Rationale and design of the Hunting for the off-target propertIes of Ticagrelor on Endothelial function and other Circulating biomarkers in Humans (HI-TECH) trial

Ariotti, Sara; Leeuwen, Maarten van; Brugaletta, Salvatore; Leonardi, Sergio; Akkerhuis, K. Martijn; Rexhaj, Emrush; Janssens, Gladys N.; Ortega‐Paz, Luis; Rizzotti, Diego; Berge, J; Heg, Dik; Francolini, Gloria; Windecker, Stephan; Valgimigli, Marco

doi:10.1016/j.ahj.2017.03.017

Cited by 8 publications

(2 citation statements)

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“…Due to inadequate knowledge about ticagrelor (in comparison with clopidogrel) and its possible side effects, it has not been sufficiently used in clinical practice to date. However, ticagrelor has been shown to have some effect on reducing vascular inflammatory reactions and stabilizing endothelial function while antagonizing platelets [13][14][15]. In this study, we research the effects of ticagrelor and clopidogrel on inflammation and endothelial function (hs-CRP, IL-6, and ESM-1), clinical prognosis with this treatment, and relevant bleeding risks, providing certain experimental evidence and a theoretical basis for the selection of safe and effective P2Y12 receptor antagonists and proper dosage, further facilitating treatment of patients with acute STEMI who undergo urgent PCI.…”

Section: Gao Et Al: Effects Of Ticagrelor and Clopidogrel On Short-tmentioning

confidence: 99%

Comparison of the Effects of Ticagrelor and Clopidogrel on Inflammatory Factors, Vascular Endothelium Functions and Short-Term Prognosis in Patients with Acute ST-Segment Elevation Myocardial Infarction Undergoing Emergency Percutaneous Coronary Intervention: a Pilot Study

Gao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Acute ST-segment elevation of myocardial infarction (STEMI) is the most severe type of acute coronary syndrome (ACS). Particular attention has been focused on studying the pathogenesis of STEMI, and how to prevent thrombosis, reduce inflammatory reaction, stabilize plaques and improve vascular endothelial functions to preserve the survived myocardium. This study aimed to compare the anti-inflammatory endothelium-protective effects, clinical prognosis, and relevant bleeding risks of ticagrelor versus clopidogrel in patients with STEMI who underwent urgent percutaneous coronary intervention (PCI) and provide certain experimental evidence and a theoretical basis for the selection of safe and effective drugs and their proper dosage, thereby further guiding clinical medication. Methods: We sequentially enrolled 193 patients (104 males and 89 females) admitted to hospital due to acute STEMI. These patients underwent urgent PCI between December 2013 and May 2015 and met the inclusion criteria. They were assigned (1: 1) into two groups according to different treatments, 97 patients in the ticagrelor group (treatment group), and 96 patients in the clopidogrel group (control group). Levels of hypersensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), and endothelial cell-specific molecule 1 (ESM-1) taken at admission and 24 h, 4 days, and 7 days after administration, as well as the correlation between the levels of IL-6, hs-CRP, and ESM-1, were determined in the two groups. At the same time, the effects of treatment with ticagrelor and clopidogrel on the efficacy endpoint events (ischemic and safety) were explored. Results: No statistically significant difference was found in the levels of hs-CRP, IL-6, or ESM-1 at admission between the two groups (P> 0.05); Their levels were significantly elevated 24 h after administration, with statistical differences between two groups (P< 0.05). Furthermore, a downward trend with statistically significant differences was found on Day 4 and Day 7 (P< 0.05); ESM-1 levels increased along with increases of hs-CRP and IL-6 levels, indicating ESM-1 was positively correlated with hs-CRP (r=0.523, P< 0.001) and IL-6 (r=0.431, P< 0.001); and the occurrence rates of ischemic endpoint events at 30 days were lower in the treatment group than in the control group. The occurrence of safety endpoint events was higher than in the control group; however, no statistically significant difference was found (P> 0.05). Conclusions: Compared with clopidogrel, ticagrelor appears to rapidly reduce the prevalence of inflammatory reactions and stabilize the functions of vascular endothelium to improve the stability of atherosclerotic plaque and decrease the occurrence rate of thrombosis as well as ischemic outcome events without any obvious increase in the risk of bleeding in patients with acute STEMI receiving urgent PCI. This renders it a potential drug for clinical practice. At the same time, measurement of ESM-1, a new biological marker for vascular endothelial function disorder, coul...

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Section: Gao Et Al: Effects Of Ticagrelor and Clopidogrel On Short-tmentioning

confidence: 99%

Comparison of the Effects of Ticagrelor and Clopidogrel on Inflammatory Factors, Vascular Endothelium Functions and Short-Term Prognosis in Patients with Acute ST-Segment Elevation Myocardial Infarction Undergoing Emergency Percutaneous Coronary Intervention: a Pilot Study

Gao

et al. 2018

Cell Physiol Biochem

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“…Furthermore, some clinical studies have now failed to detect significant effects of ticagrelor therapy on adenosine uptake and plasma adenosine levels. 6,7 In particular, the Hunting for the off-target properties of Ticagrelor on Endothelial function and other Circulating biomarkers in Humans study prospectively assessed the occurrence of ticagrelor-specific dyspnea in 28 patients by means of the Medical Research Council dyspnea scale and Baseline and Transitional Dyspnea Index. 8 Three patients (10.7%) suffered from new-onset dyspnea at rest a few hours after ticagrelor administration.…”

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confidence: 99%

Selatogrel and Other P2Y12 Inhibitors' Putative Off-Target Effects

Valgimigli

Storey

Sinnaeve

et al. 2022

Journal of Cardiovascular Pharmacology

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W e have read with great interest the article entitled "Selatogrel: A Novel Subcutaneous P2Y12 Inhibitor" by Beavers et al, 1 published ahead of print in the Journal of Cardiovascular Pharmacology. We would like to thank the authors for this important summary of the evidence on this new drug but also express concerns that they have not properly interpreted the available data regarding its safety profile. The authors have wrongly deduced the phase 2 data generated in the context of patients with chronic 2 or acute coronary syndrome 3 , whereby no instances of ventricular pauses were actually observed. In particular, the authors stated that among patients with chronic coronary syndrome, common adverse events included dyspnea, dizziness, and ventricular pauses and went on to state that among patients with acute coronary syndrome, 14.9% of them suffered from ventricular pauses with selatogrel (n = 4 with 8 mg and n = 3 with 16 mg), including 2 patients, 1 in each arm, in which they were deemed treatment-emergent serious events. The figures reported by the authors actually refer to ventricular tachycardia, which is a relatively common complication of recent or ongoing myocardial ischemia and was deemed unrelated to the study drug by the investigators. No cases of ventricular pauses were recorded in either of these 2 studies. In addition, the assumption that the mechanism of ventricular pauses would be likely due to potential inhibition of adenosine reuptake is not supported by data from Baumann et al 4 2021, showing that selatogrel is a selective antagonist of the P2Y 12 receptor and does not interfere with adenosine uptake by human red blood cells in vitro at selatogrel concentrations of 10 mM. We disagree with the authors' suggestion that "it had been assumed that dyspnea with ticagrelor and cangrelor was due to the adenosine portions of the molecules" because this was never a widely supported assumption. It was certainly speculated that antagonism of ENT1 by ticagrelor was leading to increased extracellular adenosine levels and thus causing dyspnea, but the observation of similar rates of dyspnea with cangrelor and elinogrel undermined this assumption because these drugs do not antagonize ENT1 and the inactive metabolite of cangrelor is a much weaker ENT1 antagonist than ticagrelor. 5 With such differences in chemical structure between the reversibly binding P2Y 12 receptor antagonists, it seems unlikely that the "pyrimidine core" could have an effect on adenosine receptors that was independent of From the

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Absence of differential effect of ticagrelor versus prasugrel maintenance dose on endothelial function in patients with stable coronary artery disease

Xanthopoulou¹,

Bei²,

Bampouri³

et al. 2018

Hellenic Journal of Cardiology

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Rationale and design of the Hunting for the off-target propertIes of Ticagrelor on Endothelial function and other Circulating biomarkers in Humans (HI-TECH) trial

Abstract: Background: Amongst the 3 approved oral P2Y 12 inhibitors for the treatment of patients with

Cited by 8 publications

References 42 publications

Comparison of the Effects of Ticagrelor and Clopidogrel on Inflammatory Factors, Vascular Endothelium Functions and Short-Term Prognosis in Patients with Acute ST-Segment Elevation Myocardial Infarction Undergoing Emergency Percutaneous Coronary Intervention: a Pilot Study

Comparison of the Effects of Ticagrelor and Clopidogrel on Inflammatory Factors, Vascular Endothelium Functions and Short-Term Prognosis in Patients with Acute ST-Segment Elevation Myocardial Infarction Undergoing Emergency Percutaneous Coronary Intervention: a Pilot Study

Selatogrel and Other P2Y12 Inhibitors' Putative Off-Target Effects

Absence of differential effect of ticagrelor versus prasugrel maintenance dose on endothelial function in patients with stable coronary artery disease

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