Use of alteplase from 4.5 to 9 hours in patients with ischemic stroke but with salvageable brain on perfusion imaging was superior to placebo (aRR 1.44, 95%CI 1.01-2.06; NNT = 17). Symptomatic hemorrhage was more common in the alteplase group.
Short Attention Span Summary
In this meta-analysis focusing on time since TIA, early use of aspirin after TIA reduced the incidence of recurrent stroke at 6 weeks by 60%, NNT = 72. The hazard ratio for those receiving aspirin vs control from 0-2 weeks was 0.07, NNT = 269. This is a dramatically reduced risk. Aspirin had decreased benefit after 12 weeks from the TIA. In patients discharged after TIA, tell them to take a daily aspirin for 3 months, any dose.
Lancet. 2016 May 18. pii: S0140-6736(16)30468-8. doi: 10.1016/S0140-6736(16)30468-8. [Epub ahead of print]
1Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. Electronic address:firstname.lastname@example.org.
2Department of Neurology, Rudolph Magnus Institute for Neuroscience, and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
3Nuffield Department of Population Health, University of Oxford, Oxford, UK.
4Department of Neurology, University Duisburg-Essen, Essen, Germany.
5Department of Clinical Sciences, Section of Neurology, Lund University, Sweden.
6Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Aspirin is recommended for secondary prevention after transient ischaemic attack (TIA) or ischaemic stroke on the basis of trials showing a 13% reduction in long-term risk of recurrent stroke. However, the risk of major stroke is very high for only the first few days after TIA and minor ischaemic stroke, and observational studies show substantially greater benefits of early medical treatment in the acute phase than do longer-term trials. We hypothesised that the short-term benefits of early aspirin have been underestimated.
Pooling the individual patient data from all randomised trials of aspirin versus control in secondary prevention after TIA or ischaemic stroke, we studied the effects of aspirin on the risk and severity of recurrent stroke, stratified by the following time periods: less than 6 weeks, 6-12 weeks, and more than 12 weeks after randomisation. We compared the severity of early recurrent strokes between treatment groups with shift analysis of modified Rankin Scale (mRS) score. To understand possible mechanisms of action, we also studied the time course of the interaction between effects of aspirin and dipyridamole in secondary prevention of stroke. In a further analysis we pooled data from trials of aspirin versus control in which patients were randomised less than 48 h after major acute stroke, stratified by severity of baseline neurological deficit, to establish the very early time course of the effect of aspirin on risk of recurrent ischaemic stroke and how this differs by severity at baseline.
We pooled data for 15 778 participants from 12 trials of aspirin versus control in secondary prevention. Aspirin reduced the 6 week risk of recurrent ischaemic stroke by about 60% (84 of 8452 participants in the aspirin group had an ischaemic stroke vs 175 of 7326; hazard ratio [HR] 0·42, 95% CI 0·32-0·55, p<0·0001) and disabling or fatal ischaemic stroke by about 70% (36 of 8452 vs 110 of 7326; 0·29, 0·20-0·42, p<0·0001), with greatest benefit noted in patients presenting with TIA or minor stroke (at 0-2 weeks, two of 6691 participants in the aspirin group with TIA or minor stroke had a disabling or fatal ischaemic stroke vs 23 of 5726 in the control group, HR 0·07, 95% CI 0·02-0·31, p=0·0004; at 0-6 weeks, 14 vs 60 participants, 0·19, 0·11-0·34, p<0·0001). The effect of aspirin on early recurrent ischaemic stroke was due partly to a substantial reduction in severity (mRS shift analysis odds ratio [OR] 0·42, 0·26-0·70, p=0·0007). These effects were independent of dose, patient characteristics, or aetiology of TIA or stroke. Some further reduction in risk of ischaemic stroke accrued for aspirin only versus control from 6-12 weeks, but there was no benefit after 12 weeks (stroke risk OR 0·97, 0·84-1·12, p=0·67; severity mRS shift OR 1·00, 0·77-1·29, p=0·97). By contrast, dipyridamole plus aspirin versus aspirin alone had no effect on risk or severity of recurrent ischaemic stroke within 12 weeks (OR 0·90, 95% CI 0·65-1·25, p=0·53; mRS shift OR 0·90, 0·37-1·72, p=0·99), but dipyridamole did reduce risk thereafter (0·76, 0·63-0·92, p=0·005), particularly of disabling or fatal ischaemic stroke (0·64, 0·49-0·84, p=0·0010). We pooled data for 40 531 participants from three trials of aspirin versus control in major acute stroke. The reduction in risk of recurrent ischaemic stroke at 14 days was most evident in patients with less severe baseline deficits, and was substantial by the second day after starting treatment (2-3 day HR 0·37, 95% CI 0·25-0·57, p<0·0001).
Our findings confirm that medical treatment substantially reduces the risk of early recurrent stroke after TIA and minor stroke and identify aspirin as the key intervention. The considerable early benefit from aspirin warrants public education about self-administration after possible TIA. The previously unrecognised effect of aspirin on severity of early recurrent stroke, the diminishing benefit with longer-term use, and the contrasting time course of effects of dipyridamole have implications for understanding mechanisms of action.
Wellcome Trust, the National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford.
Copyright © 2016 Rothwell et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.
PMID: 27209146 [PubMed - as supplied by publisher
Short Attention Span Summary
Low dose (0.6mg/kg) tPA was found to be (barely) inferior to standard dose (0.9mg/kg) tPA in regard to the primary outcome of death or severe disability at 90 days, but there were fewer bleeds (1% vs 2.1%) in the low-dose group. This was predominantly an Asian population, which limits generalizability.
N Engl J Med. 2016 May 10. [Epub ahead of print]
Anderson CS1, Robinson T1, Lindley RI1, Arima H1, Lavados PM1, Lee TH1, Broderick JP1, Chen X1, Chen G1, Sharma VK1, Kim JS1, Thang NH1, Cao Y1, Parsons MW1, Levi C1, Huang Y1, Olavarría VV1, Demchuk AM1, Bath PM1, Donnan GA1, Martins S1, Pontes-Neto OM1, Silva F1, Ricci S1, Roffe C1, Pandian J1, Billot L1, Woodward M1, Li Q1, Wang X1, Wang J1, Chalmers J1; ENCHANTED Investigators and Coordinators.
1From the George Institute for Global Health (C.S.A., R.I.L., H.A., X.C., L.B., M.W., Q.L., X.W., J.C.) and Sydney Medical School (C.S.A., R.I.L., H.A., X.C., L.B., M.W., Q.L., J.C.), University of Sydney, and the Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners (C.S.A.), Sydney, the Neurology Department, John Hunter Hospital, and Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW (M.W.P., C.L.), and the Florey Institute of Neuroscience and Mental Health, Parkville, VIC (G.A.D.) - all in Australia; the George Institute China, Peking University (C.S.A.), and the Department of Neurology, Peking University First Hospital (Y.H.), Beijing, the Department of Neurology, Xuzhou Central Hospital, Xuzhou (G.C.), the Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou (Y.C.), and the Shanghai Institute of Hypertension, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (J.W.) - all in China; the University of Leicester, Department of Cardiovascular Sciences and National Institute of Health Research Biomedical Research Unit, Leicester (T.R.), the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham (P.M.B.), the Department of Neurosciences, Royal Stoke University Hospital, Stoke-on-Trent (C.R.), and the George Institute for Global Health, University of Oxford, Oxford (M.W.) - all in the United Kingdom; the Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan (H.A.); Clinica Alemana de Santiago, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo (P.M.L., V.V.O.), and Departamento de Ciencias Neurológicas, Facultad de Medicina, Universidad de Chile (P.M.L.), Santiago, Chile; the Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan (T.-H.L.); the Departments of Neurology and Rehabilitation Medicine and Radiology, University of Cincinnati Neuroscience Institute, University of Cincinnati Academic Health Center, Cincinnati (J.P.B.); the Division of Neurology, Department of Medicine, National University Hospital and School of Medicine, National University of Singapore, Singapore (V.K.S.); the Department of Neurology, University of Ulsan, Asan Medical Center, Seoul, South Korea (J.S.K.); the Department of Cerebrovascular Disease, People's 115 Hospital, Ho Chi Minh City, Vietnam (N.H.T.); Calgary Stroke Program, Department of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada (A.M.D.); the Stroke Division of Neurology Service, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre (S.M.), and the Stroke Service, Neurology Division, Department of Neuroscience and Behavior, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo (O.M.P.-N.) - both in Brazil; the Neurovascular Sciences Group, Neurosciences Department, Bucaramanga, Colombia (F.S.); Unita Operativa de Neurologia, USL Umbria 1, Sedi di Città di Castello e Branca, Italy (S.R.); the Department of Neurology, Christian Medical College, Ludhiana, India (J.P.); and the Department of Epidemiology, Johns Hopkins University, Baltimore (M.W.).
Background: Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage.
Methods: Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control.
Results: The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07).
Conclusions: This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National Health and Medical Research Council of Australia and others; ENCHANTED ClinicalTrials.gov number, NCT01422616 .).
PMID: 27161018 [PubMed - as supplied by publisher]