Alteplase for Acute Ischemic Stroke Outcomes by Clinically Important Subgroups in the Third International Stroke Trial Richard I. Lindley, MD; Joanna M. Wardlaw, FRCR; William N. Whiteley, PhD; Geoff Cohen, MSc; Lisa Blackwell, BSc(HONS); Gordon D. Murray, PhD; Peter A.G. Sandercock, DM; on behalf of the IST-3 Collaborative Group Background and Purpose—Our aim was to identify whether particular subgroups of patients had an unacceptably high risk of symptomatic intracranial hemorrhage or low chance of benefit when treated with alteplase (recombinant tissue-type plasminogen activator). Methods—Third International Stroke Trial was an international randomized trial of the intravenous (IV) recombinant plasminogen activator alteplase (0.9 mg/kg) versus control in 3035 (1515 versus 1520) patients. We analyzed the effect of recombinant tissue-type plasminogen activator on 6-month functional outcome, early death, and symptomatic intracranial hemorrhage (both ≤7 days). We tested for any differences in treatment effect between subgroups by a test of interaction. Our 13 protocol prespecified subgroups were time to randomization, age, sex, stroke subtype, atrial fibrillation, early ischemic change (clinician and expert panel), prior antiplatelet use, stroke severity, diastolic and systolic blood pressure at randomization, center’s thrombolysis experience, and trial phase. Analyses were adjusted for key baseline prognostic factors. Results—There were no significant interactions in the subgroups analyzed that were consistent across all 3 outcomes. Treatment with recombinant tissue-type plasminogen activator increased the odds of symptomatic intracranial hemorrhage by a greater amount in patients taking prior antiplatelets than those who were not (P=0.019 for test of interaction), but had no clear detrimental effect on functional outcome at 6 months in this group (P=0.781 for test of interaction). Conclusions—Among the types of patient in the Third International Stroke Trial, this secondary analysis did not identify any subgroups for whom treatment should be avoided. Given the limitations of the analysis, we found no clear evidence to avoid treatment in patients with prior ischemic stroke, diabetes mellitus, or hypertension. Clinical Trial Registration—URL: http://www.controlled-trials.com. Unique identifier: ISRCTN25765518. http://www. controlled-trials.com/ISRCTN25765518.  (Stroke. 2015;46:746-756. DOI: 10.1161/STROKEAHA.114.006573.) Key Words: alteplase



intracranial hemorrhages

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ntravenous thrombolysis with recombinant tissue-type plasminogen activator (r-tPA), alteplase, improves survival free of dependency for ≤18 months after stroke, despite the risk of early symptomatic intracranial hemorrhage (sICH).1–3 Concern about the risk of fatal sICH may have been a factor in the slow uptake of stroke thrombolysis. The aims of the Third International Stroke Trial (IST-3) were to establish whether a wider group of patients would benefit from stroke thrombolysis and which categories of patients were most likely to benefit or be harmed by treatment.4 IST-3 recruited 3035 patients who were randomized to r-tPA or control within 6 hours of stroke onset; the main results and principal prespecified subgroup analyses have been previously published.1 We wished to further explore whether any factors modify the benefits (improvement in functional



stroke



thrombolytic therapy



treatment outcome

outcome at 6 months) or hazards (early sICH defined as those events occurring within 7 days or early death, defined as those occurring within 7 days). Because the effect of treatment was not nominally significant for the dichotomous primary outcome (whether unadjusted or adjusted),1 we have performed additional subgroup analyses with the more statistically efficient ordinal analysis of functional outcome (which was significant at P=0.001).5–9 In these new analyses, we tested the null hypothesis that across subgroups, there was no interaction with the treatment effect on 6-month functional outcome, deaths, or sICH within 7 days.

Methods The methods of the trial are described in detail elsewhere.4,10 Briefly, IST-3 was a randomized, open-treatment trial of intravenous r-tPA

Received June 27, 2014; final revision received December 14, 2014; accepted December 16, 2014. From the University of Sydney, Sydney, Australia (R.I.L.); University of Edinburgh, Edinburgh, UK (J.M.W., W.N.W., G.C., G.D.M., P.A.G.S.); and University of Oxford, Oxford, UK (L.B.). Correspondence to Richard I. Lindley, MD, Department of Geriatric Medicine, Sydney Medical School–Westmead Hospital, Professorial Fellow, George Institute for Global Health, University of Sydney, NSW 2006, Australia. E-mail [email protected] © 2015 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.114.006573

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Lindley et al   IST-3 Subgroup Analyses    747 (0.9 mg/kg, maximum dose of 90 mg) versus control. To be eligible, patients had to meet the following criteria: symptoms and signs of clinically definite acute stroke; the time of stroke onset was known; treatment could be started within 6 hours of onset; CT or MRI had reliably excluded both intracranial hemorrhage and structural brain lesions, which could mimic stroke (eg, cerebral tumor); and the patient or a valid proxy gave informed consent. Only if both the clinician and the patient (or their proxy) felt that the treatment was promising but unproven, that is, when there was neither a clear indication for or a clear contraindication to treatment, could the patient be included in the trial. After appropriate informed consent, baseline data were recorded during the secure central telephone or web-based computer randomization system. The system used a minimization algorithm to achieve balance for key prognostic factors.10,11 To avoid predictable alternation of treatment allocation, and thus potential loss of allocation concealment, patients were allocated with a probability of 0.80 to the treatment group that would minimize the difference between the groups on the key prognostic factors. Recruitment began in May 2000 and was completed in July 2011. Our protocol-prespecified subgroups were all based on data recorded at randomization and before the treatment allocation was generated: time from onset to randomization, age, sex, ischemic stroke subtype defined by the Oxfordshire Community Stroke Project classification,12 atrial fibrillation, the clinician’s immediate assessment of the prerandomization scan for the presence of recent ischemic change (the data recorded before treatment was allocated was the response to the question, is there evidence of recent ischemic change on the brain scan which is likely to have caused this stroke?), the expert panel’s later blinded assessment of acute ischemic change on the prerandomization scan, treatment with antiplatelet drugs in the previous 48 hours, stroke severity as defined by the National Institutes of Health Stroke Scale (NIHSS; 0–5, 6–14, 15–24, 25+),11,13 systolic (≤143, 144–164, ≥165 mm Hg) and diastolic (≤74, 75–89, ≥90 mm Hg) blood pressure, glucose level at randomization (8 mmol/L), center pretrial experience of stroke thrombolysis (defined as the treatment of ≥3 patients in the 12 months before joining the trial), and trial phase (pilot double blind start-up phase versus open label main phase). Additional data on prior medical history and treatment collected after review of medical records were recorded at 7 days or prior death or discharge of prior stroke, details of prior treatment with antiplatelet agents (aspirin, or clopidogrel, or dipyridamole), treatment for hypertension, and treatment for diabetes mellitus. The outcomes of interest for these analyses were death from any cause within 7 days, sICH within 7 days, and functional outcome at 6 months as assessed by the Oxford Handicap Score (OHS). We defined symptomatic intracranial hemorrhage as significant neurological deterioration accompanied by clear evidence of significant hemorrhage on the postrandomization scan (or autopsy if not rescanned and death occurs after 7 days), which on blinded assessment by the expert panel was thought to have contributed significantly to the burden of brain damage.

Statistical Methods We wished to test for heterogeneity in the effect of treatment on the 3 key outcomes across all subgroups with tests for interaction.14 In choosing the most appropriate approach, we took account of the likely power of the analyses to detect clinically important interactions. Analyses associated with statistically highly significant results for the overall effect on the outcome event of interest are less likely to yield false-positive or false-negative evidence of heterogeneity.14 In IST-3,1 2 outcomes met this criterion (sICH within 7 days, adjusted odds ratio (OR) of 6.94 95% confidence interval [95% CI], 4.07– 11.8], P6 hours poststroke with the true delay from stroke to randomization not well ascertained; these cases were therefore omitted from all analyses. The footnotes of Table explain the main reason for the missing values in the subgroups. Table illustrates that

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Figure 1. Continued

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Lindley et al   IST-3 Subgroup Analyses    749

Figure 1 (Continued). Effect of recombinant tissue-type plasminogen activator (r-tPA) on functional outcome at 6 months: adjusted ordinal analysis of the Oxford Handicap scale. A, Protocol-specified subgroups. B, Clinically important subgroups. Effect of treatment on odds that Oxford Handicap Score (OHS) is less than any given level; the model assumes this ratio is the same for all levels. Adjustment for linear effects of age, NIHSS, and time of randomization. BP indicates blood pressure; CI, confidence interval; LACI, lacunar infarct; NIHSS, National Institutes of Health Stroke Scale; OCSP, Oxfordshire Community Stroke Project; PACI, partial anterior circulation infarct; POCI, posterior circulation infarct; and TACI, total anterior circulation infarct.

the types of patient recruited in the 3 main time periods varied. For example, most (79.2%) of those randomized within 3 hours were over 80 years of age. Those with severe stroke, who are known to have the shortest delay to hospital admission, were more likely to be randomized early as seen in other stroke trials. There were no significant interactions at the P

Alteplase for acute ischemic stroke: outcomes by clinically important subgroups in the Third International Stroke Trial.

Our aim was to identify whether particular subgroups of patients had an unacceptably high risk of symptomatic intracranial hemorrhage or low chance of...
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