T-TIME: Low-dose Alteplase No Match for Microvascular Obstruction

Patrice Wendling

November 15, 2018

CHICAGO — Low-dose alteplase infused directly into the culprit artery early after coronary reperfusion does not reduce microvascular obstruction (MVO) in acute ST-segment elevation MI (STEMI), a randomized study shows.

"The results do not support this therapeutic strategy, as designed," Colin Berry, MD, PhD, University of Glasgow, United Kingdom, said at the American Heart Association (AHA) 2018 Scientific Sessions. "Microvascular obstruction remains a common problem, affecting half of patients with acute STEMI, but there remains no therapy to prevent or treat this problem."

Imaging with optical coherence tomography in patients with STEMI has shown that thrombus commonly persists in the culprit artery after stent implantation, even when invisible on conventional angiography. Persistent STEMI on ECG, an occluded artery, and heavy thrombus burden at initial angiography are all causally linked to MVO.

The hypothesis of the Trial of Low-dose Alteplase During Primary PCI (T-TIME) was that low-dose intracoronary fibrinolysis would improve rates of failed myocardial reperfusion, which independently predicts death and heart failure in the long term, Berry explained.

The phase 2 dose-finding study enrolled patients undergoing percutaneous coronary intervention for acute STEMI due to a proximal, midvessel occlusion of a major coronary artery who presented up to 6 hours after symptom onset. Patients received a single infusion containing placebo or alteplase 10 mg or 20 mg delivered after reperfusion but before stent implantation.

T-TIME was stopped early for futility after randomizing 440 patients, of whom 43% had anterior STEMI and 85% presented with an occluded artery. Two-thirds of patients received a single stent.

The primary outcome of amount of MVO, as measured by % left ventricular (LV) mass on contrast-enhanced MRI between days 2 and 7, occurred at similar rates in patients treated with placebo and in those treated with 20-mg alteplase (2.3% vs 3.5%; P = .32).

There was a slight increase in LV mass to 2.6% among patients treated with 10-mg alteplase, but this difference was not statistically significant (P = .28).

Patients presenting within 4 to 6 hours, compared with 0 to 2 hours or 2 to 4 hours, had more microvascular obstruction, Berry noted. This difference was statistically significant in the alteplase 20-mg group compared with the placebo group (P = .002).

The investigators also found an unexpected increase in troponin T in both alteplase groups at 0, 2, and 24 hours postreperfusion, compared with placebo. At 3 months, there were no between-group differences in angiography, MRI, and ECG outcomes, or N-terminal-pro B-type natriuretic peptide.

"My own view is that the troponin differences that Dr Perry highlighted may well be due to myocardial washout or the play of chance given these other measures," commented invited discussant Paul W. Armstrong, MD, University of Alberta, Edmonton, Canada.

MVO, he said, is perceived as the "final frontier" of STEMI and is affected by patient characteristics, preprocedure and urgently applied therapies, as well as the nature and timeliness of reperfusion.

T-TIME randomized the right patients, was well balanced, and achieved an extraordinary rapid door-to-balloon time of 24 minutes, he said. However, there was a wide 2- to 7-day MRI acquisition window; variability in the sequencing of procedures and tissue plasma activator (tPA) administration; and 30% of patients underwent thrombus aspiration, which is "not an evidence-based approach based on large-scale clinical trials."

Other potential modulators of the primary outcome are the adequacy and timing of the antiplatelet therapy and, in particular, the low use of glycoprotein IIb/IIIa inhibitors.

"As many in the audience will recognize, the combination of fibrinolytic and glycoprotein inhibitors is very effective in producing reperfusion at both myocardial and epicardial levels, regrettably with excess hemorrhage," Armstrong said. "However, with intracoronary tPA, one might have achieved a different result."

To address the challenge of MVO going forward, there needs to be better understanding of its heterogeneous mechanistic targets and confounders, and "we need a better taxonomy associated with microvascular obstruction to provide more informed solutions," he concluded.

Session moderator Christopher Granger, MD, Duke University, Durham, North Carolina, told theheart.org | Medscape Cardiology that T-TIME asked an important question but the signal is quite clear: alteplase it is not the right approach for MVO.

"Part of the problem is that part of the reason for microvascular obstruction is simply that there has been irreversible infarction and therefore the blood vessels aren't working in the infarcted area because of the infarction itself," he said. "So there also is a question of how much of this microvascular obstruction is reversible. I think some of it is, but that's an ongoing question."

Berry reports institutional agreements between the University of Glasgow and Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Coroventis, DalCor, GSK, Novartis, and Philips. Armstrong reports research funding Boehringer Ingelheim for the ongoing STREAM-2 trial. Granger reports having received funding for Boehringer Ingelheim.

American Heart Association (AHA) Scientific Sessions 2018: Abstract 19547. Presented November 11, 2018.

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