Safety and feasibility of low‐dose ticagrelor in patients with ST‐segment elevation myocardial infarction

Abstract Background Previous studies have confirmed the safety and feasibility of half‐dose ticagrelor in Chinese patients with acute coronary syndrome, but currently there is no plan for the use of ticagrelor for Chinese ST‐segment elevation myocardial infarction (STEMI) patients. Hypothesis It is safe and feasible of low‐dose ticagrelor in patients with STEMI. Methods The STEMI patients who were undergoing emergency intervention and taking ticagrelor were enrolled. Patients whose level of platelet aggregation rate (PAR) less than 30% after 7‐day treatment with standard‐dose ticagrelor were randomly divided into low‐dose group (LD group, 45 mg twice daily) and standard‐dose group (SD group, 90 mg twice daily). The changes of levels of platelet parameters were compared between the two groups. The incidence of major adverse cardiac events (MACE), bleeding events were compared between the two groups within 6 months of follow‐up. Results The levels of PAR in the SD group decreased compared with baseline, and was lower than those of LD group at the same time point. The levels of platelet distribution width in both groups decreased from the baseline values (all p < .05) at 1, 3, and 6 months after grouping treatment, but there was no significant difference between the two groups. The incidence of MACE was similar between the two groups of patients. There were decreasing trends in the incidences of minimal bleeding event, minor bleeding event, dyspnea, and gout in the LD group. Conclusion It is safe and feasible of low‐dose ticagrelor for patients with STEMI based on the monitoring of PAR.

complete occlusion of coronary arteries. Excessive platelet activation and aggregation are central to the pathogenesis of STEMI. Ticagrelor is an oral, reversibly binding, direct-acting P2Y 12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). 1 Compared with clopidogrel, the antiplatelet effect of ticagrelor is faster with stronger inhibition on platelet aggregation. 2 The application of ticagrelor in STEMI patients has been unanimously recommended by many guidelines. [3][4][5][6] Importantly, East Asians show increased responses to ticagrelor compared with Caucasians. 7 In recent years, individual treatment regimens of ticagrelor have received attention in Chinese patients. Previous studies have confirmed the safety and feasibility of half-dose ticagrelor in Chinese patients with NST-ACS, but currently there is no plan for the use of ticagrelor for Chinese STEMI patients.
The purpose of this study was to explore the safety and feasibility of low-dose ticagrelor in the treatment of STEMI based on the monitoring of platelet aggregation rate (PAR).

| MATERIALS AND METHODS
This study is a single-center, prospective, randomized controlled study. The STEMI patients who underwent emergency intervention in our chest pain center from January 2019 to December 2019 were enrolled. The research plan was approved by the Ethics Committee of the

| Treatment strategy and grouping
After admission, patients were given oral loading doses of aspirin 300 mg and ticagrelor 180 mg. Following the guidelines and clinical path, the emergency coronary angiography was performed. According to the lesion of infarction related artery (IRA), the appropriate interventional treatment was performed by interventional cardiologist. The oral administration of aspirin 100 mg once daily and ticagrelor 90 mg twice daily was administered to all patients. Other therapeutic drugs such as heparin, low-molecular-weight heparin, β-blockers, angiotensin converting enzyme inhibitor (ACEI) drugs, and statins are given in accordance with current guidelines.
The level of PAR was rechecked 7 days after intervention, and patients who met the inclusion criteria were randomly divided into a low-dose group (LD group, ticagrelor doses of 45 mg twice daily) and a standarddose group (SD group, ticagrelor doses of 90 mg twice daily).
PAR examination: The blood samples were centrifuged for 5 min at 120 g to obtain platelet-rich plasma and further centrifuged for 10 min at 850 g to obtain platelet-poor plasma. The platelet rich plasma and platelet-poor plasma were stored at room temperature to be used within 2-3 h. The PAR was assessed by traditional light transmission aggregometry, which was performed as previously described. 8 Briefly, platelets were stimulated with 5 μmol/L adenosine diphosphate (ADP).
The PAR was expressed as the maximum percentage change in light transmittance from baseline, with platelet-poor plasma as a reference.

| Observation parameters
The clinical data including demographic data, previous medical history, and laboratory examinations were recorded and compared between the two groups. The changes of PAR, PLT, MPV, and PDW were compared between the two groups at the time of grouping, 1 week, 2 weeks, 1 month, 3 months, and 6 months after grouping. The incidence of major adverse cardiac events (MACE), bleeding events, and adverse reactions were compared between the two groups within 6 months of follow-up.
Bleeding complications were defined according to PLATO trail. 9 data were expressed by numerical value and percentage, using χ 2 test (when the counting data was less than 5, Fisher's exact probability method was used for testing). Platelet parameters and PAR measured at different time points were tested using repeated analysis of variance. p < .05 considered the difference to be statistically significant.

| Comparison of baseline characteristics between the two groups
There was no significant difference in clinical baseline data (age, gender, body mass index, previous medical history, myocardial infarction site, cardiac function grading, and baseline laboratory test results) between the two groups (all p > .05) ( Table 1).

| Comparison of intervention data between the two group
Both groups of patients underwent emergency intervention after admission. There was no significant difference between the two groups in the door-balloon time, IRA distribution, TIMI blood flow grading before and after intervention, and stent implantation (all p > .05) ( Table 2). Table 3 shows the changes in levels of PAR, PLT, MPV, and PDW before groups and at 1 week, 2 weeks, 1 month, 3 months, and 6 months after grouping. After grouping, the levels of PAR in LD group were similar to baseline (all p > .05). The levels of PAR in the SD group decreased compared with baseline (all p < .05), and was lower than those of LD group measured at the same time (all p < .05).

| Changes of platelet parameters before and after grouping
There was no significant change in levels of PLT and MPV before and after treatment in both groups, and there was no significant difference between the two groups. It was found that the levels of PDW in both groups decreased from the baseline values (all p < .05) at 1 month, 3 months, and 6 months after grouping, but there was no significant difference between the two groups. activation and aggregation is the initial link in the onset of STEMI, which has important significance in the onset of STEMI. Therefore, antiplatelet therapy is of great significance in STEMI treatment.

| Results of 6-month follow-up
Ticagrelor is the first reversibly binding, oral, direct-acting P2Y 12 receptor antagonist that binds reversibly and noncompetitively to the P2Y 12 receptor. Recently, studies showed that standard-dose ticagrelor has a more rapid onset of effect and a greater inhibition of platelet aggregation compared with high-dose clopidogrel therapy. 10,11 At present, the application of ticagrelor in STEMI treatment has been unanimously recommended by many guidelines. However, standard-dose ticagrelor is associated with a significant increase in the risk of bleeding, incidence of dyspnea [12][13][14] and higher discontinuation rates due to adverse effects compared with clopidogrel. Studies have reported that a switch to a high-dose of clopidogrel, ticagrelor, or prasugrel may be indicated. 15 Previous studies demonstrated that a half-dose of ticagrelor had an inhibitory effect on platelet aggregation that was better than clopidogrel [16][17][18] and even that half-dose ticagrelor produced a similar effect of platelet reactivity inhibition as standard-dose ticagrelor in Chinese patients. 19 However, there are still no relevant studies on low-dose ticagrelor for STEMI patients. The results of this study found that it is safe and feasible to use low-dose ticagrelor based on the monitoring of PAR.
The PAR induced by ADP is a commonly used to detect the effect of P2Y12 receptor inhibitors on platelet aggregation function. The detection is convenient and repeatable. In previously published studies, with 20 mM ADP as the agonist, mean inhibition of platelet aggregation observed with clopidogrel 300 mg PAR ranges from 20% to 40%. 20,21 The STEMI patients enrolled in this study had a good response on ticagrelor treatment and the levels of PAR were all of less than 30% after 7 days of treatment with standard dose ticagrelor, which ensured the effectiveness of the antiplatelet treatment. In this study, the level of PAR was also used as an important indicator for evaluating of effects of low-dose ticagrelor treatment. In our study, although the levels of PAR in LD group were higher than the those in the SD group after grouping, it could still make platelet aggregation function maintain a low level without increasing the ischemic events during  26 Previous study has indicated that PDW and plateletcrit levels seem to be independent markers of STEMI in young patients and may reflect prothrombotic state in this specific population, 27 and PDW could also be used as an early risk stratification of patients with acute myocardial infarction. 28 In this study, after 1 month of treatment with different doses of ticagrelor, the PDW level of both groups of STEMI patients decreased significantly, suggesting that antiplatelet therapy could help reduce the platelet activation status and reduce the risk of ischemia in STEMI patients.
In conclusion, the results of this study found that the use of lowdose ticagrelor is safe and feasible for patients with STEMI based on the monitoring of PAR. However, due to the small sample size and the relatively simple means of monitoring PAR, it is still necessary to expand the sample size and adopt a method such as thromboelastography to evaluate the strategy more comprehensively.

CONFLICT OF INTEREST
The authors declare no potential conflict of interest.

DATA AVAILABILITY STATEMENT
No additional unpublished data are available.