Jean Marc Olivot

Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials

Summary Background Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. Methods We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3–6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. Findings Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35–2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05–1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95–1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01–7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11–10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98–12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99–1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3–6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. Interpretation Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. Funding UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

Addition of brain and carotid imaging to the ABCD² score to identify patients at early risk of stroke after transient ischaemic attack: a multicentre observational study.

BACKGROUND The ABCD² score improves stratification of patients with transient ischaemic attack by early stroke risk. We aimed to develop two new versions of the score: one that was based on preclinical information and one that was based on imaging and other secondary care assessments. METHODS We analysed pooled data from patients with clinically defined transient ischaemic attack who were investigated while in secondary care. Items that contribute to the ABCD² score (age, blood pressure, clinical weakness, duration, and diabetes), other clinical variables, carotid stenosis, and abnormal acute diffusion-weighted imaging (DWI) were recorded and were included in multivariate logistic regression analysis of stroke occurrence at early time intervals after onset of transient ischaemic attack. Scores based on the findings of this analysis were validated in patients with transient ischaemic attack from two independent population-based cohorts. FINDINGS 3886 patients were included in the study: 2654 in the derivation sample and 1232 in the validation sample. We derived the ABCD³ score (range 0-9 points) by assigning 2 points for dual transient ischaemic attack (an earlier transient ischaemic attack within 7 days of the index event). C statistics (which indicate discrimination better than chance at >0·5) for the ABCD³ score were 0·78 at 2 days, 0·80 at 7 days, 0·79 at 28 days, and 0·77 at 90 days, compared with C statistics for the ABCD² score of 0·71 at 2 days (p=0·083), 0·71 at 7 days (p=0·012), 0·71 at 28 days (p=0·021), and 0·69 at 90 days (p=0·018). We included stenosis of at least 50% on carotid imaging (2 points) and abnormal DWI (2 points) in the ABCD³-imaging (ABCD³-I) score (0-13 points). C statistics for the ABCD³-I score were 0·90 at 2 days (compared with ABCD² score p=0·035), 0·92 at 7 days (p=0·001), 0·85 at 28 days (p=0·028), and 0·79 at 90 days (p=0·073). The 90-day net reclassification improvement compared with ABCD² was 29·1% for ABCD³ (p=0·0003) and 39·4% for ABCD³-I (p=0·034). In the validation sample, the ABCD³ and ABCD³-I scores predicted early stroke at 7, 28, and 90 days. However, discrimination and net reclassification of patients with early stroke were similar with ABCD³ compared with ABCD². INTERPRETATION The ABCD³-I score can improve risk stratification after transient ischaemic attack in secondary care settings. However, use of ABCD³ cannot be recommended without further validation. FUNDING Health Research Board of Ireland, Irish Heart Foundation, and Irish National Lottery.

Addition of Brain Infarction to the ABCD2 Score (ABCD2I) A Collaborative Analysis of Unpublished Data on 4574 Patients

Background and Purpose— The ABCD system was developed to predict early stroke risk after transient ischemic attack. Incorporation of brain imaging findings has been suggested, but reports have used inconsistent methods and been underpowered. We therefore performed an international, multicenter collaborative study of the prognostic performance of the ABCD2 score and brain infarction on imaging to determine the optimal weighting of infarction in the score (ABCD2I). Methods— Twelve centers provided unpublished data on ABCD2 scores, presence of brain infarction on either diffusion-weighted imaging or CT, and follow-up in cohorts of patients with transient ischemic attack diagnosed by World Health Organization criteria. Optimal weighting of infarction in the ABCD2I score was determined using area under the receiver operating characteristic curve analyses and random effects meta-analysis. Results— Among 4574 patients with TIA, acute infarction was present in 884 (27.6%) of 3206 imaged with diffusion-weighted imaging and new or old infarction was present in 327 (23.9%) of 1368 imaged with CT. ABCD2 score and presence of infarction on diffusion-weighted imaging or CT were both independently predictive of stroke (n=145) at 7 days (after adjustment for ABCD2 score, OR for infarction=6.2, 95% CI=4.2 to 9.0, overall; 14.9, 7.4 to 30.2, for diffusion-weighted imaging; 4.2, 2.6 to 6.9, for CT; all P<0.001). Incorporation of infarction in the ABCD2I score improved predictive power with an optimal weighting of 3 points for infarction on CT or diffusion-weighted imaging. Pooled areas under the curve increased from 0.66 (0.53 to 0.78) for the ABCD2 score to 0.78 (0.72 to 0.85) for the ABCD2I score. Conclusions— In secondary care, incorporation of brain infarction into the ABCD system (ABCD2I score) improves prediction of stroke in the acute phase after transient ischemic attack.

Reduction in Early Stroke Risk in Carotid Stenosis With Transient Ischemic Attack Associated With Statin Treatment

Background and Purpose— Statins reduce stroke risk when initiated months after transient ischemic attack (TIA)/stroke and reduce early vascular events in acute coronary syndromes, possibly via pleiotropic plaque stabilization. Few data exist on acute statin use in TIA. We aimed to determine whether statin pretreatment at TIA onset modified early stroke risk in carotid stenosis. Methods— We analyzed data from 2770 patients with TIA from 11 centers, 387 with ipsilateral carotid stenosis. ABCD2 score, abnormal diffusion weighted imaging, medication pretreatment, and early stroke were recorded. Results— In patients with carotid stenosis, 7-day stroke risk was 8.3% (95% confidence interval [CI], 5.7–11.1) compared with 2.7% (CI, 2.0%–3.4%) without stenosis (P<0.0001; 90-day risks 17.8% and 5.7% [P<0.0001]). Among carotid stenosis patients, nonprocedural 7-day stroke risk was 3.8% (CI, 1.2%–9.7%) with statin treatment at TIA onset, compared with 13.2% (CI, 8.5%–19.8%) in those not statin pretreated (P=0.01; 90-day risks 8.9% versus 20.8% [P=0.01]). Statin pretreatment was associated with reduced stroke risk in patients with carotid stenosis (odds ratio for 90-day stroke, 0.37; CI, 0.17–0.82) but not nonstenosis patients (odds ratio, 1.3; CI, 0.8–2.24; P for interaction, 0.008). On multivariable logistic regression, the association remained after adjustment for ABCD2 score, smoking, antiplatelet treatment, recent TIA, and diffusion weighted imaging hyperintensity (adjusted P for interaction, 0.054). Conclusions— In acute symptomatic carotid stenosis, statin pretreatment was associated with reduced stroke risk, consistent with findings from randomized trials in acute coronary syndromes. These data support the hypothesis that statins started acutely after TIA symptom onset may also be beneficial to prevent early stroke. Randomized trials addressing this question are required.

Combined spin‐ and gradient‐echo perfusion‐weighted imaging

In this study, a spin‐ and gradient‐echo echo‐planar imaging (SAGE EPI) MRI pulse sequence is presented that allows simultaneous measurements of gradient‐echo and spin‐echo dynamic susceptibility‐contrast perfusion‐weighted imaging data. Following signal excitation, five readout trains were acquired using spin‐ and gradient‐echo echo‐planar imaging, all of them with echo times of less than 100 ms. Contrast agent concentrations in brain tissue were determined based on absolute R  2* and R2 estimates rather than relative changes in the signals of individual echo trains, producing T1‐independent dynamic susceptibility‐contrast perfusion‐weighted imaging data. Moreover, this acquisition technique enabled vessel size imaging through the simultaneous quantification of R  2* and R2, without an increase in acquisition time. In this work, the concepts of SAGE EPI pulse sequence and results in stroke and tumor imaging are presented. Overall, SAGE EPI combined the advantages of higher sensitivity to contrast agent passage of gradient‐echo perfusion‐weighted imaging with better microvascular selectivity of spin‐echo perfusion‐weighted imaging. Magn Reson Med, 2012.

Hypoperfusion Intensity Ratio Predicts Infarct Progression and Functional Outcome in the DEFUSE 2 Cohort

Background and Purpose— We evaluate associations between the severity of magnetic resonance perfusion-weighted imaging abnormalities, as assessed by the hypoperfusion intensity ratio (HIR), on infarct progression and functional outcome in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2). Methods— Diffusion-weighted magnetic resonance imaging and perfusion-weighted imaging lesion volumes were determined with the RAPID software program. HIR was defined as the proportion of TMax >6 s lesion volume with a Tmax >10 s delay and was dichotomized based on its median value (0.4) into low versus high subgroups as well as quartiles. Final infarct volumes were assessed at day 5. Initial infarct growth velocity was calculated as the baseline diffusion-weighted imaging (DWI) lesion volume divided by the delay from symptom onset to baseline magnetic resonance imaging. Total Infarct growth was determined by the difference between final infarct and baseline DWI volumes. Collateral flow was assessed on conventional angiography and dichotomized into good and poor flow. Good functional outcome was defined as modified Rankin Scale ⩽2 at 90 days. Results— Ninety-nine patients were included; baseline DWI, perfusion-weighted imaging, and final infarct volumes increased with HIR quartiles (P<0.01). A high HIR predicted poor collaterals with an area under the curve of 0.73. Initial infarct growth velocity and total infarct growth were greater among patients with a high HIR (P<0.001). After adjustment for age, DWI volume, and reperfusion, a low HIR was associated with good functional outcome: odds ratio=4.4 (95% CI, 1.3–14.3); P=0.014. Conclusions— HIR can be easily assessed on automatically processed perfusion maps and predicts the rate of collateral flow, infarct growth, and clinical outcome.

Magnetic resonance imaging in the evaluation of acute stroke.

The ability to use physiologic imaging with either magnetic resonance (MR) or computed tomography to help define irreversibly injured brain (the infarct core) and tissue at risk of infarct (reversible ischemic penumbra) holds great promise in the future treatment of stroke. The physiologic principles and concepts underlying the evaluation for mismatch between injured tissue and tissue at risk are similar for the 2 imaging techniques. Multimodal MR imaging (diffusion-weighted imaging/perfusion-weighted imaging/MR angiography) provides a validated penumbral selection criteria based on the results of 2 clinical trials (diffusion and perfusion imaging evaluation for understanding stroke evolution and echoplanar imaging thrombolysis evaluation). Computed tomographic perfusion parameters have also been calculated to optimize final infarct prediction. Both techniques await further study to prove their capability of selecting cases for short-term recanalization/reperfusion therapy.

Florbetapir imaging in cerebral amyloid angiopathy-related hemorrhages

Objective: To assess whether 18F-florbetapir, a PET amyloid tracer, could bind vascular amyloid in cerebral amyloid angiopathy (CAA) by comparing cortical florbetapir retention during the acute phase between patients with CAA-related lobar intracerebral hemorrhage (ICH) and patients with hypertension-related deep ICH. Methods: Patients with acute CAA-related lobar ICH were prospectively enrolled and compared with patients with deep ICH. 18F-florbetapir PET, brain MRI, and APOE genotype were obtained for all participants. Cortical florbetapir standard uptake value ratio (SUVr) was calculated with the whole cerebellum used as a reference. Patients with CAA and those with deep ICH were compared for mean cortical florbetapir SUVr values. Results: Fifteen patients with acute lobar ICH fulfilling the modified Boston criteria for probable CAA (mean age = 67 ± 12 years) and 18 patients with acute deep ICH (mean age = 63 ± 11 years) were enrolled. Mean global cortical florbetapir SUVr was significantly higher among patients with CAA-related ICH than among patients with deep ICH (1.27 ± 0.12 vs 1.12 ± 0.12, p = 0.001). Cortical florbetapir SUVr differentiated patients with CAA-ICH from those with deep ICH (area under the curve = 0.811; 95% confidence interval [CI] 0.642–0.980) with a sensitivity of 0.733 (95% CI 0.475–0.893) and a specificity of 0.833 (95% CI 0.598–0.948). Conclusions: Cortical florbetapir uptake is increased in patients with CAA-related ICH relative to those with deep ICH. Although 18F-florbetapir PET can label vascular β-amyloid and might serve as an outcome marker in future clinical trials, its diagnostic value in acute CAA-related ICH seems limited in clinical practice.

MR perfusion lesions after TIA or minor stroke are associated with new infarction at 7 days

Objective: To investigate the relationship between acute perfusion-weighted imaging (PWI) lesions occurring within the first hours after a TIA or a minor brain infarction (BI) and the incidence of new BI detected on a systematic MRI at 1 week. Methods: Consecutive patients who experienced a TIA or BI with a neurologic deficit that lasted <24 hours, did not receive any revascularization therapy (thrombolysis/thrombectomy), and underwent DWI/PWI at baseline and fluid-attenuated inversion recovery (FLAIR)/DWI 1 week after symptom onset were enrolled. Investigators blinded to clinical information independently assessed the presence of acute ischemic lesions on baseline DWI/PWI and follow-up DWI and FLAIR. Baseline and follow-up MRIs were then compared to determine the occurrence and location of new infarctions. Results: Sixty-four patients met the inclusion criteria. Median (IQR) ABCD2 score was 4 (3–5). Median delay from onset to baseline and follow-up MRI was 5 (2–10) hours and 6 (5–7) days, respectively. MRI revealed an acute ischemic lesion on DWI and/or PWI in 38 patients. Nine patients (14%) had a new infarction on follow-up MRI. Each had a PWI and 4 had a DWI lesion on baseline MRI. All new BIs except one were asymptomatic and in the same location as the acute PWI lesion. Conclusions: Our results showed that 30% of the acute focal PWI lesions detected after a TIA are associated with a new BI at 1 week. Those new BIs may result from the progression of the initial ischemic injury.

Radiological examinations of transient ischemic attack.

Neuroimaging is critical in the evaluation of patients with TIA. CT and MRI are the two available options for imaging. Head CT is more widely available and commonly used. Diffusion MRI is the recommended modality to image an ischemic lesion. The presence of a diffusion lesion in a patient with transient neurological symptoms is an indicator of a high risk of recurrent stroke. Perfusion imaging with perfusion MRI or CT perfusion may improve the detection of ischemic lesions. Noninvasive vessel imaging may detect a symptomatic vessel lesion associated with an increased risk of stroke.