P2707Invasive coronary physiology during primary percutaneous coronary intervention in patients treated with intracoronary alteplase or placebo: the double-blind T-TIME physiology substudy
Authors: Maznyczka A , McCartney P , Oldroyd K G , McEntegart M , Lindsay M , Eteiba H , Rocchiccioli P , Good R , Shaukat A , Kodoth V , Greenwood J , Robertson K , Cotton J , McConnachie A , Berry C 
Published: October 2019

Abstract

Background
Impaired microcirculatory reperfusion worsens prognosis post-primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). Intracoronary (IC) alteplase targets persisting thrombus post-reperfusion & distal embolisation. In the T-TIME trial microvascular obstruction on cardiac magnetic resonance (CMR) did not differ with IC alteplase vs placebo.

Purpose
To prospectively determine if index of microcirculatory resistance (IMR) is lower & coronary flow reserve (CFR) or resistive reserve ratio (RRR) are higher (improved) with IC alteplase, & to provide mechanistic insights.

Methods
A pre-planned substudy of the main protocol. From 2016–2017, STEMI patients from 3 UK hospitals ≤6 hrs ischaemic time were randomised in a 1:1:1 dose-ranging, double-blind design. Following standard care reperfusion, alteplase (10 or 20mg) or placebo was infused over 5–10 mins proximal to the culprit lesion pre-stenting. IMR (primary outcome), CFR & RRR (secondary outcomes) were measured in the culprit artery post-PCI. Physiology results were obscured from clinicians acquiring the data, to maintain blinding. CMR was performed 2 days & 3 months post-STEMI. Subgroup analyses were prespecified including by ischaemic time (<2 hours, 2–4 hrs, >4 hrs) & IMR threshold >32.

Results
In 144 patients (mean age 59 yrs, 80% male), IMR, CFR or RRR post-PCI did not differ with alteplase vs placebo (Table). Patients with ischaemic time <2 hrs had a dose related increase in CFR (placebo 1.2 [IQR 1.1–1.7], alteplase 10mg 1.4 [IQR 1.0–1.8], alteplase 20mg 2.0 [IQR 1.8–2.3] p=0.01 for interaction) & RRR (placebo 1.5 [IQR 1.3–1.9], alteplase 10mg 1.6 [1.1–2.2], alteplase 20mg 2.2 [2.0–2.6], p=0.03 for interaction). In subjects with post-PCI IMR>32, % ST-resolution at 60 mins was worse with alteplase 10mg vs placebo (23.1±53.9 vs 50.9±31.5) & in those with IMR≤32% ST-resolution at 60 mins was better with alteplase 20mg vs placebo (68.0±30.7 vs 39.1±43.2), p=0.002 for interaction. The CMR findings in the substudy & overall trial populations were consistent.
Main results Placebo Alteplase 10mg Alteplase 20mg (n=53) (n=41) (n=50) IMR, median (IQR) 33.0 (17.0–57.0) 22.0 (17.0–42.0) 37.0 (20.0–57.8) p=0.15 p=0.78 CFR, median (IQR) 1.3 (1.1–1.8) 1.4 (1.1–1.9) 1.5 (1.1–2.0) p=0.92 p=0.74 RRR, median (IQR) 1.6 (1.3–2.2) 1.6 (1.4–2.6) 1.8 (1.3–2.4) p=0.69 p=0.81 P-values for comparison of alteplase with placebo.

Conclusions
In acute STEMI with ischaemic time ≤6 hrs, IMR, CFR or RRR post-PCI did not differ with alteplase vs placebo. In those with shorter ischaemic times (<2 hrs) CFR & RRR, but not IMR, were improved with alteplase. We observed interactions between alteplase dose, ischaemic time & mechanisms of effect.

Acknowledgement/Funding
Dr Maznyczka is funded by a fellowship from the British Heart Foundation (FS/16/74/32573). T-TIME was funded by grant 12/170/4 from NIHR-EME