Author + information
- Received October 16, 2019
- Revision received January 8, 2020
- Accepted January 13, 2020
- Published online March 23, 2020.
- Peter J. McCartney, MBChBa,b,
- Annette M. Maznyczka, MDa,b,
- Hany Eteiba, MDa,b,
- Margaret McEntegart, PhDa,b,
- Keith G. Oldroyd, MD(Hons)b,
- John P. Greenwood, PhDc,
- Neil Maredia, MDd,
- Matthias Schmitt, PhDe,
- Gerry P. McCann, MDf,
- Timothy Fairbairn, PhDg,
- Elisa McAlindon, PhDh,
- Campbell Tait, MBChBi,
- Paul Welsh, PhDa,
- Naveed Sattar, PhDa,
- Vanessa Orchard, MScb,
- David Corcoran, PhDa,
- Thomas J. Ford, PhDa,j,
- Aleksandra Radjenovic, PhDa,
- Ian Ford, PhDk,
- Alex McConnachie, PhDk,
- Colin Berry, PhDa,b,∗ (, )@UofGICAMS,
- for the T-TIME Investigators
- aBritish Heart Foundation Glasgow Cardiovascular Research Center, University of Glasgow, Glasgow, United Kingdom
- bWest of Scotland Heart and Lung Center, Golden Jubilee National Hospital, Clydebank, United Kingdom
- cLeeds University and Leeds Teaching Hospitals National Health Service (NHS) Trust, Leeds, United Kingdom
- dSouth Tees Hospitals NHS Foundation Trust, Middlesbrough, United Kingdom
- eManchester University NHS Foundation Trust, Manchester, United Kingdom
- fUniversity of Leicester and the National Institute for Health Research Leicester Biomedical Research Center, Leicester, United Kingdom
- gLiverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, United Kingdom
- hNew Cross Hospital, Royal Wolverhampton NHS Trust, Wolverhampton, United Kingdom
- iDepartment of Hematology, Royal Infirmary, Glasgow, United Kingdom
- jDepartment of Cardiology, Gosford Hospital, Gosford, New South Wales, Australia
- kRobertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom
- ↵∗Address for correspondence:
Dr. Colin Berry, British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, 126 University Place, University of Glasgow, Glasgow, G12 8TA Scotland, United Kingdom.
Background Microvascular obstruction affects one-half of patients with ST-segment elevation myocardial infarction and confers an adverse prognosis.
Objectives This study aimed to determine whether the efficacy and safety of a therapeutic strategy involving low-dose intracoronary alteplase infused early after coronary reperfusion associates with ischemic time.
Methods This study was conducted in a prospective, multicenter, parallel group, 1:1:1 randomized, dose-ranging trial in patients undergoing primary percutaneous coronary intervention. Ischemic time, defined as the time from symptom onset to coronary reperfusion, was a pre-specified subgroup of interest. Between March 17, 2016, and December 21, 2017, 440 patients, presenting with ST-segment elevation myocardial infarction within 6 h of symptom onset (<2 h, n = 107; ≥2 h but <4 h, n = 235; ≥4 h to 6 h, n = 98), were enrolled at 11 U.K. hospitals. Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145). The primary outcome was the amount of microvascular obstruction (MVO) (percentage of left ventricular mass) quantified by cardiac magnetic resonance imaging at 2 to 7 days (available for 396 of 440).
Results Overall, there was no association between alteplase dose and the extent of MVO (p for trend = 0.128). However, in patients with an ischemic time ≥4 to 6 h, alteplase increased the mean extent of MVO compared with placebo: 1.14% (placebo) versus 3.11% (10 mg) versus 5.20% (20 mg); p = 0.009 for the trend. The interaction between ischemic time and alteplase dose was statistically significant (p = 0.018).
Conclusion In patients presenting with ST-segment elevation myocardial infarction and an ischemic time ≥4 to 6 h, adjunctive treatment with low-dose intracoronary alteplase during primary percutaneous coronary intervention was associated with increased MVO. Intracoronary alteplase may be harmful for this subgroup. (A Trial of Low-Dose Adjunctive Alteplase During Primary PCI [T-TIME]; NCT02257294)
- microvascular obstruction
- myocardial hemorrhage
- primary percutaneous coronary intervention
- ST-segment elevation myocardial infarction
The trial was funded by Efficacy and Mechanism Evaluation program of the National Institute for Health Research. Boehringer Ingelheim U.K. Ltd. provided the study drugs including alteplase (10 mg, 20 mg), matched placebo, and sterile water for injection. These organizations had no other involvement in the conduct of the study or in any aspect of this manuscript. The chief investigator had full access to the study data and had final responsibility for the decision to submit for publication. Dr. Maznyczka has received grants from British Heart Foundation Clinical Research Training Fellowship (FS/16/74/32573). Dr. McEntegart has a proctoring agreement with Boston Scientific and Vascular Perspectives. Prof. Oldroyd has received consultant and speaker fees from Abbott Vascular and Boston Scientific. Prof. McCann has received research grants from the National Institute for Health Research and the British Heart Foundation. Prof. Tait has received personal fees from Bayer Healthcare, Pfizer, Shire, Novo Nordisk, Sanofi, Sobi, CSL Behring, and Daiichi-Sankyo. Dr. Welsh has received grants from Boehringer Ingelheim, Roche, and AstraZeneca. Dr. McConnchie has received grants from Medical Research Council and the National Institute for Health Research—Efficacy and Mechanism Evaluation Programme. Prof. Berry is employed by the University of Glasgow, which holds consultancy and research agreements with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, HeartFlow, Menarini, Ospens, Philips, and Siemens Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received October 16, 2019.
- Revision received January 8, 2020.
- Accepted January 13, 2020.
- 2020 The Authors