Kenneth Butcher

Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial

BACKGROUND Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3-6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). METHODS We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3-6 h after onset of ischaemic stroke. PWI and DWI were done before and 3-5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. FINDINGS We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71.6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1.24 with alteplase and 1.78 with placebo (ratio 0.69, 95% CI 0.38-1.28; Students t test p=0.239); the median relative infarct growth was 1.18 with alteplase and 1.79 with placebo (ratio 0.66, 0.36-0.92; Wilcoxons test p=0.054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than was no reperfusion. INTERPRETATION Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.

Persistent Poststroke Hyperglycemia Is Independently Associated With Infarct Expansion and Worse Clinical Outcome

BACKGROUND AND PURPOSE Hyperglycemia at the time of ischemic stroke is associated with increased mortality and morbidity. Animal studies suggest that infarct expansion may be responsible. The influence of persisting hyperglycemia after stroke has not previously been examined. We measured the blood glucose profile after acute ischemic stroke and correlated it with infarct volume changes using T2- and diffusion-weighted MRI. METHODS We recruited 25 subjects within 24 hours of ischemic stroke symptoms. Continuous glucose monitoring was performed with a glucose monitoring device (CGMS), and 4-hour capillary glucose levels (BGL) were measured for 72 hours after admission. MRI and clinical assessments were performed at acute (median, 15 hours), subacute (median, 5 days), and outcome (median, 85 days) time points. RESULTS Mean CGMS glucose and mean BGL glucose correlated with infarct volume change between acute and subacute diffusion-weighted MRI (r>or=0.60, P<0.01), acute and outcome MRI (r=0.56, P=0.01), outcome National Institutes of Health Stroke Scale (NIHSS; r>or=0.53, P<0.02), and outcome modified Rankin Scale (mRS; r>or=0.53, P=0.02). Acute and final infarct volume change and outcome NIHSS and mRS were significantly higher in patients with mean CGMS or mean BGL glucose >or=7 mmol/L. Multiple regression analysis indicated that both mean CGMS and BGL glucose levels >or=7 mmol/L were independently associated with increased final infarct volume change. CONCLUSIONS Persistent hyperglycemia on serial glucose monitoring is an independent determinant of infarct expansion and is associated with worse functional outcome. There is an urgent need to study normalization of blood glucose after stroke.

Refining the Perfusion–Diffusion Mismatch Hypothesis

Background and Purpose— The Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) tests the hypothesis that perfusion-weighted imaging (PWI)–diffusion-weighted imaging (DWI) mismatch predicts the response to thrombolysis. There is no accepted standardized definition of PWI-DWI mismatch. We compared common mismatch definitions in the initial 40 EPITHET patients. Methods— Raw perfusion images were used to generate maps of time to peak (TTP), mean transit time (MTT), time to peak of the impulse response (Tmax) and first moment transit time (FMT). DWI, apparent diffusion coefficient (ADC), and PWI volumes were measured with planimetric and thresholding techniques. Correlations between mismatch volume (PWIvol-DWIvol) and DWI expansion (T2Day 90-vol-DWIAcute-vol) were also assessed. Results— Mean age was 68±11, time to MRI 4.5±0.7 hours, and median National Institutes of Health Stroke Scale (NIHSS) score 11 (range 4 to 23). Tmax and MTT hypoperfusion volumes were significantly lower than those calculated with TTP and FMT maps (P<0.001). Mismatch ≥20% was observed in 89% (Tmax) to 92% (TTP/FMT/MTT) of patients. Application of a +4s (relative to the contralateral hemisphere) PWI threshold reduced the frequency of positive mismatch volumes (TTP 73%/FMT 68%/Tmax 54%/MTT 43%). Mismatch was not significantly different when assessed with ADC maps. Mismatch volume, calculated with all parameters and thresholds, was not significantly correlated with DWI expansion. In contrast, reperfusion was correlated inversely with infarct growth (R=−0.51; P=0.009). Conclusions— Deconvolution and application of PWI thresholds provide more conservative estimates of tissue at risk and decrease the frequency of mismatch accordingly. The precise definition may not be critical; however, because reperfusion alters tissue fate irrespective of mismatch.

Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target

Ischaemic stroke results from acute arterial occlusion leading to focal hypoperfusion. Thrombolysis is the only proven treatment. Advanced neuroimaging techniques allow a detailed assessment of the cerebral circulation in patients with acute stroke, and provide information about the status of collateral vessels and collateral blood flow, which could attenuate the effects of arterial occlusion. Imaging of the brain and vessels has shown that collateral flow can sustain brain tissue for hours after the occlusion of major arteries to the brain, and the augmentation or maintenance of collateral flow is therefore a potential therapeutic target. Several interventions that might augment collateral blood flow are being investigated.

Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulation Reversal

Background and Purpose Anticoagulant-associated intracranial hemorrhage (aaICH) presents with larger hematoma volumes, higher risk of hematoma expansion, and worse outcome than spontaneous intracranial hemorrhage. Prothrombin complex concentrates (PCCs) are indicated for urgent reversal of anticoagulation after aaICH. Given the lack of randomized controlled trial evidence of efficacy, and the potential for thrombotic complications, we aimed to determine outcomes in patients with aaICH treated with PCC. Methods We conducted a prospective multicenter registry of patients treated with PCC for aaICH in Canada. Patients were identified by local blood banks after the release of PCC. A chart review abstracted clinical, imaging, and laboratory data, including thrombotic events after therapy. Hematoma volumes were measured on brain CT scans and primary outcomes were modified Rankin Scale at discharge and in-hospital mortality. Results Between 2008 and 2010, 141 patients received PCC for aaICH (71 intraparenchymal hemorrhages). The median age was 78 years (interquartile range, 14), 59.6% were male, and median Glasgow Coma Scale was 14. Median international normalized ratio was 2.6 (interquartile range, 2.0) and median parenchymal hematoma volume was 15.8 mL (interquartile range, 31.8). Median post-PCC therapy international normalized ratio was 1.4: 79.5% of patients had international normalized ratio correction (<1.5) within 1 hour of PCC therapy. Patients with intraparenchymal hemorrhage had an in-hospital mortality rate of 42.3% with median modified Rankin Scale of 5. Significant hematoma expansion occurred in 45.5%. There were 3 confirmed thrombotic complications within 7 days of PCC therapy. Conclusions PCC therapy rapidly corrected international normalized ratio in the majority of patients, yet mortality and morbidity rates remained high. Rapid international normalized ratio correction alone may not be sufficient to alter prognosis after aaICH.

Pretreatment diffusion- and perfusion-MR lesion volumes have a crucial influence on clinical response to stroke thrombolysis

We hypothesized that pretreatment magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) lesion volumes may have influenced clinical response to thrombolysis in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). In 98 patients randomized to intravenous (IV) tissue plasminogen activator (tPA) or placebo 3 to 6 h after stroke onset, we examined increasing acute DWI and PWI lesion volumes (Tmax—with 2-sec delay increments), and increasing PWI/DWI mismatch ratios, on the odds of both excellent (modified Rankin Scale (mRS): 0 to 1) and poor (mRS: 5 to 6) clinical outcome. Patients with very large PWI lesions (most had internal carotid artery occlusion) had increased odds ratio (OR) of poor outcome with IV-tPA (58% versus 25% placebo; OR=4.13, P=0.032 for Tmax +2-sec volume >190 mL). Excellent outcome from tPA treatment was substantially increased in patients with DWI lesions <18 mL (77% versus 18% placebo, OR=15.0, P<0.001). Benefit from tPA was also seen with DWI lesions up to 25 mL (69% versus 29% placebo, OR=5.5, P=0.03), but not for DWI lesions >25 mL. In contrast, increasing mismatch ratios did not influence the odds of excellent outcome with tPA. Clinical responsiveness to IV-tPA, and stroke outcome, depends more on baseline DWI and PWI lesion volumes than the extent of perfusion–diffusion mismatch.

Assessing Reperfusion and Recanalization as Markers of Clinical Outcomes After Intravenous Thrombolysis in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)

Background and Purpose— Reperfusion and recanalization have both been used as surrogate markers of clinical outcome in trials of stroke thrombolysis. We aimed to prove that the beneficial impact of recanalization with intravenous tissue plasminogen activator on clinical outcomes is attributable to reperfusion in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). Methods— EPITHET was a prospective, randomized, placebo-controlled trial of intravenous tissue plasminogen activator in the 3- to 6-hour window. Reperfusion was defined as >90% reduction in magnetic resonance perfusion-weighted imaging lesion volume and recanalization as improvement of MR angiographic Thrombolysis In Myocardial Infarction grading by ≥2 points from baseline to Day 3 to 5. Results— At Day 3 to 5, reperfusion and recanalization with intravenous tissue plasminogen activator were strongly correlated. Reperfusion was associated with improved clinical outcome independent of whether recanalization occurred. In contrast, recanalization was not associated with clinical outcome when reperfusion was included as a covariate in regression analyses. Conclusion— Reperfusion is a surrogate marker of clinical outcomes independent of recanalization based on the criteria applied in EPITHET. The impact of recanalization on clinical outcomes was attributable to reperfusion.

Selection of thrombolytic therapy beyond 3 h using magnetic resonance imaging

Purpose of reviewUse of intravenous thrombolytic therapy in ischaemic stroke is restricted to a 3-h time window because of the proof of this time window in pivotal clinical trials. Thrombolysis is aimed at recanalization of occluded arteries and reperfusion of the ischaemic penumbra, a region of critically hypoperfused, functionally impaired, but potentially viable brain. There are a number of current prospective trials that are testing the hypothesis that the presence of the penumbra will predict thrombolytic responders beyond 3 h. Recent findingsUsing magnetic resonance imaging, a mismatch between a larger perfusion-weighted imaging lesion and smaller diffusion-weighted imaging lesion is considered to represent the ischaemic penumbra. Perfusion-weighted imaging provides semiquantitative cerebral blood flow imaging and diffusion-weighted imaging is an index of the largely irreversible ischaemic core. This definition has been modified with the recognition that the perfusion-weighted imaging lesion includes benign oligaemia and that a portion of the diffusion-weighted imaging core is potentially salvageable with rapid reperfusion. Most acute stroke patients have a magnetic resonance imaging-penumbral signature within 6 h of stroke onset. The penumbra is commonly, but not invariably, associated with proximal arterial occlusion and is time-dependent. Preliminary studies have shown benefit from thrombolytic therapy beyond the established 3-h window. SummaryPenumbral imaging using magnetic resonance imaging with perfusion over diffusion weighted imaging mismatch can provide a physiological ‘tissue clock’ in individual patients. Based on this hypothesis, a number of prospective trials are being performed. These include EPITHET, DEFUSE, DIAS, MR RESCUE and ROSIE. Abbreviations ADC: apparent diffusion coefficient; DWI: diffusion-weighted imaging; EPITHET: Echoplanar Imaging Thrombolytic Evaluation Trial; MRA: magnetic resonance angiography; MRI: magnetic resonance imaging; MTT: mean contrast transit time; PWI: perfusion-weighted imaging; tPA: tissue plasminogen activator.

The Benefits of Intravenous Thrombolysis Relate to the Site of Baseline Arterial Occlusion in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)

Background and Purpose— In ischemic stroke, the site of arterial obstruction has been shown to influence recanalization and clinical outcomes. However, this has not been studied in randomized controlled trials, nor has the impact of arterial obstruction site on reperfusion and infarct growth been assessed. We studied the influence of site and degree of arterial obstruction patients enrolled in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). Methods— EPITHET was a prospective, randomized, placebo-controlled trial of intravenous tissue plasminogen activator (tPA) in the 3- to 6-hour time window. Arterial obstruction site and degree were rated on magnetic resonance angiography blinded to treatment allocation and outcomes. Results— In 101 EPITHET patients, 87 had adequate quality magnetic resonance angiography, of whom 54 had baseline arterial obstruction. Infarct growth attenuation was greater in those with tPA treatment compared to placebo among patients with middle cerebral artery (MCA) obstruction (P=0.037). The treatment benefit of tPA over placebo in attenuating infarct growth was greater for MCA than internal carotid artery (ICA) obstruction (P=0.060). With tPA treatment, good clinical outcome was more likely with MCA than with ICA obstruction (P=0.005). Most patients with ICA obstruction did not achieve good clinical outcome, whether treated with tPA (100%) or placebo (77%). The study was underpowered to prove any treatment benefit of tPA among patients with any or severe degree of arterial obstruction. Conclusions— Arterial obstruction site strongly predicts outcomes. ICA obstruction carries a uniformly poor prognosis, whereas good outcomes with MCA obstruction are associated with tPA therapy.

Regional Very Low Cerebral Blood Volume Predicts Hemorrhagic Transformation Better Than Diffusion-Weighted Imaging Volume and Thresholded Apparent Diffusion Coefficient in Acute Ischemic Stroke

Background and Purpose— Currently, diffusion-weighted imaging (DWI) lesion volume is the most useful magnetic resonance imaging predictor of hemorrhagic transformation (HT). Preliminary studies have suggested that very low cerebral blood volume (VLCBV) predicts HT. We compared HT prediction by VLCBV and DWI using data from the EPITHET study. Methods— Normal-percentile CBV values were calculated from the nonstroke hemisphere. Whole-brain masks with CBV thresholds of the <0, 2.5, 5, and 10th percentiles were created. The volume of tissue with VLCBV was calculated within the acute DWI ischemic lesion. HT was graded as per ECASS criteria. Results— HT occurred in 44 of 91 patients. Parenchymal hematoma (PH) occurred in 13 (4 symptomatic) and asymptomatic hemorrhagic infarction (HI) in 31. The median volume of VLCBV was significantly higher in cases with PH. VLCBV predicted HT better than DWI lesion volume and thresholded apparent diffusion coefficient lesion volume in receiver operating characteristic analysis and logistic regression. A cutpoint at 2 mL VLCBV with the <2.5th percentile had 100% sensitivity for PH and, in patients treated with tissue plasminogen activator, defined a population with a 43% risk of PH (95% CI, 23% to 66%, likelihood ratio=16). VLCBV remained an independent predictor of PH in multivariate analysis with traditional clinical risk factors for HT. Conclusions— VLCBV predicted HT after thrombolysis better than did DWI or apparent diffusion coefficient volume in this large patient cohort. The advantage was greatest in patients with smaller DWI volumes. Prediction was better in patients who recanalized. If validated in an independent cohort, the addition of VLCBV to prethrombolysis decision making may reduce the incidence of HT.