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Original Investigation
January 1/8, 2019

Effect of Low-Dose Intracoronary Alteplase During Primary Percutaneous Coronary Intervention on Microvascular Obstruction in Patients With Acute Myocardial Infarction: A Randomized Clinical Trial

Author Affiliations
  • 1British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
  • 2West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Clydebank, Clydebank, United Kingdom
  • 3Leeds University and Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
  • 4James Cook University Hospital NHS Trust, Middlesbrough, United Kingdom
  • 5South Manchester Hospitals NHS Trust, Manchester, United Kingdom
  • 6Leicester University Hospitals NHS Trust, Leicester, United Kingdom
  • 7Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, United Kingdom
  • 8Royal Wolverhampton University Hospital NHS Trust, Wolverhampton, United Kingdom
  • 9Barts and the London Hospital, London, United Kingdom
  • 10University Hospital Southampton Foundation Trust, Southampton, United Kingdom
  • 11Greater Glasgow and Clyde Health Board, Glasgow, United Kingdom
  • 12Electrocardiography Core Laboratory, University of Glasgow, Glasgow, United Kingdom
  • 13Department of Haematology, Royal Infirmary, Glasgow, United Kingdom
  • 14University Hospital Hairmyres, East Kilbride, United Kingdom
  • 15University of Edinburgh, Edinburgh, United Kingdom
  • 16Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom
JAMA. 2019;321(1):56-68. doi:10.1001/jama.2018.19802
Key Points

Question  In patients undergoing primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction (STEMI), does adjunctive fibrinolytic therapy with low-dose intracoronary alteplase given after reperfusion and before stent implant reduce microvascular obstruction?

Findings  In this randomized clinical trial that included 440 participants randomized to receive alteplase 20 mg, alteplase 10 mg, or placebo, the primary analysis demonstrated that the amount of microvascular obstruction (% left ventricular mass) revealed by magnetic resonance imaging was 3.5% in the alteplase 20-mg group and 2.3% in the placebo group, a difference that was not statistically significant.

Meaning  Adjunctive low-dose intracoronary alteplase given early during primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction did not reduce microvascular obstruction.

Abstract

Importance  Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction (STEMI) and is associated with adverse outcomes.

Objective  To determine whether a therapeutic strategy involving low-dose intracoronary fibrinolytic therapy with alteplase infused early after coronary reperfusion will reduce microvascular obstruction.

Design, Setting, and Participants  Between March 17, 2016, and December 21, 2017, 440 patients presenting at 11 hospitals in the United Kingdom within 6 hours of STEMI due to a proximal–mid-vessel occlusion of a major coronary artery were randomized in a 1:1:1 dose-ranging trial design. Patient follow-up to 3 months was completed on April 12, 2018.

Interventions  Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145) by manual infusion over 5 to 10 minutes. The intervention was scheduled to occur early during the primary PCI procedure, after reperfusion of the infarct-related coronary artery and before stent implant.

Main Outcomes and Measures  The primary outcome was the amount of microvascular obstruction (% left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging (MRI) conducted from days 2 through 7 after enrollment. The primary comparison was the alteplase 20-mg group vs the placebo group; if not significant, the alteplase 10-mg group vs the placebo group was considered a secondary analysis.

Results  Recruitment stopped on December 21, 2017, because conditional power for the primary outcome based on a prespecified analysis of the first 267 randomized participants was less than 30% in both treatment groups (futility criterion). Among the 440 patients randomized (mean age, 60.5 years; 15% women), the primary end point was achieved in 396 patients (90%), 17 (3.9%) withdrew, and all others were followed up to 3 months. In the primary analysis, the mean microvascular obstruction did not differ between the 20-mg alteplase and placebo groups (3.5% vs 2.3%; estimated difference, 1.16%; 95% CI, −0.08% to 2.41%; P = .32) nor in the analysis of 10-mg alteplase vs placebo groups (2.6% vs 2.3%; estimated difference, 0.29%; 95% CI, −0.76% to 1.35%; P = .74). Major adverse cardiac events (cardiac death, nonfatal MI, unplanned hospitalization for heart failure) occurred in 15 patients (10.1%) in the placebo group, 18 (12.9%) in the 10-mg alteplase group, and 12 (8.2%) in the 20-mg alteplase group.

Conclusions and Relevance  Among patients with acute STEMI presenting within 6 hours of symptoms, adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction. The study findings do not support this treatment.

Trial Registration  ClinicalTrials.gov Identifier: NCT02257294

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