A multi-center randomized, double blind, placebo-controlled, parallel group clinical trial has shown that among patients with acute ST-elevation myocardial infarction (STEMI) presenting within 6 hours of symptoms, adjunctive low-dose intracoronary alteplase given after reperfusion via primary percutaneous intervention does not reduce microvascular obstruction.
The results of the trial were presented at the American Heart Association 2018 Scientific Sessions by Dr. Colin Berry, MD, PhD (University of Glasgow, Scotland) and simultaneously published in JAMA . The T-Time trial enrolled 440 participants (15% females) with STEMI (proximal to mid-level obstruction) and randomized in a 1:1:1 fashion to either receive placebo, 20 mg alteplase and 10 mg alteplase after reperfusion and before stent placement. Only patients presenting within 6 hours of STEMI were enrolled to include participants with salvageable myocardium. The primary outcome was the amount of microvascular obstruction (percentage of left ventricular mass) revealed by late gadolinium contrast-enhanced MRI 10-15 minutes after contrast administration on an MRI scan performed 2-7 days post-MI. The investigators were unable to show significant difference in microvascular obstruction between the 20-mg alteplase group and the placebo group (mean, 3.5% vs 2.3%; estimated difference, 1.16%; 95% CI, −0.08% to 2.41%; van Elteren test, P = .32). The comparison of the 10-mg alteplase group and the placebo group also did not reveal any significant difference in rates of microvascular obstruction (mean, 2.6% vs 2.3%; estimated difference, 0.29%; 95% CI, −0.76% to 1.35%; van Elteren test, P = .74). Alteplase is a tissue plasminogen activator and a fibrinolytic drug, which may increase the risk of cerebrovascular and systemic bleeding events, however, in this trial a targeted intracoronary infusion of alteplase was used to minimize the systemic effects and in turn reduce bleeding events. In addition, patients with risk factors for bleeding were excluded to further reduce associated bleeding events. Consequently, major bleeds were uncommon, occurring in 1 patient in each of the 10-mg and 20-mg alteplase groups.
Coronary microvascular obstruction occurs in up to half of patients undergoing successful primary PCI and is associated with worse outcomes, including adverse cardiac remodeling. Ischemia-related injury, reperfusion-related injury, distal embolization, and individual susceptibility play key mechanistic roles in microvascular obstruction. The gold standard method for assessing microvascular function is the direct measurement of coronary blood flow velocity using an intracoronary Doppler wire, which is an invasive procedure. Cardiac MRI can provide a non-invasive accurate quantification, and localization of coronary microvascular obstruction and infarct size relative to the entire left ventricle (expressed as a percentage).
Over the years, several efforts have been made to define an effective strategy to prevent microvascular obstruction, and so far no treatment has proved to be beneficial for the prevention or treatment of microvascular obstruction in a randomized controlled setting. Failure of therapies involving adenosine, atrial natriuretic peptide (ANP), abciximab, pexelizumab, exenatide and routine manual thrombectomy has led investigators to seek alternative treatment strategies to address this issue. There is a growing interest in the potential efficacy of adjunctive intracoronary fibrinolytic therapy during primary PCI for prevention and treatment of microvascular obstruction. Phase III randomized clinical trials such as the STRIVE trial and RESTORE-MI trial are currently underway to investigate the efficacy of tissue plasminogen activators for prevention and treatment of microvascular obstruction. The STRIVE and RESTORE-MI trials plan on infusing tissue plasminogen activators at the end of primary PCI, after stent implantation as opposed to the current T-TIME trial, in which the adjunctive alteplase dose was given before stent implantation.
In terms of limitations, the trial was limited to study short-term findings up to 3 months. Secondly, the trial was discontinued by the data and safety monitoring board (DSMB) when the pre-specified futility criteria were met and premature discontinuation may have limited comprehensive evaluation of this treatment strategy.
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