# Factors Determining Ticagrelor-Induced Dyspnea in Patients with Acute Coronary Syndrome
## 4 Discussion  
The aim of this study was to determine clinical and genetic factors that would allow prediction of the development of dyspnea in patients receiving ticagrelor. Based on the results of the large-scale clinical ONSET/OFFSET trial, dyspnea was documented in 38.6, 9.3, and 8.3% of patients receiving ticagrelor, clopidogrel, and pra-sugrel, respectively [32; 34]. In our study, dyspnea of varying severity was reported by 34.3% of patients. This study enrolled patients in whom the occurrence of dyspnea due to other causes was unlikely. The severity of dyspnea was evaluated with the modified Borg acute dyspnea scale, which was used in early clinical trials investigating the effect of ticagrelor [29; 35]. As patients with diabetes mellitus often have other comorbidities that were included in the exclusion criteria, patients with diabetes mellitus in our study accounted for only 12.3%. In agreement with other studies, dyspnea experienced by our patients was not associated with the indicators of heart failure or pulmonary function impairment (confirmed by spirometry, auscultation, or chest X-ray) [31]. There is evidence that severe renal or hepatic impairment enhances the effect of ticagrelor [10]. This is in line with the results of our study. Our patients with poorer renal function experienced dyspnea more frequently. Different studies have reported that the incidence of dyspnea is greater in patients with advanced coronary atherosclerosis, thyroid pathology, and older patients, receiving ticagrelor [10]. Our data also support these statements as, based on epidemiological data, older patients in the entire population had advanced atherosclerotic lesions (two- and three-vessel CAD) and underlying diseases (i.e., hypothyroidism) more frequently. The findings of our study confirm the results of other authors that treatment of ACS (with beta blockers and angiotensin-converting enzyme inhibitors) defined by the ESC guidelines has no impact on the incidence of ticagrelor-related dyspnea [31]. Additional analysis of the PLATO trial aimed to investigate possible interactions between ticagrelor and statins (atorvastatin and simvastatin). In the presence of ticagrelor, the simvastatin concentration increased 3-4 times in some patients while the atorvastatin concentration increased marginally (up to 23%) and was considered as clinically irrelevant [10; 36]. There is evidence that ticagrelor conjugated to glucuronic acid during metabolism in the body can inhibit cytochrome P450 enzymes. The metabolism of ticagrelor is slowed down and its removal from the body is affected [37], resulting in increased levels of ticagrelor in blood. Even in 2010, the study on human hepatocytes carried out by [PERSON] et al. demonstrated that statins induced the activities of enzymes belonging to the cytochrome P450 family in the following order: atorvastatin > simvastatin > lovastatin > rousvastatin. Stating showed the strongest effect on the activity of _CYP2C8_ followed by _CYP3A4_, _CYP2C9_, _CYP2B6_, and _CYP2C19_[38]. In our study, all the patients received treatment with atorvastatin or rosuvastatin. Any-intensity rousvastatin therapy had no impact on the occurrence of dyspnea while the administration of any dose of atorvastatin lower than 80 mg (or no atorvastatin) increased the likelihood of developing ticagrelor-related dyspnea by more than 2 times. We make an assumption that atorvastatin can reduce the incidence of ticagrelor-related dyspnea by having an effect on ticagrelor metabolism through the dose-dependent activation of P450 enzymes. \begin{table}
\begin{tabular}{c c c} \hline \hline
**Variable** & **OR (95\% CD)** & \(p\) \\ \hline ADP HS \textgreater{} 19.5 & 1 & \\ ADP HS \textgreater{} 19.5 & 4.07 (2.37–6.99) & \textless{}0.001 \\ \hline Maximal atorvastatin & & \\ mg & & \\ Any atorvastatin & & \\ atorvastatin & & \\ \end{tabular}
\end{table} 
Table 6: Factors increasing the risk of dyspnea. Variability in the therapeutic effect of clopidogrel depending on various gene polymorphisms has been documented [16].