This article is more than 5 years old. Information may no longer be current.
T-TIME: Alteplase during PCI fails to reduce microvascular obstruction
Click Here to Manage Email Alerts
CHICAGO — Intracoronary alteplase administered during primary PCI for STEMI does not reduce microvascular obstruction, according to results of the T-TIME trial.
“Failed myocardial reperfusion — in other words, microvascular obstruction — is a predictor of all-cause death and HF. There is no treatment for this problem and, therefore, presents an unmet therapeutic need,” Colin Berry, PhD, FRCP, from the University of Glasgow, U.K., said during a presentation at the American Heart Association Scientific Sessions.
To determine whether intracoronary alteplase administered early after coronary reperfusion reduces failed myocardial reperfusion, Berry and colleagues conducted the multicenter, double-blind, randomized T-TIME trial comparing alteplase 20 mg and alteplase 10 mg with placebo in patients with acute STEMI due to a proximal, mid-vessel occlusion of a major coronary artery presenting less than 6 hours from symptom onset.
For the intervention, the drug was made up to a volume of 20 mL and, following reperfusion, was manually infused over 5 to 10 minutes by the guide catheter or by an intracoronary catheter to the culprit coronary artery, with the drug administered proximal to the culprit lesion. The stent was then implanted and final angiography was obtained.
Multiparametric MRI was used to assess other pathologies and repeated 3 months later for additional secondary outcomes.
No benefit with alteplase
In the primary analysis of alteplase 20 mg vs. placebo, there was no difference in the amount of microvascular obstruction, expressed as a percentage of left ventricular mass, at 2 to 7 days after MI (P = .32).
This result relegated the alteplase 10-mg dose comparison with placebo to a secondary outcome. There was a numerical trend toward an increase in microvascular obstruction with treatment (P = .28).
In prespecified tests of interaction on the primary outcome for baseline characteristics, the researchers found no overall differences in sex, age, MI location, smoking status, initial TIMI flow grade and antiplatelet therapy for the interaction. However, there was an association with ischemic time that was borderline statistically significant in the subgroup of patients presenting at 4 to 6 hours, as compared with 0 to 2 hours or 2 to 4 hours, and in those patients treated with alteplase 20 mg, there was an increase in microvascular obstruction, Berry noted.
Secondary analyses also showed an unexpected increase in area under the curve for troponin at 2 and 24 hours with both alteplase doses when compared with placebo, according to Berry.
There were no differences between groups in major adverse CV outcomes or bleeding events or in outcomes assessed by angiography, ECG, MRI and N-terminal pro-B-type natriuretic peptide.
The trial was discontinued by the independent data and safety monitoring committee on Dec. 21, 2017, noting no safety issues, after enrollment of 440 patients.
Clinical characteristics of the study patients were typical for the population of patients with acute STEMI. Berry noted, however, that 43% had anterior STEMI, ischemic time was less than 3 hours and the door-to-balloon time was 24 minutes.
In terms of procedural characteristics, 85% of patients had an occluded artery at enrollment. The primary reperfusion strategy was aspiration thrombectomy in 27% of patients and balloon angioplasty in 73% of patients. Approximately two-thirds of patients received one stent.
Ninety percent of patients received two antiplatelet drugs before alteplase administration and the dose of unfractionated heparin was 10,000 U overall. Although T-TIME was a double-blind study, Berry and colleagues observed an increase in administration of IV or intracoronary glycoprotein IIb/IIIa inhibitor therapy in patients treated with alteplase, as compared with placebo.
‘Points to ponder’
In light of these data, Berry noted that low-dose intracoronary alteplase given during primary PCI, when compared with placebo, did not reduce microvascular obstruction and was associated with an increase in AUC for troponin.
“The results do not support this therapeutic strategy as designed and microvascular obstruction remains a common problem,” he said.
Paul W. Armstrong, MD, from the University of Alberta in Canada, noted there are “several points to ponder” with T-TIME. The total ischemic time, for instance, is an unreliable estimate based on symptom onset and baseline Q in the distribution of the MI is actually prognostically more useful. Additionally, the window of 2 to 7 days for MRI acquisition was wide and had this time frame been tighter, the data may have been different.
The adequacy and timing of the antiplatelet therapy and, in part, the low use of glycoprotein IIb/IIIa inhibitors is noteworthy because the combination of fibrinolytic therapy and glycoprotein inhibitors is very effective in producing reperfusion at both the myocardial and epicardial level, according to Armstrong.
“In thinking about the problem going forward, there is heterogeneity of the mechanistic targets and confounders,” he said. “We need a better taxonomy associated with microvascular obstruction to provide more formal solutions.” – by Melissa Foster
Reference:
Berry C. LBS.04 – Preserving Brain and Heart in Acute Care Cardiology. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.
Disclosures: Berry reports there are institutional agreements between the University of Glasgow, his employer, and Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Coroventis, DalCor, GlaxoSmithKline, Novartis and Philips. Armstrong reports he receives research grants from Bayer, CSL Limited, Merck and Sanofi-Aventis Recherche and Développement, and he is a consultant or on the advisory board of AstraZenca, Merck and Novartis.
Perspective
Back to Top
C. Michael Valentine, MD, FACC
T-TIME tested a hypothesis that thousands of interventional cardiologists have thought about in the last 20 years — whether adjunctive alteplase at the time of intervention could help microperfusion and long-term LV function.
When I spoke with interventional cardiologists, they wondered why the trial had not been performed before. There were many different trials in which there was “drip and ship,” but this occurred at the time of primary PCI. And, many were hoping that there would be a positive result out of this trial because it made clinical sense. It would have been great if a significant difference had been observed in one of the arms, but I think we’re all disappointed that we did not see any improvement. However, it was an interesting trial and a question that needed to be answered.
Centra Health, Lynchburg, Virginia
President, American College of Cardiology
Click Here to Manage Email Alerts