Low-dose intracoronary alteplase during primary percutaneous coronary intervention in patients with acute myocardial infarction: the T-TIME three-arm RCT
Authors: McCartney Peter J , Eteiba Hany , Maznyczka Annette M , McEntegart Margaret , Greenwood John P , Muir Douglas F , Chowdhary Saqib , Gershlick Anthony H , Appleby Clare , Cotton James M , Wragg Andrew , Curzen Nick , Oldroyd Keith G , Lindsay Mitchell , Rocchiccioli J Paul , Shaukat Aadil , Good Richard , Watkins Stuart , Robertson Keith , Malkin Christopher , Martin Lynn , Gillespie Lynsey , Ford Thomas J , Petrie Mark C , Macfarlane Peter W , Tait R Campbell , Welsh Paul , Sattar Naveed , Weir Robin A , Fox Keith A , Ford Ian , McConnachie Alex , Berry Colin 
Published: November 2020

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.

Funding
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 5. See the NIHR Journals Library website for further project information.