Contemporary Clinical Application And Individualized Anti-platelet Treatment With Ticagrelor In ACS Patients

As a novel class of P2Y12 receptor inhibitor, ticagrelor, has been widely used to prevent ischemic events in patients with acute coronary syndrome (ACS) and those who undergoing percutaneous coronary intervention (PCI). However, the real-world clinical application in ticagrelor-treated ACS patients in China is rarely known. Ticagrelor, compared with clopidogrel, could improve the prognosis of ACS patients, whereas it also increases the risk of bleeding and dyspnea side effects. Therefore, further evaluation of the individualized anti-platelet treatment with ticagrelor in ACS patients is urgently required. The aim of the present study focused on the evaluation of the clinical application and individualized anti-platelet treatment with ticagrelor in ACS patients.Part 1. Contemporary practice and impact on clinical outcomes of Switching between ticagrelor and clopidogrel in ACS patientsObjective:To analysis the clinical characteristics, the incidence, related factors, time and dose bridging of the in-hospital switching between ticagrelor and clopidogrel and impact on clinical outcomes of the switching from ticagrelor to clopidogrel during hospitalization and within 3-month after hospitalization in PCI-treated ACS patients.Methods:Consecutive ticagrelor-treated ACS patients from January 2014 to August 2015 in 301 hospital. We carried out an exhaustive statistics on the clinical status, the incidence, related factors, time and dose bridging of the in-hospital switching between ticagrelor and clopidogrel in ticagrelor-treated ACS patients. After 6 months follow up, the compliance and switching reasons of ticagrelor within 3-month after hospitalization were recorded. The difference of ischemic, bleeding events and net clinical outcomes between the switching from ticagrelor to clopidogrel during hospitalization and within 3-month after hospitalization and consecutive ticagrelor treatment in ACS patients undergoing PCI were also analyzed.Results:Overall,948 ticagrelor-treated ACS patients were recruited, with 728 patients (76.79%) in unstable angina (UA),148 (15.61%) in ST-elevated myocardial infarction (STEMI),72 (7.59%) in Non-STEMI,834 (87.97%) in PCI and 764 (91.61%) in PCI for complex coronary lesions. There were 44 patients (4.64%) occurring ticagrelor-related dyspnea and 37 patients (3.90%) occurring ticagrelor-related bleeding in hospital. In our study, in-hospital switching between ticagrelor and clopidogrel occurred in 682 (71.94%) patients, with 622 (65.61%) switching from clopidogrel to ticagrelor and 60 (6.33%) switching from ticagrelor to clopidogrel. The main reason of switching from clopidogrel to ticagrelor was complex coronary lesion and of switching from ticagrelor to clopidogrel was occurring ticagrelor-related dyspnea. The two different ways of the switching happened more frequently at post-PCI but before-discharge in ACS patients undergoing PCI. The switching from clopidogrel to ticagrelor was more frequent in pre-PCI patients and the switching from ticagrelor to clopidogrel was more occurred at discharge. After 6-month follow-up, the incidence of ticagrelor withdrawal within 3-month after hospitalization was 27.59%(245/888), with the occurrence of the switching from ticagrelor to clopidogrel being 26.01%. Moreover, compared with patients under continuous ticagrelor treatment (n=517), in ACS patients undergoing PCI, patients treated with the switching from ticagrelor to clopidogrel during hospitalization and within 3-month after hospitalization (n=247) had a higher risk of major ischemic events (5.67% vs.2.32%, HR:2.70,95%CI:1.14-6.37, P=0.02), composited ischemic events (10.12% vs.5.42%, HR:1.83,95%CI:1.02-3.29, P=0.04) and net clinical outcomes (6.88% vs.3.48%, HR:2.07,95%CI:1.01-4.27, P=0.05). No significant difference was found for the risk of PLATO major and minor bleeding events between these patients, but the switching from ticagrelor to clopidogrel had a lower risk of PLATO minimor bleeding events (21.46% vs.30.56%, HR:0.59,95% CI:0.40-0.87, P=0.008).Conclusions:In real clinical world, the phenomenon of switching between ticagrelor and clopidogrel was common. Although could decrease the occurrence of PLATO minimor bleeding events, early switching from ticagrelor to clopidogrel might have a high risk of serious cardiovascular ischemic events in PCI-treated ACS patients.Part 2. Individualized anti-platelet treatment with ticagrelor in ACS patients undergoing PCI by combining, platelet function and pharmacogenomics testObjective:To assess the difference of anti-platelet effect between ticagrelor and clopidogrel in PCI-treated ACS patients with different sensitivity of clopidogrel defined by combing the genotype and platelet function test (PFT), which may provide feasible and effective clinical evidence for individualized anti-platelet therapy.Methods:Consecutive ACS patients undergoing PCI with continuously clopidogrel treatment from January 2012 to June 2013 and ticagrelor treatment from January 2014 to March 2015 in 301 hospital. Those patients must have been the CYP2C19 (*2 or*3) genotype or PFT by light transmission aggregation (LTA) or thrombelastography (TEG) with 2 to 3 days maintenance dose of clopidogrel treatment. It was defined as clopidogrel insensitive when patients carried CYP2C19LOF (loss of function, including*2 and*3) or were high on-treatment platelet reactivity (HTPR) (LTA-RPA>46% or TEG-MAADP>47mm), and clopidogrel sensitive when patients carried CYP2C19*1/*1 or were not HTPR. The occurrence of ischemic, bleeding events and net clinical outcomes were followed up for 12 months (clinical outcomes defined as Part one).Results:Overall, ACS patients undergoing PCI were recruited with 232 patients (25.08%) in ticagrelor treatment,693 patients (74.92%) in copidogrel treatment. After 12-month follow-up, in clopidogrel insensitive patients (550), ticagrelor therapy, compared with clopidogrel therapy, had a lower risk of major ischemic events(9.02% vs.16.36%, HR:0.41 95%CI:0.19-0.88, P=0.02), composited ischemic events (18.85% vs.31.54%, HR:0.45 95%CI:0.26-0.78, P=0.004) and net clinical outcomes(11.48% vs.16.82%, HR:0.56, 95%CI:0.16-0.92, P=0.03), but had a high risk of PLATO composited bleeding events(32.79% vs.9.81%, HR:7.47,95%CI:4.11-13.58, P<0.001). Moreover, in clopidogrel sensitive patients (375), ticagrelor therapy, compared with clopidogrel therapy, had a lower risk of composited ischemic events (18.18% vs. 26.79%, HR:0.53 95%CI:0.28-0.99, P=0.05), but have a high risk of PLATO composited bleeding events (28.18% vs.15.09%, HR:2.07,95%CI:1.09-3.96, P=0.03). There were no significant difference in major ischemic events (9.09% vs.12.83% HR:0.5195%CI:0.21-1.27, P=0.15) and net clinical outcomes (10.91% vs.14.34% HR:0.58,95%CI:0.25-1.33, P=0.20) between these clopidogrel sensitive patients.Conclusion:Compared with copidogrel therapy, ticagrelor therapy had a significantly benefit in copidogrel insensitive patients defined by combing the genotype and PFT. The difference of copidogrel sensitivity defined by combing the genotype and PFT had a reference significance to guide individualized anti-platelet therapy of ticagrelor and clopidogrel.Part 3. Relationship between ADP-induced platelet-fibrin clot strength (MAADP) and anti-platelet responsiveness in ticagrelor treated ACS patientsObjective:This study aimed to display the relationship between ADP-induced platelet-fibrin clot strength (MAADP) and clinical outcomes in ticagrelor treated ACS patients.Methods:Consecutive ACS patients who received maintenance dose of ticagrelor were recruited. After 3 to 5 days maintenance dose of ticagrelor treatment, MAAXDP, measured by TEG, were recorded for the evaluation of ticagrelor anti-platelet reactivity. Pre-specified cutoffs of MAADP> 47mm for high on-treatment platelet reactivity (HTPR) and MAADP< 31mm for low on-treatment platelet reactivity (LTPR) were applied for evaluation. The occurrences of clinical ischemic events, the PLATO defined bleeding events and ticagrelor related dyspnea were recorded after 6 months follow-up (clinical outcomes defined as Part one).Results:Overall,341 ACS patients under ticagrelor maintenance dose treatment were recruited. The value of MAADP ranged from 1.2% to 72.9% [(20.6±12.2)% on average], with the distribution higher skewed towards the lower values. Using the pre-specific cutoffs for HTPR and LTPR,15 patients (4.40%) were identified as HTPR and 279 patients (81.82%) as LTPR. After a follow-up of 6 months in 338 patients, major ischemic events occurred in 9 patients (9/338,2.66%), with 3 patients (1.09%) classified as LTPR,2 patients (4.26%) in therapeutic range and 4 patients (26.67%) classified as HTPR (P<0.001). Composited of ischemic events occurred in 31 patients (31/338,9.17%), with 20 patients (7.25%) classified as LTPR,5 patients (10.64%) in therapeutic range and 6 patients (40.00%) classified as HTPR (P=0.004). There were 7 patients occurred PLATO major bleeding events with all patients being classified as LTPR and 36 patients occurred PLATO minor bleeding events, with 34 patients (12.32%) classified as LTPR and 2 patients (4.26%) in therapeutic range (P=0.04). Ticagrelor related dyspnea occurred in 73 patients (73/338,21.60%), with 64 (23.19%) classified as LTPR,9 (19.15%) in therapeutic range and no one as HTPR (P=0.02).Conclusion:In ticagrelor treated ACS patients, MAADP, measured by TEG, might be valuable for the prediction of antithrombotic effect, PLATO bleeding and ticagrelor related adverse events.