Reection and Reaction

EPITHET: failed chance or new hope?

Published Online February 22, 2008 DOI:10.1016/S14744422(08)70045-0 See Articles page 299

Approval of recombinant tissue plasminogen activator (alteplase) as an intravenous thrombolytic therapy is currently limited to a 3 h time window after stroke onset. However, many stroke centres worldwide also give thrombolytic therapy beyond 3 h, with selection of patients (by perfusion CT, MRI, ultrasound, or angiography) and use of various delivery routes (intravenous, intra-arterial, or both [bridging]), of devices (eg, EKOS, Penumbra, or Merci), and of inhibitors of glycoprotein IIb/IIIa (eg, abciximab). The most common approaches are intra-arterial thrombolysis with alteplase or urokinase and intravenous thrombolytic therapy based on MRI, for which the patients are usually selected according to their mismatch in diusionweighted MRI (DWI) and perfusion imaging (PI). All previously published trials of intravenous thrombolytic therapy more than 3 h after stroke onset in unselected patients (with intracranial haemorrhage excluded by CT) have been negative.1 However, this time window is now being challenged again, by the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET),2 the third European Cooperative Acute Stroke Study (ECASS-3),3 and the Third International Stroke Trial (IST-3).4 On the basis of trial status and recruitment rates, the results from ECASS-3 and IST-3 will be available in 2008 and 2034, respectively, and those from EPITHET are published in this issue of The Lancet Neurology. Until now, no randomised controlled trial of alteplase beyond 3 h has included patients on the basis of a simple visual assessment of PIDWI mismatch,5 but there is ample class III evidence from hundreds of patients that MRIbased intravenous thrombolytic therapy is safer with respect to symptomatic intracranial haemorrhage and is potentially more eective than is standard CT-based intravenous thrombolytic therapy.6 So is EPITHET a failed chance? The EPITHET investigators aimed to do a randomised, double-blinded, placebocontrolled trial to test the hypothesis that alteplase promotes reperfusion and attenuates infarct growth when given 36 h after onset in patients with PIDWI mismatch. However, they selected patients beyond 3 h by CT criteria, randomly assigned them to alteplase or placebo, and then did MRI but did not use the MRI ndings to select patients. Reperfusion was assessed at day 35, which is suboptimum for this surrogate endpoint because many

patients already have spontaneous recanalisation by this time, so the eect of the thrombolytic drug (ie, early enhancement of presumably nutritive reperfusion) was not assessed. This point was addressed in the Diusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study,7 which had a similar but non-randomised and uncontrolled design and measured reperfusion within 48 h after intravenous thrombolytic therapy. A more rigorous randomised controlled trial of intravenous thrombolytic therapy on the basis of PIDWI mismatch would have used MRI to select patients and randomise them between alteplase and placebo. Although EPITHET did not show signicance for the primary endpointattenuation of geometric mean relative growth of infarct volumevarious secondary analyses showed dierences that were closer to signicance or were positive. These analyses included other volume-based denitions of infarct growth and reperfusion in patients who had a mismatch. However, these measures did not translate into better clinical outcomes in the alteplase group than in the placebo group. Overall, the number of patients with a mismatch who received alteplase was lower than that in DEFUSE, because of the placebocontrolled design (there were 37 patients with mismatch in the alteplase group of EPITHET, and 43 in the placebo group). Furthermore, day 90 volumes were available in only 74 of the 101 enrolled patients (because 20 had died and seven were lost to follow up; 19 patients were lost from the alteplase group and eight from the alteplase group), which weakened the power of the study. On a side note, the volume change from day 30 to day 90 seems to be insignicant,8 and volume assessments at day 30 seem to be less susceptible to loss to follow-up than do those at day 90.7 Late reperfusion was more common with alteplase than with placebo (56% vs 26%), and was associated with reduced infarct growth and improved neurological and functional outcomes. This nding is consistent with DEFUSE, and gives hope that alteplase might be benecial after the 3 h time window. The value of PIDWI mismatch for selection of patients has been criticised by some researchers, although these analyses have some weaknesses.9,10 However, they correctly state that Standardised denitions of mismatch and perfusion are needed, and more data are needed from studies including patients with and without mismatch, and
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randomised treatment allocation, to determine the role of mismatch. Two phase II trials11,12 of another thrombolytic drug, desmoteplase, were positive for surrogate and clinical endpoints but the paramount study, the second Desmoteplase in Acute Ischemic Stroke Trial (DIAS-2), was negative, supposedly owing partly to the use of selection methods other than MRI. After the setback of DIAS-2, the planned combined analysis of DEFUSE and EPITHET provides new hope that the eects of alteplase beyond 3 h after stroke will be better understood, although great care must be taken in pooling of endpoints that are not consistent in these trials (eg, time of tissue outcome or reperfusion assessment). Finally, I hope that after the promising hypotheses tested in the secondary endpoints of EPITHET, and after the results of ECASS-3 become available in autumn 2008, a randomised controlled trial based exclusively on MRI mismatch will be designed and initiated, whether it looks at administration of alteplase beyond 3 h or beyond 45 h. The time is right for a joint international eort to plan and undertake such a trial. Peter D Schellinger
Department of Neurology, University at Erlangen, D-91054 Erlangen, Germany peter.schellinger@uk-erlangen.de
I am a member of the speakers bureau and advisory board of Boehringer Ingelheim (the manufacturer of alteplase) and have received honoraria for these functions.

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Schellinger PD, Fiebach JB, Mohr A, Ringleb PA, Jansen O, Hacke W. Thrombolytic therapy for ischemic strokea review. Part IIntravenous thrombolysis. Crit Care Med 2001; 29: 181218. Davis SM, Donnan GA, Parsons MW et al, for the EPITHET investigators. Eects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008; available online Feb 22. DOI: 10.1016/S14744422(08)70044-9. ECASS 3: The European Cooperative Acute Stroke Study. Available at http://www.ecass3.com/ (accessed Feb 2, 2008). The Third International Stroke Trial. Available at http://www.strokecenter. org/trials/TrialDetail.aspx?tid=81 (accessed Feb 2, 2008). Schellinger PD, Fiebach JB, Hacke W. Imaging-based decision making in thrombolytic therapy for ischemic stroke: present status. Stroke 2003; 34: 57583. Schellinger PD, Thomalla G, Fiehler J, et al. MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an analysis of 1210 patients. Stroke 2007; 38: 264045. Albers GW, Thijs VN, Wechsler L, et al. Magnetic resonance imaging proles predict clinical response to early reperfusion: the diusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006; 60: 50817. Gaudinski MR, Henning EC, Miracle A, et al. Establishing nal infarct volume: stroke lesion evolution past 30 days is insignicant. Stroke (in press). Kane I, Carpenter T, Chappell F, et al. Comparison of 10 dierent magnetic resonance perfusion imaging processing methods in acute ischemic stroke: eect on lesion size, proportion of patients with diusion/perfusion mismatch, clinical scores, and radiologic outcomes. Stroke 2007; 38: 315864. Kane I, Sandercock P, Wardlaw J. Magnetic resonance perfusion diusion mismatch and thrombolysis in acute ischaemic stroke: a systematic review of the evidence to date. J Neurol Neurosurg Psychiatry 2007; 78: 48591. Furlan AJ, Eyding D, Albers GW, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and ecacy 3 to 9 hours after stroke onset. Stroke 2006; 37: 122731. Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005; 36: 6673.

Does donepezil improve executive function in patients with CADASIL?

Clinical trials of cholinesterase inhibitors and memantine for cerebrovascular cognitive impairment have required that the participants have dementia.1 Vascular dementia has been dened in these trials in accordance with the NINDS-AIRENS criteria2 for probable vascular dementia as cognitive decline that manifests as impairment of memory and decit in two or more cognitive domains;2 decits that are severe enough to interfere with activities of daily living; cerebrovascular disease dened by focal signs; and an association between the dementia and cerebrovascular disease. As a result, patients with cerebrovascular disease who have been entered into recent trials had, on average, a moderately severe dementia, and their older age and advanced memory impairment also mean that many also have Alzheimers disease. Thus, the outcomes of vascular
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dementia trials are dicult to interpret. The current criteria for diagnosing vascular dementia do not describe a suciently homogeneous clinical sample for a therapeutic claim, and this is one reason why the FDA has not approved a cholinesterase inhibitor for treating cognitive impairment in the context of cerebrovascular disease. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has a clear pathogenesis; it is diagnosed by characteristic mutations in NOTCH3 and small artery angiopathy seen on electron microscopy. The predominant neuropsychological impairments in CADASIL are in processing speed and executive function,3,4 but the variability in the expression of the illness (eg, age of onset of transient ischemic attacks or stroke, the pattern of subcortical ischemic lesions, and

Published Online February 22, 2008 DOI:10.1016/S14744422(08)70047-4 See Articles page 310

FDA Peripheral and Central Nervous System Drugs Advisory Committee, March 14, 2001, http://www.fda.gov/ohrms/ dockets/ac/01/minutes/3724m2. pdf

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