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      Efficacy and safety of low dose alteplase for intravenous thrombolysis in Asian stroke patients: a meta-analysis

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          Abstract

          Whether low dose alteplase is comparable to standard dose in efficacy and safety for intravenous thrombolysis (IVT) in Asian stroke patients remains unverified. PubMed, EMBASE, and Cochrane Library Database from the beginning to June 30, 2017 were searched. IVT efficacy was measured by favorable outcome (modified Rankin Scale scores of 0–1) at 3 months, and safety measured by mortality within 3 months and symptomatic intracerebral hemorrhage (SICH). Pooled estimates were conducted using fixed- or random-effects model depending on heterogeneity. For SICH, studies were pooled separately according to different definitions. Twelve studies involving 7,905 participants were included. No association was found between alteplase dose and favorable outcome (OR = 0.94, 95% CI 0.78–1.14, P = 0.5; heterogeneity: P hetero  = 0.01, I 2 = 57.3%) and mortality (OR = 0.87, 95% CI 0.74–1.02, P = 0.08; P hetero  = 0.83, I 2 = 0) using random- and fixed-effects models, respectively. Low dose alteplase was associated with lower SICH as defined by the National Institute of Neurological Disorders and Stroke study (OR = 0.79, 95% CI 0.64–0.99, P = 0.04; P hetero  = 0.57, I 2 = 0) using fixed-effects model. Subgroup and sensitivity analysis could change the results significantly. Current limited evidence was insufficient to support the speculation that low dose alteplase was comparable to standard dose in thrombolytic efficacy and safety in Asian stroke patients.

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          Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis

          Summary Background Recombinant tissue plasminogen activator (rt-PA, alteplase) improved functional outcome in patients treated soon after acute ischaemic stroke in randomised trials, but licensing is restrictive and use varies widely. The IST-3 trial adds substantial new data. We therefore assessed all the evidence from randomised trials for rt-PA in acute ischaemic stroke in an updated systematic review and meta-analysis. Methods We searched for randomised trials of intravenous rt-PA versus control given within 6 h of onset of acute ischaemic stroke up to March 30, 2012. We estimated summary odds ratios (ORs) and 95% CI in the primary analysis for prespecified outcomes within 7 days and at the final follow-up of all patients treated up to 6 h after stroke. Findings In up to 12 trials (7012 patients), rt-PA given within 6 h of stroke significantly increased the odds of being alive and independent (modified Rankin Scale, mRS 0–2) at final follow-up (1611/3483 [46·3%] vs 1434/3404 [42·1%], OR 1·17, 95% CI 1·06–1·29; p=0·001), absolute increase of 42 (19–66) per 1000 people treated, and favourable outcome (mRS 0–1) absolute increase of 55 (95% CI 33–77) per 1000. The benefit of rt-PA was greatest in patients treated within 3 h (mRS 0–2, 365/896 [40·7%] vs 280/883 [31·7%], 1·53, 1·26–1·86, p<0·0001), absolute benefit of 90 (46–135) per 1000 people treated, and mRS 0–1 (283/896 [31·6%] vs 202/883 [22·9%], 1·61, 1·30–1·90; p<0·0001), absolute benefit 87 (46–128) per 1000 treated. Numbers of deaths within 7 days were increased (250/2807 [8·9%] vs 174/2728 [6·4%], 1·44, 1·18–1·76; p=0·0003), but by final follow-up the excess was no longer significant (679/3548 [19·1%] vs 640/3464 [18·5%], 1·06, 0·94–1·20; p=0·33). Symptomatic intracranial haemorrhage (272/3548 [7·7%] vs 63/3463 [1·8%], 3·72, 2·98–4·64; p<0·0001) accounted for most of the early excess deaths. Patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early. Interpretation The evidence indicates that intravenous rt-PA increased the proportion of patients who were alive with favourable outcome and alive and independent at final follow-up. The data strengthen previous evidence to treat patients as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke. Funding UK Medical Research Council, Stroke Association, University of Edinburgh, National Health Service Health Technology Assessment Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm (Arbetsmarknadens Partners Forsakringsbolag), Karolinska Institute, Marianne and Marcus Wallenberg Foundation, Research Council of Norway, Oslo University Hospital.
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            Global burden of intracranial atherosclerosis.

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              Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT).

              Based on previous studies comparing different recombinant tissue plasminogen activator (rt-PA) doses, we performed a clinical trial with 0.6 mg/kg, which is lower than the internationally approved dosage of 0.9 mg/kg, aiming to assess the efficacy and safety of alteplase in acute ischemic stroke for the Japanese. Our prospective, multicenter, single-arm, open-label trial was designed with a target sample size of 100 patients. The primary end points were the proportion of patients with a modified Rankin Scale (mRS) score of 0 to 1 at 3 months and the incidence of symptomatic intracranial hemorrhage (sICH) within 36 hours. Thresholds for these end points were determined by calculating 90% CIs of weighted averages derived from published reports. The protocol was defined according to the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA stroke study with slight modifications. Among the 103 patients enrolled, 38 had an mRS of 0 to 1 at 3 months; this proportion (36.9%) exceeded the predetermined threshold of 33.9%. sICH within 36 hours occurred in 6 patients; this incidence (5.8%) was lower than the threshold of 9.6%. In patients receiving 0.6 mg/kg alteplase, the outcome and the incidence of sICH were comparable to published data for 0.9 mg/kg. These findings indicate that alteplase, when administered at 0.6 mg/kg to Japanese patients, might offer a clinical efficacy and safety that are compatible with data reported in North America and the European Union for a 0.9 mg/kg dose.
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                Author and article information

                Contributors
                zjllxx1968@163.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                22 November 2017
                22 November 2017
                2017
                : 7
                : 16076
                Affiliations
                Department of Neurology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041 Sichuan Province China
                Author information
                http://orcid.org/0000-0003-0391-4548
                Article
                16355
                10.1038/s41598-017-16355-9
                5700077
                29167555
                61cf5e39-8975-4f87-8387-4327ffc87ed0
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 7 July 2017
                : 10 November 2017
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