Intra-Coronary Administration of Tacrolimus Improves Myocardial Perfusion and Left Ventricular Function in Patients with ST-Segment Elevation Myocardial Infarction (COAT-STEMI) Undergoing Primary Percutaneous Coronary Intervention

Abstract

Background: Ischemia-reperfusion injury following acute ST-segment elevation myocardial infarction (STEMI) is strongly related to inflammation. However, whether intracoronary (IC) tacrolimus, an immunosuppressant, can improve myocardial perfusion is uncertain.

Methods: A multicenter double-blind randomized controlled trial was conducted in Taiwan from 2014 to 2017. Among 316 STEMI patients with Killip class ≤ 3 undergoing primary percutaneous coronary intervention (PCI), 151 were assigned to the study group treated with IC tacrolimus 2.5 mg to the culprit vessel before first balloon inflation, and the remaining 165 were assigned to the placebo group receiving IC saline only. The primary endpoint was percentage of post-PCI TIMI-3 flow. The primary composite endpoints included achievement of TIMI-3 flow, TIMI- myocardial perfusion (TMP) grade, or 90-min ST-segment resolution (STR). The secondary endpoints were left ventricular ejection fraction (LVEF) and 1-month/1-year major adverse cardio-cerebral vascular events (MACCEs) (defined as death, myocardial infarction, stroke, target-vessel revascularization or re-hospitalization for heart failure).

Results: Although post-PCI TIMI-3 epicardial flow and MACCE rate at 1 month and 1 year did not differ between the two groups, TMP grade (2.54 vs. 2.23, p < 0.001) and 90-min STR (67% vs. 61%, p < 0.001) were significantly higher in the tacrolimus-treated group than in the placebo group. The STEMI patients treated with tacrolimus also had significantly higher 3D LVEF and less grade 2 or 3 LV diastolic dysfunction at 9 months compared to those without.

Conclusions: IC tacrolimus for STEMI improved coronary microcirculation and 9-month LV systolic and diastolic functions. However, the benefit of tacrolimus on clinical outcomes remains inconclusive due to insufficient patient enrollment.

Keywords: Left ventricular systolic and diastolic function; Microcirculation; Myocardial perfusion; ST-segment elevation myocardial infarction; Tacrolimus.

Figure 1

Algorithm for patients’ enrollment and allocation. The supplemental figure shows how we screened and recruited study subjects at emergency room and catheterization laboratory, assigned two groups randomly, excluded those who were ineligible to enrollment, and did follow-up during study period. AR, aortic regurgitation; AS, aortic stenosis; CPCR, cardiopulmonary and cerebral resuscitation; ECMO, extracorporeal membrane oxygenation; LAD, left anterior descending artery; MI, myocardial infarction; PCI, percutaneous coronary intervention; PEA, pulseless electrical activity; RCA, right coronary artery; STEMI, ST-segment elevation myocardial infarction; VF, ventricular fibrillation; VT, ventricular tachycardia.

Supplemental Figure 1

Subgroup analysis for better improvement of coronary microcirculation. Forest plots demonstrates tacrolimus treatment was better than placebo to achieve post-PCI TMP grade 2/3 or 90-min STR > 50% among all subgroups. Data is displayed by % of event (number of patients). CAD, coronary artery disease; CI, confidence interval; GP, glycoprotein; MI, myocardial infarction; STR, ST-segment resolution; TIMI, Thrombolysis In Myocardial Infarction; TMP, TIMI myocardial performance.

Figure 2

Kaplan-Meier curves for cumulative incidences of MACCE and CV death during one-year follow-up period. Kaplan-Meier survival analysis with Log-rank test displays there were no significant differences in 1-year MACCE and CV mortality between two groups. CV, cardiovascular; MACCE, major adverse cardio-/cerebro-vascular events.

Supplemental Figure 2

How IC tacrolimus improves coronary microcirculation and LV function through suppressing IR injury during primary PCI. Combined reperfusion strategies of primary PCI and IC tacrolimus restored epicardial coronary and facilitated microcirculatory blood flow, and then attained better improvement of LV systolic and diastolic functions. CAD, coronary artery disease; CK-MB, creatinine kinase MB isoenzyme; cTn-I, cardiac troponin-I; EKG, electrocardiography; IC, intracoronary; IR, ischemia-reperfusion; LV, left ventricular; PCI, percutaneous coronary intervention; ROS, reactive oxygen species; STEMI, ST-segment elevation myocardial infarction; TIMI, Thrombolysis In Myocardial Infarction; TMP, TIMI myocardial performance.