# Factors Determining Ticagrelor-Induced Dyspnea in Patients with Acute Coronary Syndrome
###### Abstract  
(1) Background: The aim of this study was to determine clinical and genetic factors predicting the development of dyspnea in patients receiving ticagrelor. (2) Methods: A total of 277 patients with acute myocardial infarction (with and without ST-segment elevation), who underwent coronary angiography and PTCA with stent implantation and treated with antiplatelet drugs (ticagrelor and aspirin), were enrolled in this study. Platelet aggregation (induction with high-sensitivity ADP, ADP HS) testing was performed using a MULTIPLATE analyzer and reagents for the determination of P2Y12 receptor activity. Venous blood samples were collected for genotyping. (3) Results: Patients experiencing ticagrelor-related dyspnea had lower ADP HS. ROC curve analysis showed that an ADP HS cut-off of \(\leq\)19.5 U was associated with the development of dyspnea. The ADP HS value of \(\leq\)19.5 U and any dose of atorvastatinatin lower than 80 mg (or no atorvastatinatin) increased the risk of dyspnea by more than 4 and 2 times, respectively (OR = 4.07, \(p\)\(\leq\) 0.001 and OR = 2.25; \(p\) = 0.008). (4) Conclusion: A lower ADP HS value possibly indicates greater ticagrelor activity and a higher plasma concentration of this drug. Atorvastatinatin might have an impact on the occurrence of ticagrelor-related dyspnea by affecting ticagrelor metabolism. No impact of any genetic variant on the development of dyspnea was determined. ticagrelor; dyspnea; antiplatelet therapy; ticagrelor pharmacogenomics; platelet aggregation; ADP HS; gene polymorphisms +
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underwent PTCA with stent implantation [5]. However, the administration of dual or triple antiplatelet therapy leads to numerous clinical challenges [6]. The most frequent clinical challenge associated with ticagrelor administration is its premature discontinuation attributed to sudden-onset dyspnea or bleeding [7]. It is well-known that ticagrelor causes dyspnea and can be responsible for bleeding; only the incidence of these adverse events differs. Discontinuation of ticagrelor attributed to these causes leads to an increased risk of stent thrombosis and recurrent ACS [6; 7]. Stent thrombosis and recurrent ACS are associated with significantly greater mortality, longer hospital stay, and worse functional status and quality of life in patients [7]. Ticagrelor is a cyclopentyltriazolo-pyrimidine (CPTP) that directly and reversibly binds to P2Y\({}_{12}\) receptors. The drug reversibly inhibits the binding of endogenous adenosine diphosphate (ADP) to platelet membrane-bound P2Y\({}_{12}\) receptors and blocks platelet aggregation. The maximum plasma concentration of ticagrelor is reached within 1.3-2 h, and the mean elimination half-life is 7-12 h. Ticagrelor is metabolized to its active metabolite, AR-C124910 XX. Ticagrelor and its active metabolite are highly bound to plasma proteins (99.8%); the bioavailability of ticagrelor is about 36%. Ticagrelor-related dyspnea of varying severity usually appears suddenly 2-3 h after drug administration and lasts for several hours, days, or the whole period of drug use. It is directly associated with the maximum plasma concentration of the drug [8; 9; 10]. Drugs of the thienopyridine class (clopidogrel, prasugrel) bind to P2Y\({}_{12}\) receptors irreversibly and, therefore, inhibit platelet aggregation longer than ticagrelor (for the entire lifespan of platelets, i.e., 7-10 days) [11]. Clopidogrel is metabolically activated in the liver, and its antiplatelet effect directly depends on a genetic polymorphism. Prasugrel exhibits a more consistent and less metabolism-dependent antiplatelet effect but is associated with a significantly higher risk of bleeding [11]. The results of large-scale PLATO, DISPERSE-2, RESPOND, and ONSET/OFFSET clinical trials showed that ticagrelor in combination with aspirin was superior to a combination of clopidogrel and aspirin in reducing the incidence of cardiovascular death, recurrent myocardial infarction, and stroke [12; 13; 14; 15].