Low-dose intracoronary alteplase during primary percutaneous coronary intervention in patients with acute myocardial infarction: the T-TIME three-arm RCT

McCartney, P. J. et al. (2020) Low-dose intracoronary alteplase during primary percutaneous coronary intervention in patients with acute myocardial infarction: the T-TIME three-arm RCT. Efficacy and Mechanism Evaluation, 7(5), (doi: 10.3310/eme07050) (PMID:33175484)

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Abstract

BACKGROUND:Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction and is independently associated with adverse outcomes. OBJECTIVE:To determine whether or not a strategy involving low-dose intracoronary fibrinolytic therapy infused early after coronary reperfusion will reduce microvascular obstruction. DESIGN:This was a multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging trial. SETTING:The trial took place at 11 hospitals in the UK between 17 March 2016 and 21 December 2017. PARTICIPANTS:Patients with acute ST-segment elevation myocardial infarction and a symptom onset to reperfusion time of ≤ 6 hours were eligible for randomisation. Radial artery access was a requirement, and further angiographic criteria included a proximal-to-middle coronary artery occlusion or impaired coronary flow in the presence of a definite thrombus in the culprit coronary artery. Exclusion criteria included a functional coronary collateral supply to the infarct-related artery, any contraindication to fibrinolysis and lack of informed consent. Additional exclusion criteria for safety were (1) requirement for immunosuppressive drug therapy for ≤ 3 months and (2) treatment with an antimicrobial agent. INTERVENTION:A total of 440 participants were randomly assigned 1 : 1 : 1 to treatment with placebo (n = 151), 10 mg of alteplase (n = 144) or 20 mg of alteplase (n = 145) administered by manual infusion directly into the infarct-related coronary artery over 5–10 minutes. The intervention was scheduled to happen after reperfusion and before stent implantation. OUTCOMES:The primary outcome was the amount of microvascular obstruction (percentage of left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging at 2–7 days after enrolment. The primary analysis was the comparison between the 20 mg of alteplase group and the placebo group; if this comparison was not significant, the comparison of the 10 mg of alteplase group with the placebo group was considered as a secondary analysis. SAMPLE SIZE:A total of 618 patients (minimum of 558 patients). Recruitment was halted on 21 December 2017 given that conditional power for the primary outcome based on a prespecified analysis of the first 267 randomised participants was < 30% in both treatment groups (futility criterion). METHODS:The primary outcome was compared between groups using a stratified Wilcoxon rank-sum test (van Elteren test), stratified by the location of the myocardial infarction. RESULTS:Among the 440 patients (mean age of 60.5 years; 15% women), the primary end point was measured in 396 (90%) patients, 17 (3.9%) withdrew, seven died and all other patients were followed up to 3 months. The amount (mean percentage of left ventricular mass) of microvascular obstruction was 2.3% versus 2.6% versus 3.5% in the placebo, 10 mg of alteplase and 20 mg of alteplase groups, respectively. In the primary analysis, microvascular obstruction did not differ between the 20 mg of alteplase group and the placebo group: 3.5% versus 2.3%, estimated difference 1.16% (95% confidence interval –0.08% to 2.41%; p = 0.32). In the secondary analysis, microvascular obstruction did not differ between the 10 mg of alteplase group and the placebo group: 2.6% versus 2.3%, estimated difference 0.29% (95% confidence interval –0.76% to 1.35%; p = 0.74). By 3 months, major adverse cardiac events (cardiac death, non-fatal myocardial infarction and unplanned hospitalisation for heart failure) had occurred in 15 (10.1%) patients in the placebo group, 18 (12.9%) in the 10 mg of alteplase group and 12 (8.2%) in the 20 mg of alteplase group. CONCLUSIONS:Adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction compared with placebo. LIMITATIONS:Premature discontinuation of enrolment limited the power of the secondary and safety analyses. FUTURE WORK:Low-dose intracoronary alteplase or tenecteplase could be compared with placebo at the end of primary percutaneous coronary intervention in patients with an ischaemic time of < 4 hours. TRIAL REGISTRATION:This trial is registered as ClinicalTrials.gov NCT02257294.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Macfarlane, Professor Peter and McConnachie, Professor Alex and Ford, Thomas and Robertson, Dr Keith and Shaukat, Dr Aadil and Rocchiccioli, Dr John and McEntegart, Dr Margaret and Welsh, Dr Paul and Petrie, Professor Mark and Gillespie, Dr Lynsey and McCartney, Dr Peter and Oldroyd, Dr Keith and Watkins, Dr Stuart and Ford, Professor Ian and Berry, Professor Colin and Maznyczka, Dr Annette Marie and Eteiba, Dr Hany and Tait, Dr Robert and Sattar, Professor Naveed
Authors: McCartney, P. J., Eteiba, H., Maznyczka, A. M., McEntegart, M., Greenwood, J. P., Muir, D. F., Chowdhary, S., Gershlick, A. H., Appleby, C., Cotton, J. M., Wragg, A., Curzen, N., Oldroyd, K. G., Lindsay, M., Rocchiccioli, J. P., Shaukat, A., Good, R., Watkins, S., Robertson, K., Malkin, C., Martin, L., Gillespie, L., Ford, T. J., Petrie, M. C., Macfarlane, P. W., Tait, R. C., Welsh, P., Sattar, N., Weir, R. A., Fox, K. A., Ford, I., McConnachie, A., and Berry, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Efficacy and Mechanism Evaluation
Publisher:NIHR Journals Library
ISSN:2050-4365
ISSN (Online):2050-4373
Copyright Holders:Copyright © 2020 Queen’s Printer and Controller of HMSO
First Published:First published in Efficacy and Mechanism Evaluation 7(5)
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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