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Browsing by Author "Martins, Sheila"

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Applicability of ENCHANTED trial results to current acute ischemic stroke patients eligible for intravenous thrombolysis in England and Wales: Comparison with the Sentinel Stroke National Audit Programme registry
(Sage Publishing, 2019-10) Robinson, Thompson; Bray, Benjamin; Paley, Lizz; Sprigg, Nikola; Wan, Xia; Arima, Hisatomi; Bath, Philip; Broderick, Joseph; Durham, Alice; Kim, Jong; Lavados, Pablo; Lee, Tsong-Hai; Martins, Sheila; Nguyen, Thang; Pandian, Jeyaraj; Parsons, Mark; Pontes-Neto, Octavio; Ricci, Stefano; Sharma, Vijay; Wang, Jiguang; Woodward, Mark; Rudd, Anthony; Chalmers, John; Anderson, Craig; ENCHANTED Investigators
Background: Randomized controlled trials provide high-level evidence, but the necessity to include selected patients may limit the generalisability of their results. Methods: Comparisons were made of baseline and outcome data between patients with acute ischemic stroke (AIS) recruited into the alteplase-dose arm of the international, multi-center, Enhanced Control of Hypertension and Thrombolysis Stroke study (ENCHANTED) in the United Kingdom (UK), and alteplase-treated AIS patients registered in the UK Sentinel Stroke National Audit Programme (SSNAP) registry, over the study period June 2012 to October 2015. Results: There were 770 AIS patients (41.2% female; mean age 72 years) included in ENCHANTED at sites in England and Wales, which was 19.5% of alteplase-treated AIS patients registered in the SSNAP registry. Trial participants were significantly older, had lower baseline neurological severity, less likely Asian, and had more premorbid symptoms, hypertension and atrial fibrillation. Although ENCHANTED participants had higher rates of symptomatic intracerebral hemorrhage than those in SSNAP, there were no differences in onset-to-treatment time, levels of disability (assessed by the modified Rankin scale) at hospital discharge, and mortality over 90 days between groups. Conclusions: Despite the high level of participation, equipoise over the dose of alteplase among UK clinician investigators favored the inclusion of older, frailer, milder AIS patients in the ENCHANTED trial.
Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial
(2023) Chen, Chen; Ouyang, Menglu; Ong, Sheila; Zhang, Luyun; Zhang, Guobin; Delcourt, Candice; Mair, Grant; Liu, Leibo; Billot, Laurent; Li, Qiang; Chen, Xiaoying; Parsons, Mark; Broderick, Joseph; Demchuk, Andrew; Bath, Philip; Donnan, Geoffrey; Levi, Christopher; Chalmers, John; Lindley, Richard; Martins, Sheila; Pontes-Neto, Octavio; Munoz Venturelli, Paula; Olavarría, Verónica V.; Lavados, Pablo; Robinson, Thompson; Wardlaw, Joanna; Li, Gang; Wang, Xia; Song, Lili; Anderson, Craig
Background: Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130-140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target <180 mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018. Methods: All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24-36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings: There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24-36 h. Mean achieved systolic blood pressures over 1-24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24-36 h (0.3 [IQR 0.0-16.6] in the intensive group and 0.9 [0.0-12.5] in the guideline group; log Δmean -0.17, 95% CI -0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses. Interpretation: Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity. Funding: National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.
Flat-head positioning increases cerebral blood flow in anterior circulation acute ischemic stroke. A cluster randomized phase IIb trial.
(Sage Publications, 11/09/2017) Olavarria, Veronica; Lavados, Pablo; Muñoz Venturelli, Paula; Gonzalez, Francisca; Gaete, Javier; Martins, Sheila; Arima, Hisatomi; Anderson, Craig; Brunser, Alejandro
Background Whether lying-flat improves blood flow in patients with acute ischemic stroke is unknown. Our aim was to investigate if lying-flat "changes" cerebral blood flow velocities assessed by transcranial Doppler in acute ischemic stroke patients. Methods In a multicenter cluster clinical trial, we randomly assigned patients within 12 h from onset of a neurological deficit due to cerebral ischemia of the anterior circulation to lying-flat or upright head positioning. The primary outcome was a change of 8 cm/s or more in mean cerebral blood flow velocities on transcranial Doppler to the middle cerebral artery at 1 and 24 h post-randomization, adjusted for imbalance in baseline variables. Secondary outcomes included serious adverse events and physical functioning at 90 days. Results Ninety-four of 304 patients screened were recruited. The primary outcome occurred in 11 (26%) of 43 patients in the lying-flat group and in 6 (12%) of 51 in the upright group at 1 h (adjusted odds ratio, 3.81; 95% CI, 1.07 to 13.54), and in 23 (53%) and 18 (36%) patients in these respective groups at 24 h (adjusted odds ratio, 3.04; 95% CI, 1.08 to 8.53). There were no between-group differences in serious adverse events, including pneumonia, heart failure or mortality, nor in functional outcome at 3 months (adjusted common odds ratio, 1.38; 95% CI 0.64 to 3.00). Conclusion The lying-flat head position was associated with a significant increase in cerebral blood flow velocities at one and 24 h within the ipsilateral hemisphere of anterior circulation acute ischemic stroke, without serious safety concerns. Clinical trial registration-URL: http://www.clinicaltrials.gov . Unique identifier: NCT01706094.
Head position and cerebral blood flow in acute ischemic stroke patients: protocol for the pilot phase, cluster randomized, Head Position in Acute Ischemic Stroke Trial (HeadPoST pilot)
(Sage Publications, 2016) Brunser, Alejandro; Muñoz Venturelli, Paula; Lavados, Pablo; Gaete, Javier; Martins, Sheila; Arima, Hisatomi; Anderson, Craig; Olavarría, Verónica
RATIONALE: Few proven interventions exist for acute ischemic stroke (AIS), and most are expensive and restricted in applicability. Lying flat 'head down' positioning of AIS patients has been shown to increase by as much as 20%, mean cerebral blood flow velocities (CBFV) measured by transcranial Doppler (TCD) but whether this translates into clinical improvement is uncertain. AIM: To determine if the lying flat position increases mean CBFV in the affected territory as compared to the sitting up position in AIS patients. METHODS AND DESIGN: Head Position in Acute Ischemic Stroke Trial (HeadPoST pilot) is a cluster randomized (clusters being months), assessor-blinded end-point, phase IIb trial, where consecutive adults with anterior circulation AIS within 12 h of symptom onset are positioned to a randomized position for 48 h with TCD performed serially. STUDY OUTCOMES: Primary outcome is mean CBFV on TCD at 1 and 24 h after positioning. Secondary outcomes include: serious adverse events, neurological impairment at seven days, and death and disability at 90 days. SAMPLE SIZE ESTIMATES: Assuming an increase of 8.3 (SD 11.4) cm/s in average of mean CBFV when tilted from 30° to 0°, 46 clusters are required (92 patients in total) to detect a 20% increase of mean CBFV with 90% power and 5% level of significance. CONCLUSION: HeadPoST pilot is a cluster randomized multicenter clinical trial investigating the effect of head positioning on mean CBFV in anterior circulation AIS.
Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial
(Elsevier Ltd., 2019-03) Anderson, Craig; Huang, Yining; Lindley, Richard; Chen, Xiaoying; Arima, Hisatomi; Chen, Guofang; Li, Qiang; Billot, Laurent; Delcourt, Candice; Bath, Philip; Broderick, Joseph; Demchuk, Andrew; Donnan, Geoffrey; Durham, Alice; Lavados, Pablo; Lee, Tsong-Hai; Levi, Christopher; Martins, Sheila; Olavarria, Veronica; Pandian, Jeyaraj; Parsons, Mark; Pontes-Neto, Octavio; Ricci, Stefano; Sato, Shoichiro; Sharma, Vijay; Silva, Federico; Song, Lili; Thang, Nguyen; Wardlaw, Joanna; Wang, Ji-Guang; Wang, Xia; Woodward, Mark; Chalmers, John; Robinson, Thompson; ENCHANTED Investigators and Coordinators
Background Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. Methods We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130–140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6–4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87–1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60–0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70–1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. Interpretation Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group.
Low- versus standard-dose alteplase in patients on prior antiplatelet therapy: the ENCHANTED trial (enhanced control of hypertension and thrombolysis stroke study)
(American Heart Association, 2017) Robinson, Thompson; Wang, Xia; Arima, Hisatomi; Bath, Philip; Billot, Laurent; Broderick, Joseph; Demchuk, Andrew M; Donnan, Geoffery; Kim, Jong S; Lavados, Pablo; Lee, Tsong-Hai; Lindley, Richard; Martins, Sheila; Olavarria, Veronica; Pandian, Jeyaraj; Parsons, Mark W.; Pontes-Neto, Octavio; Ricci, Stefano; Sato, Shoichiro; Sharma, Vijay; Nguyen, Thang; Wang, Ji-Guang; Woodward, Mark; Chalmers, John; Anderson, Craig; ENCHANTED Investigators
BACKGROUND AND PURPOSE: Many patients receiving thrombolysis for acute ischemic stroke are on prior antiplatelet therapy (APT), which may increase symptomatic intracerebral hemorrhage risk. In a prespecified subgroup analysis, we report comparative effects of different doses of intravenous alteplase according to prior APT use among participants of the international multicenter ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study). METHODS: Among 3285 alteplase-treated patients (mean age, 66.6 years; 38% women) randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset, 752 (22.9%) reported prior APT use. Primary outcome at 90 days was the combined end point of death or disability (modified Rankin Scale [mRS] scores, 2-6). Other outcomes included mRS scores 3 to 6, ordinal mRS shift, and symptomatic intracerebral hemorrhage by various standard criteria. RESULTS: There were no significant differences in outcome between patients with and without prior APT after adjustment for baseline characteristics and management factors during the first week; defined by mRS scores 2 to 6 (adjusted odds ratio [OR], 1.01; 95% confidence interval [CI], 0.81-1.26; P=0.953), 3 to 6 (OR, 0.95; 95% CI, 0.75-1.20; P=0.662), or ordinal mRS shift (OR, 1.03; 95% CI, 0.87-1.21; P=0.770). Alteplase-treated patients on prior APT had higher symptomatic intracerebral hemorrhage (OR, 1.82; 95% CI, 1.00-3.30; P=0.051) according to the safe implementation of thrombolysis in stroke-monitoring study definition. Although not significant (P-trend, 0.053), low-dose alteplase tended to have better outcomes than standard-dose alteplase in those on prior APT compared with those not using APT (mRS scores of 2-6; OR, 0.84; 95% CI, 0.62-1.12 versus OR, 1.16; 95% CI, 0.99-1.36). CONCLUSIONS: Low-dose alteplase may improve outcomes in thrombolysis-treated acute ischemic stroke patients on prior APT, but this requires further evaluation in a randomized controlled trial.
Rationale, design, and progress of the ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) trial: An international multicenter 2 × 2 quasi-factorial randomized controlled trial of low- vs. standard-dose rt-PA and early intensive vs. guideline-recommended blood pressure lowering in patients with acute ischaemic stroke eligible for thrombolysis treatment
(Sage Publications, 2015) Huang, Yining; Sharma, Vijay; Robinson, Thompson; Lindley, Richard; Chen, Xiaoying; Kim, Jong Sung; Lavados, Pablo; Olavarría, Verónica; Arima, Hisatomi; Fuentes, Sully; Nguyen, Huy Thang; Lee, Tsong-Hai; Parsons, Mark; Levi, Christopher; Demchuk, Andrew; Bath, Philip; Broderick, Joseph; Donnan, Geoffrey; Martins, Sheila; Pontes-Neto, Octavio; Silva, Federico; Pandian, Jeyaraj; Ricci, Stefano; Stapf, Christian; Woodward, Mark; Wang, Jiguang; Chalmers, John; Anderson, Craig
RATIONALE: Controversy exists over the optimal dose of intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0·6 mg/kg) is more efficacious than standard-dose (0·9 mg/kg) i.v. rt-PA, and guidelines recommend reducing systolic BP to <185 mmHg before and <180 mmHg after use of i.v. rt-PA, despite observational studies indicating better outcomes at much lower (<140 mmHg) systolic BP levels in this patient group. AIMS: The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0·6 mg/kg body weight; maximum 60 mg) i.v. rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0·9 mg/kg body weight; maximum 90 mg) i.v. rt-PA; and (ii) early intensive BP lowering (systolic target 130-140 mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target < 180 mmHg). DESIGN: The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent,2 × 2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] 'rt-PA dose' and/or Arm [B] 'BP control', using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately. STUDY OUTCOMES: The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2-6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift ('improvement') in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs. RESULTS: Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required sample sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide >90% power to detect non-inferiority of low-dose i.v. rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. CONCLUSIONS: Low-dose i.v. rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.
Stroke Care and Application of Thrombolysis in Ibero-America: Report From the SITS-SIECV Ibero-American Stroke Register
(2019) Alonso de Leciñana, María; Mazya, Michael V.; Kostulas, Nikolaos; Del Brutto, Oscar H.; Abanto, Carlos; Massaro, Ayrton; Bastos, Mario de; Martins, Sheila; Ameriso, Sebastian F.; Gongora-Rivera, Fernando; Sacks, Claudio; Hoppe, Arnold; Abad, Patricio; Meza, Gloria; Arauz-Gongora, Antonio; Wahlgren, Nils; Díez-Tejedor, Exuperio; SITS-SIECV Investigators
Background and Purpose— Standardized registries may provide valuable data to further improve stroke care. Our aim was to obtain updated information about characteristics of stroke patients and management of stroke across the Ibero-American countries, using a common in-hospital registry (Safe Implementation of Treatments in Stroke–Sociedad Iberoamericana de Enfermedades Cerebrovasculares) as a basis for further quality improvement. Methods— Data for this study were entered into the Safe Implementation of Treatments in Stroke registry from September 2009 to December 2013 by 58 centers in 14 countries. Data included demographics, risk factors, onset-to-door time, National Institutes of Health Stroke Scale score, stroke subtype, ischemic stroke etiology, treatments, 3-month mortality, and modified Rankin Scale score. Time to treatment was also recorded for patients treated with thrombolysis. Results— Five thousand four hundred one patients were registered; median age, 65 years; 46% women; 3915 (72.5%) ischemic strokes; 686 (13.7%) hemorrhagic strokes; 213 (4.3%) subarachnoid hemorrhages; 414 (8.3%) transient ischemic attacks; and 31 (0.6%) cerebral vein thrombosis. The most prevalent risk factors were hypertension (71.3%), dyslipidemia (35.2%), and diabetes mellitus (23.6%). Atrial fibrillation was present in 15.1%. Three hundred one ischemic strokes were treated with intravenous thrombolysis (IVT; 7.7%). Patients undergoing IVT were more severely affected (median baseline National Institutes of Health Stroke Scale score, 11 versus 6). The rate of symptomatic intracerebral hemorrhages after IVT was 5.7%. At 3 months, 60.3% of IVT-treated patients and 59.1% of untreated patients were independent (modified Rankin Scale score, 0–2). Mortality was 11.4% in treated and 12.8% in untreated patients. Conclusions— Safe Implementation of Treatments in Stroke–Sociedad Iberoamericana de Enfermedades Cerebrovasculares is the largest registry of a general stroke population and the first study to evaluate the level of IVT use in Ibero-America. It provides valuable information that may help to improve the quality of stroke care in the Ibero-American region.
The distribution of the modified Rankin scale scores change according to eligibility criteria in acute ischemic stroke trials: A consideration for sample size calculations when using ordinal regression analysis
(Elsevier, 2017) Olavarria, Veronica; Brunser, Alejandro; Cabral, Norberto; Martins, Sheila; Muñoz Venturelli, Paula; Cavada, Gabriel; Lavados, Pablo
Background: Distribution shifts of the modified Rankin scale (mRs) is used as outcome measure in acute ischemic stroke (AIS) randomized controlled trials (RCT). Distribution across strata of mRs is relevant for sample size calculations and may be affected by eligibility criteria. Aim: We aimed to assess the distribution of mRs scores across its different strata in AIS according to usual eligibility criteria. Methods: We computed follow-up mRs strata distribution between an unselected cohort and samples with (a) time from symptom onset < 6 h (b) National Institutes of Health Stroke Scale (NIHSS) scores > 3 and < 25, and (c) both criteria combined. We compared distributions with the Mann-Whitney U Test and calculated sample sizes for each distribution. Results: We included 5849 AIS patients. The unselected sample had a non-normal distribution with a median of 2. All selection criteria yielded significantly different distributions of mRs (p = 004, 0.02 and 0.02 respectively). This resulted in a significant variation in the calculated sample size when applying different selection criteria, with smaller numbers when RCT selection criteria are used (3616 versus 1553). Conclusions: The use of usual RCT eligibility criteria result in significant differences in mRs distribution and smaller sample sizes compared to unselected AIS samples.

Browsing by Author "Martins, Sheila"

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