Rationale and Design of the High Platelet Inhibition with Ticagrelor to Improve Left Ventricular Remodeling in Patients with ST-Segment Elevation Myocardial Infarction (HEALING-AMI) Trial

Yongwhi Park, Si Wan Choi, Ju Hyeon Oh, Eun Seok Shin, Sang Yeub Lee, Jeongsu Kim, Weon Kim, Jeong Won Suh, Dong Heon Yang, Young Joon Hong, Mark Y Chan, Jin Sin Koh, Jin Yong Hwang, Jae Hyeong Park, Young Hoon Jeong, HEALING-AMI Trial Investigators, Yongwhi Park, Si Wan Choi, Ju Hyeon Oh, Eun Seok Shin, Sang Yeub Lee, Jeongsu Kim, Weon Kim, Jeong Won Suh, Dong Heon Yang, Young Joon Hong, Mark Y Chan, Jin Sin Koh, Jin Yong Hwang, Jae Hyeong Park, Young Hoon Jeong, HEALING-AMI Trial Investigators

Abstract

Background and objectives: Impaired recovery from left ventricular (LV) dysfunction is a major prognostic factor after myocardial infarction (MI). Because P2Y₁₂ receptor blockade inhibits myocardial injury, ticagrelor with off-target properties may have myocardial protection over clopidogrel. In animal models, ticagrelor vs. clopidogrel protects myocardium against reperfusion injury and improves remodeling after MI. We aimed to investigate the effect of ticagrelor on sequential myocardial remodeling process after MI.

Methods: High platelet inhibition with ticagrelor to improve LV remodeling in patients with ST-segment elevation MI (HEALING-AMI) is an investigator-initiated, randomized, open-label, assessor-blinded, multi-center trial done at 10 sites in Korea. Patients will be enrolled if they have ST-segment elevation MI (STEMI) treated with primary percutaneous coronary intervention and a planned duration of dual antiplatelet treatment of at least 6 months. Screened patients will be randomly assigned (1:1) using an internet-based randomization with a computer-generated blocking with stratification across study sites to either ticagrelor or clopidogrel treatment. The co-primary primary endpoints are LV remodeling index with three-dimensional echocardiography and the level of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) at 6 months representing post-MI remodeling processes. Changes of LV end-systolic/diastolic volume indices and LV ejection fraction between baseline and 6-month follow-up will be also evaluated. Analysis is per protocol.

Conclusions: HEALING-AMI is testing the effect of ticagrelor in reducing adverse LV remodeling following STEMI. Our trial would show the benefit of ticagrelor vs. clopidogrel related to the recovery of post-MI LV dysfunction beyond potent platelet inhibition.

Trial registration: ClinicalTrials.gov Identifier: NCT02224534.

Keywords: Clopidogrel; Myocardial infarction; Platelet; Ticagrelor; Ventricular Remodeling.

Conflict of interest statement

The authors have no financial conflicts of interest.

Copyright © 2019. The Korean Society of Cardiology.

Figures

Figure 1. Predictors of adverse LV remodeling…
Figure 1. Predictors of adverse LV remodeling in the REMODELING trial.
AUC = area under the curve; CI = confidence interval; CK = creatine kinase; hs-CRP = high sensitivity C-reactive protein; LV = left ventricular; LVEDVI = left ventricular end-diastolic volume index; LVESVI = left ventricular end-systolic volume index; OR = odds ratio; PRU = P2Y12 reaction units; REMODELING = role of platelet reactivity in left ventricular remodeling after ST-segment elevation myocardial infarction.
Figure 2. Flow diagram of the HEALING-AMI…
Figure 2. Flow diagram of the HEALING-AMI trial.
AF = atrial fibrillation; HEALING-AMI = high platelet inhibition with ticagrelor to improve left ventricular remodeling in patients with ST-segment elevation myocardial infarction; hs-CRP = high-sensitivity C-reactive protein; IRA = infarct related artery; LBBB = left bundle branch block; MI = myocardial infarction; NT-proBNP = N-terminal prohormone B-type natriuretic peptide; OAC = oral anticoagulant; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction; TIMI = thrombolysis in myocardial infarction; 3D = three-dimensional.
Figure 3. Schedule of measurement.
Figure 3. Schedule of measurement.
AE = adverse event; CK-MB = creatine kinase-MB; CRP = high-sensitivity C-reactive protein; ECG = electrocardiography; hs-CRP = high-sensitivity C-reactive protein; MACE = major adverse cardiovascular event; MRI = magnetic resonance imaging; NT-proBNP = N-terminal prohormone B-type natriuretic peptide; NYHA = New York Heart Association; SAE = serious adverse event; 3D = three-dimensional.
Figure 4. Incidence of adverse LV remodeling…
Figure 4. Incidence of adverse LV remodeling according to distribution of platelet reactivity (PRU measured by VerifyNow test).
LV = left ventricular; LVR = left ventricular remodeling; PRU = P2Y12 reaction units.

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