Effects of Intracoronary Alteplase on Microvascular Function in Acute Myocardial Infarction

Background Impaired microcirculatory reperfusion worsens prognosis following acute ST‐segment–elevation myocardial infarction. In the T‐TIME (A Trial of Low‐Dose Adjunctive Alteplase During Primary PCI) trial, microvascular obstruction on cardiovascular magnetic resonance imaging did not differ with adjunctive, low‐dose, intracoronary alteplase (10 or 20 mg) versus placebo during primary percutaneous coronary intervention. We evaluated the effects of intracoronary alteplase, during primary percutaneous coronary intervention, on the index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio. Methods and Results A prespecified physiology substudy of the T‐TIME trial. From 2016 to 2017, patients with ST‐segment–elevation myocardial infarction ≤6 hours from symptom onset were randomized in a double‐blind study to receive alteplase 20 mg, alteplase 10 mg, or placebo infused into the culprit artery postreperfusion, but prestenting. Index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were measured after percutaneous coronary intervention. Cardiovascular magnetic resonance was performed at 2 to 7 days and 3 months. Analyses in relation to ischemic time (<2, 2–4, and ≥4 hours) were prespecified. One hundred forty‐four patients (mean age, 59±11 years; 80% male) were prospectively enrolled, representing 33% of the overall population (n=440). Overall, index of microcirculatory resistance (median, 29.5; interquartile range, 17.0–55.0), coronary flow reserve(1.4 [1.1–2.0]), and resistive reserve ratio (1.7 [1.3–2.3]) at the end of percutaneous coronary intervention did not differ between treatment groups. Interactions were observed between ischemic time and alteplase for coronary flow reserve (P=0.013), resistive reserve ratio (P=0.026), and microvascular obstruction (P=0.022), but not index of microcirculatory resistance. Conclusions In ST‐segment–elevation myocardial infarction with ischemic time ≤6 hours, there was overall no difference in microvascular function with alteplase versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02257294.

• Multivessel percutaneous coronary intervention (PCI) intended before the day 2-7 cardiovascular magnetic resonance (CMR) scan • Estimated body weight <60 kg • Non-cardiac co-morbidity with expected survival <1 year • Contra-indication to contrast-enhance CMR imaging • Hypersensitivity to gentamicin, or natural rubber • Incapacity, or inability to provide informed consent • Previous randomization to this study, or participation in a study with an investigational drug, or medical device within 90 days prior to randomization • Women of child bearing potential (i.e. pre-menopausal), or breast feeding • Requirement for immunosuppressive therapy at any time during the preceding 3 months. This would include corticosteroids (but not inhaled or topical), drugs used following transplantation (e.g tacrolimus, cyclosporine), anti-metabolite therapies (e.g. mycophenolic acid, azathioprine, leflunomide and immunomodulators including biologics (e.g. adalimumab, or etanercept) and disease modifying anti-rheumatic drugs. This list is not exhaustive. treatment allocation. Catheter calibration was performed using the catheter calibration function on MEDIS QAngio. For each lesion, a view perpendicular to the long axis of the vessel was used in order to avoid foreshortening and overlap of branches. The single plane projection showing the best opacified and most severe lesion with minimal foreshortening and minimal branch overlap was selected.
Feedback was provided to sites on the quality and completeness of the angiograms.

TIMI Coronary Flow Grade
The TIMI coronary flow grade was assessed using the following definitions 1 : TIMI coronary flow grade Definition cardiac cycles after injection (washout phase), but fades minimally is also classified as grade 3.

TIMI Frame Count
The TIMI frame count represents the amount of time (in frames) for contrast dye to reach a standardized distal landmark 2 . If the culprit vessel was the left anterior descending artery the frame count was divided by 1.7 (correcting for longer vessel length). Erlangen, Germany and Philips Intera, Best, The Netherlands). The imaging protocol followed a standard operating procedure that included planning and localisers, T1-mapping, T2*-mapping, cine CMR with steady-state free precession (SSFP), and late gadolinium enhancement imaging 10 -15 minutes after administration of contrast media 4 . The scan acquisitions were spatially co-registered and also included different slice orientations to enhance diagnostic confidence.

TIMI Coronary Thrombus Grade
The intravenous contrast agent used in this study was gadobutrol (Gadovist®, Bayer: 1.5 mmol/ml solution for injection), which was administered in two doses. The first dose injection (0.05 mmol/kg) was given to initiate the first-pass of contrast. The second dose (0.1 mmol/kg) was given immediately after the first-pass. Therefore, the total dose of gadobutrol was 0.15 mmol/kg.

Late Enhancement
Late microvascular obstruction (MVO) was imaged 10-15 minutes after intravenous Gadovist contrast administration, using in general a motion corrected T1-weighted phasesensitive inversion recovery radiofrequency pulse sequence. A full stack, aligned to T2* scans (or cines) and 3 long axis views (vertical long axis, horizontal long axis and 3 chamber view) were acquired.
MVO was defined as a dark zone on early gadolinium enhancement imaging 1, 3, 5 and 7-minutes post-contrast injection that remained present within an area of late gadolinium enhancement at 15 minutes. The endocardial and epicardial borders were contoured. The myocardial mass (grams) of the dark zone was quantified by manual delineation and expressed as a percentage of total left ventricular (LV) mass.

Infarct Definition & Size
The presence of acute infarction was established based on abnormalities in cine wall motion, rest first-pass myocardial perfusion, and late gadolinium enhancement imaging in two imaging planes. The myocardial mass of late gadolinium (grams) was quantified using computer assisted planimetry and the territory of infarction was delineated using a 5 standard deviation method and expressed as a percentage of total LV mass.

Myocardial Edema
The presence of myocardial oedema was established based on an area of increased signal intensity on the SSFP cine images (acquired two minutes after gadolinium contrast injection). The myocardial mass was calculated by manual delineation in end-diastole and end-systole. The values were averaged and expressed as a percentage of LV mass 4 .

Myocardial Salvage
Myocardial salvage was calculated by subtraction of percent infarct size from percent area-at risk, as reflected by the extent of oedema. The myocardial salvage index was calculated by dividing the myocardial salvage area by the initial area-at-risk.