Multi-Omics Signatures Link to Ticagrelor Effects on Vascular Function in Patients With Acute Coronary Syndrome

Abstract

BACKGROUND: Long-term antiplatelet agents including the potent P2Y12 antagonist ticagrelor are indicated in patients with a previous history of acute coronary syndrome. We sought to compare the effect of ticagrelor with that of aspirin monotherapy on vascular endothelial function in patients with prior acute coronary syndrome. METHODS: This was a prospective, single center, parallel group, investigator-blinded randomized controlled trial. We randomized 200 patients on long-term aspirin monotherapy with prior acute coronary syndrome in a 1:1 fashion to receive ticagrelor 60 mg BD (n=100) or aspirin 100 mg OD (n=100). The primary end point was change from baseline in brachial artery flow-mediated dilation at 12 weeks. Secondary end points were changes to platelet activation marker (CD41_62p) and endothelial progenitor cell (CD34/133) count measured by flow cytometry, plasma level of adenosine, IL-6 (interleukin-6) and EGF (epidermal growth factor), and multi-omics profiling at 12 weeks. RESULTS: After 12 weeks, brachial flow-mediated dilation was significantly increased in the ticagrelor group compared with the aspirin group (ticagrelor: 3.48±3.48% versus aspirin: −1.26±2.85%, treatment effect 4.73 [95% CI, 3.85–5.62], P <0.001). Nevertheless ticagrelor treatment for 12 weeks had no significant effect on platelet activation markers, circulating endothelial progenitor cell count or plasma level of adenosine, IL-6, and EGF (all P >0.05). Multi-omics pathway assessment revealed that changes in the metabolism and biosynthesis of amino acids (cysteine and methionine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis) and phospholipids (glycerophosphoethanolamines and glycerophosphoserines) were associated with improved brachial artery flow-mediated dilation in the ticagrelor group. CONCLUSIONS: In patients with prior acute coronary syndrome, ticagrelor 60 mg BD monotherapy significantly improved brachial flow-mediated dilation compared with aspirin monotherapy and was associated with significant changes in metabolomic and lipidomic signatures. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03881943.

Ticagrelor and Endothelial Function: An Effect That Persists Far From the Acute Phase and in Monotherapy

“…However, the main difference in the study design is related to the innovative use of monotherapy with ticagrelor. In line with recent trials as GLOBAL LEADERS (Clinical Study Comparing Two Forms of Anti-Platelet Therapy After Stent Implantation) and TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention), 8,9 both proposing the use of ticagrelor monotherapy after ACS or high risk-percutaneous coronary intervention, respectively (of course after a brief period of DAPT with aspirin), Tam et al 7…”

“…However, the main difference in the study design is related to the innovative use of monotherapy with ticagrelor. In line with recent trials as GLOBAL LEADERS (Clinical Study Comparing Two Forms of Anti-Platelet Therapy After Stent Implantation) and TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention), 8,9 both proposing the use of ticagrelor monotherapy after ACS or high risk-percutaneous coronary intervention, respectively (of course after a brief period of DAPT with aspirin), Tam et al 7 chose to propose low-dose ticagrelor (60 mg bid) in monotherapy in patients with previous MI (occurring 18 months or more before randomization) and so in a stable state. This is an intriguing never tested mix, because in the GLOBAL LEADERS and TWILIGHT trials 8,9 ticagrelor was given at 90 mg bid, whereas the 60 mg bid dose was tested in the PEGASUS TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared With Placebo on a Background of Aspirin) and THEMIS (Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes) trials, 10,11 but in association with aspirin.…”

“…5 In contrast, the HI-TECH trial (Hunting for the Off-Target Properties of Ticagrelor on Endothelial Function in Humans), focused on stable patients after ACS and showed that ticagrelor did not improved endothelial function in terms of reactive hyperemia index, flow-mediated dilatation, systemic adenosine plasma level or vascular biomarkers compared with prasugrel and clopidogrel. 6 The study of Tam et al 7 ranks midway between the results of these 2 studies. [3][4][5][6] It uses the same population evaluated by the HI-TECH trial 6 (Stable Patients After ACS) investigating the mechanisms underlying the complicated network that forms the basis of the endothelial response.…”

“…The study of Tam et al 7 ranks midway between the results of these 2 studies. 3–6 It uses the same population evaluated by the HI-TECH trial 6 (Stable Patients After ACS) investigating the mechanisms underlying the complicated network that forms the basis of the endothelial response.…”

‘All roads lead to Rome’: the long journey of ticagrelor effect on endothelial function

“…As a result, ticagrelor enhances the biological effects of endogenous adenosine by prolonging the half-life of adenosine and increasing its concentration as documented in animal models 3 . This pleiotropic effect has been recently questioned, suggesting that ticagrelor induces significant changes in the metabolism and biosynthesis of amino acids (cysteine and methionine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis) and phospholipids (glycerophosphoethanolamines and glycerophosphoserines) and that these changes were associated with improved endothelial function 4,5 . Independently of biological mechanisms, many authors concorded that ticagrelor exhibits a positive modulation on endothelial function, and that this effect is the prime suspect, altogether for stronger and stable platelet inhibition, for the significant benefit on cardiovascular mortality.…”