of atrial fibrillation (OR = 0.79, 95% CI 0.63-0.99) were associated with lower odds of research participation. A history of hypertension (OR = 1.50, 95% CI 1.08-2.07) and current smoking (OR = 1.23, 95% CI 1.01-1.50) on the other hand were associated with higher odds of research participation. CONCLUSIONS: The results of this study indicate that stroke patients who take part in clinical research do not represent 'typical' patient admitted to a stroke unit. The imbalance of prognostic factors between stroke participants and non-participants has serious implications for interpretation of research findings reported in stroke literature. This study provides insights into clinical, demographic, and socio-economic characteristics of stroke patients that could potentially be targeted to enhance generalizability of stroke research studies. Given the imbalance of prognostic factors between research participants and non-participants, future studies need to examine differences in stroke outcomes of these groups of patients.

CT perfusion improves diagnostic accuracy and confidence in acute ischaemic stroke.

BACKGROUND AND OBJECTIVE: CT perfusion (CTP) is rapid and accessible for emergency ischaemic stroke diagnosis. The feasibility of introducing CTP and diagnostic accuracy versus non-contrast CT (NCCT) in a tertiary hospital were assessed. METHODS: All patients presenting <9 h from stroke onset or with wake-up stroke were eligible for CTP (Siemens 16-slice scanner, 2×24 mm slabs) unless they had estimated glomerular filtration rate (eGFR)<50 ml/min or diabetes with unknown eGFR. NCCT was assessed by a radiologist and stroke neurologist for early ischaemic change and hyperdense arteries. CTP was assessed for prolonged time to peak and reduced cerebral blood flow. Technical adequacy was defined as 2 CTP slabs of sufficient quality to diagnose stroke. RESULTS: Between January 2009 and September 2011, 1152 ischaemic stroke patients were admitted, 475 (41%) were <9 h/wake-up onset. Of these, 276 (58%) had CTP. Reasons for not performing CTP were diabetes with unknown eGFR (48 (10%)), known kidney disease (36 (8%)), established infarct on NCCT (27 (6%)), posterior circulation syndrome (25 (5%)) and patient motion/instability (16 (3%)). Clinician discretion excluded a further 47 (10%). CTP was more frequently diagnostic than NCCT (80% vs 50%, p<0.001). Non-diagnostic CTP was due to lacunar infarction (28 (10%)), infarct outside slab coverage (21 (8%)), technical failure (4 (1%)) and reperfusion (2 (0.7%)). Normal CTP in 86/87 patients with stroke mimics supported withholding tissue plasminogen activator. CTP technical adequacy improved from 56% to 86% (p<0.001) after the first 6 months. Median time for NCCT/CTP/arch-vertex CT angiogram (including processing and interpretation) was 12 min. No clinically significant contrast nephropathy occurred. CONCLUSIONS: CTP in suspected stroke is widely applicable, rapid and increases diagnostic confidence.

Who, why and when: stroke care unit patients seen by a palliative care service within a large metropolitan teaching hospital.

OBJECTIVES: To investigate factors associated with referral of patients from an Australian stroke care unit (SCU) to an inpatient palliative care service (PCS). METHODS: This retrospective observational cohort study included patients who were referred to the PCS after SCU admission between 1 January and 31 December 2008. Variables measured included patient demographics, premorbid functional status, premorbid living situation, stroke type, history of previous stroke and discharge outcomes. Group differences between all SCU patients seen and not seen by the PCS were compared using univariate analyses. Multivariate logistic regression analysis was undertaken to identify factors associated with PCS involvement. Group differences were also compared between deceased stroke patients seen and not seen by the PCS. RESULTS: 544 patients were admitted to the SCU during the study period with 62 (11.4%) referred to the PCS. Assistance with end-of-life care was the commonest reason for referral. From univariate analyses, factors significantly associated with PCS involvement included age, gender, premorbid modified Rankin score, living situation prior to stroke and stroke type. Factors predicting PCS involvement for SCU patients from logistic regression were: increasing age, higher premorbid modified Rankin score and haemorrhagic stroke. 87 (16.0%) SCU patients died during their admission, with 49 (56.3%) seen by PCS. Deceased patients seen were significantly older, more disabled premorbidly and lived significantly longer. CONCLUSIONS: This study indicates there are patient and condition-level factors associated with referral of stroke patients to PCS. It highlights factors that might better stratify hospitalised stroke patients to timely palliative care involvement, and adds an Australian perspective to limited data addressing this patient population.

Managing a stroke unit: an example from Australia with an emphasis on nursing roles.

Stroke care units (SCUs), which are co-ordinated by dedicated multidisciplinary teams and geographically located in one area, are currently the most generaliseable form of effective treatment for stroke. Although the evidence for SCUs is compelling, to date there has been limited evidence regarding the contribution of the different clinical team members who assist in producing the better patient outcomes observed in SCUs. In particular, there has been limited exploration of the different nursing roles. The purpose of this special report is to describe how an SCU operates and highlight the contribution of the various nursing roles as part of the multidisciplinary stroke team. The article is based on one of the longest established stroke services in Melbourne, Australia. The characteristics and composition of the Royal Melbourne Hospital stroke service in providing clinical care and management will be highlighted as an example. Further, the nursing roles related to avoiding complications, education for patients and families and other staff in the unit, as well as participation in research and future career development opportunities are discussed.