After acute coronary syndrome (ACS) or receiving percutaneous coronary intervention (PCI) treatment, patients are required to take dual antiplatelet therapy for 12 months in order to prevent recurrence of cardiovascular events and cardiovascular mortality.[1,2] Of note, aspirin combined a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) is the cornerstone of dual antiplatelet therapy, which is strongly recommended by the recent guidelines for ACS patients.[1,2]
Notably, clopidogrel is a pro-drug which requires to be metabolized into its active form via the cytochrome peptide 450 (CYP450) enzyme systems.[3,4] In contrast, ticagrelor is an active antiplatelet medication which has rapid and potent effects on platelet inhibition compared to clopidogrel. In addition, recent clinical studies have demonstrated that compared to clopidogrel, ticagrelor has better effects on reducing cardiovascular events and mortality in ACS patients after coronary artery stenting.
Nevertheless, compared to clopidogrel, the expenditure for ticagrelor is much higher and physicians usually have to switch ticagrelor to clopidogrel after acute period of ACS.[7,8] Prior study indicated that in ACS patients, after switching prasugrel to clopidogrel, the on-treatment platelet reactivity was increased. Interestingly, one recent study also indicated that within the first 48 hours of switching, platelet reactivity was found to rebound and be significantly higher in the clopidogrel group compared to the ticagrelor group. However, whether these short-term pharmacodynamic differences would influence cardiovascular outcome is unknown. We, therefore, conducted a prospective study to evaluate whether switching ticagrelor to clopidogrel would impact platelet reactivity and cardiovascular outcomes in ACS patients after PCI treatment. Results from our present study would shed lights into the clinical relevance of the short-term pharmacodynamic changes in relation to anti-platelet drug switching.
2.1 Study design and participants enrolment
This was a prospective, observational and single-center study. Present study was approved by the Clinical Research Ethic Committee of The Third People's Hospital of Huizhou. Informed consent was obtained before enrolment and all participants were treated in accordance with the Declaration of Helsinki. Participants’ enrolments were conducted from October 1, 2017 to January 31, 2018 and the inclusion criteria were as follows: participants were hospitalized for ACS and had received PCI during the indexed hospitalization. Exclusion criteria were as follows: the ACS patients with complicated acute decompensated heart failure, required medical inotrope (dopamine or dobutamine), or intra-aorta balloon pump support, or the ACS patients had arrhythmias with hemodynamic unstable, had coronary artery complication (rupture or aneurysm) during indexed PCI or had major bleeding.
2.2 Data collection
Baseline characteristics including age, gender, smoking status, systolic/diastolic blood pressure (SBP/DBP), and heart rate (HR) at admission were collected by 2 investigators. Risk factors including documented hypertension, diabetes mellitus and dyslipidemia, and history of atrial fibrillation, congestive heart failure, myocardial infarction, ischemic stroke, chronic kidney disease (CKD), and prior PCI or coronary artery bypass graft (CABG) and current medication usages were extracted from electronic health record.
Fasting venous blood was drawn for assessment of low-density lipoprotein cholesterol (LDL-C), glycated hemoglobin A1c (HbA1c), serum reatinine (Scr), high sensitivity cardiac troponin-I (Hs-CTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels.
2.3 Antiplatelet medications usage and platelet reactivity evaluation
At admission, all ACS patients were prescribed a loading dose of ticagrelor (180 mg) and then continued on maintenance dose of ticagrelor (90 mg twice daily) before discharge. Blood samples were collected to evaluate baseline platelet reactivity before switching ticagrelor to clopidogrel. Patients were informed of the potential harms and benefits of medications switching, and whether acceptance of switching ticagrelor to clopidogrel was at the patient's discretion. Those switching to clopidogrel would take 300 mg loading dose of clopidogrel at 12 hours after the final dose of ticagrelor and then continues on 75 mg clopidogrel daily as a maintenance dose. Forty-eight hours later, patients were required to come back to hospital for blood sampling to evaluate platelet reactivity after switching. Platelets from peripheral blood were stimulated with adenosine diphosphate (10μmol/L) and the absolute reduction in maximal platelet aggregation from baseline (ΔMPA) were reported and compared.
2.4 Study endpoints
Participants were followed for 30 days after discharge via phone call or at outpatient clinic. Ischemic event included non-fatal myocardial infarction, non-fatal ischemic stroke, definite stent thrombosis, and cardiovascular death. Bleeding events included intracranial hemorrhage and gastrointestinal bleeding. Study endpoints were adjudicated by 1 independent cardiologist who was unaware of the usage of antiplatelet medications. Composite study endpoints comprise both ischemic events and bleeding events.
2.5 Statistical analysis
Continuous variables were expressed as mean ± SD or median (interquartile ranges) and categorical variables were expressed as number and frequency of cases. Between-group differences were evaluated by the independent Student t test or the Mann–Whitney U test for continuous variables, or the Chi-square analysis or Fisher exact tests for the categorical variables as appropriate. Cox proportional hazards regression analysis was used to evaluate the association of clopidogrel switching and composite study endpoints. Statistical analysis was conducted in SPSS 23.0 (IBM). All P values were 2 sides, and statistical significance was defined as P <.05.
3.1 General characteristics
A total of 287 ACS patients had received PCI in our hospital during enrolment period and 236 patients agreed to participate in our study. After exclusion of 32 patients, 204 patients were recruited. Two patients did not come back for platelet reactivity assessment after discharge and no patients were loss of follow-up. Therefore, 202 patients were included into final analysis (Fig. 1).
Among the 202 ACS patients, 138 patients (68%) were switched to clopidogrel and the others remained on ticagrelor treatment. General characteristics were compared (Table 1). Compared to the ticagrelor group, patients in the clopidogrel group were more likely to be male and current smokers and had higher prevalence of hypertension. No significant between-group differences in other general characteristics were observed. Before PCI treatment, nearly 19.6% and 20.3% of patients in both groups were taking clopidogrel and none was on ticagrelor treatment.
3.2 Baseline procedure characteristics
Baseline procedure characteristics were compared and as represented in Table 2, the frequency of right coronary artery lesion was significantly higher in the ticagrelor group compared to the clopidogrel group (34.4% vs 30.4%), and no other significant between-group differences were observed. Of note, the mean numbers of stent implantation in both groups were 1.8 versus 1.7 and most of the stents implanted were drug eluting stents.
3.3 Platelet reactivity assessment
The duration of patients treated with ticagrelor before baseline platelet reactivity assessment was 4.1 ± 0.3 days in clopidogrel group versus 4.2 ± 0.3 days in ticagrelor group. As shown in the Figure 2, there were no significant differences in baseline platelet reactivity in both groups (37.6 ± 5.2% versus 38.4 ± 4.9%). Forty-eight hours after switching to clopidogrel, the platelet reactivity in the clopidogrel group was increased, which was significantly higher than that in the ticagrelor group (46.3 ± 5.6% vs 38.1 ± 5.0%, P <.05).
3.4 Endpoints at 30 days
Patients were followed for 30 days after discharge and study endpoints were compared. As presented in the Table 3, compared to the ticagrelor group, patients in the clopidogrel group were more likely to have non-fatal myocardial infarction and definite stent thrombosis although there was no statistical significance. In the composite study endpoints, patients in the clopidogrel group had significantly higher incidence of events compared to patients in the ticagrelor group (3.6% vs 1.6%, P <.05). In specific, in the clopidogrel group, 3 patients had non-fatal myocardial infarction and 2 patients had stent thrombosis and no bleeding events occurred. While no ischemic events and 1 bleeding event occurred in the ticagrelor group.
In the Cox proportional hazards regression model 1, after adjusted for age, male gender, smoking status, hypertension, vessel lesions location, number of stent implantation and stent diameter and length, clopidogrel treatment was significantly associated with the composite endpoints, with hazard ratio 1.20 (95% confidence interval 1.14–1.48, P = .019). However, after further adjusted for the platelet reactivity at 48 hours of switching, clopidogrel treatment was not significantly associated with the composite endpoints, with hazard ratio 1.08 (95% confidence interval 0.98–1.21, P = .063), indicating that platelet reactivity was a critical mediator between antiplatelet drug switching and cardiovascular outcomes.
Our current study shows that in ACS patients after coronary artery stenting, switching ticagrelor to clopidogrel results in platelet activity rebound which is consistent to prior reports.[9,10] In addition, our current study also indicates that the short-term pharmacodynamics change is associated with increased short-term risk of cardiovascular events. However, after adjusting for the platelet reactivity, clopidogrel switching is not significantly associated with cardiovascular outcomes, suggesting that platelet activity increase after switching ticagrelor to clopidogrel may mediate the association between clopidogrel switching and short-term cardiovascular outcomes.
Notably, dual antiplatelet therapy profoundly reduces stent thrombosis and restenosis and cardiovascular events.[12,13] In the last 2 decades, clopidogrel combined aspirin is the mainstay of dual antiplatelet therapy for ACS patients and those receiving coronary artery stenting. However, accumulating evidence has demonstrated that a substantial portion of patients is resistant to clopidogrel treatment due to their loss-of-function of CYP450 2C19 gene,[3,4,11] which plays a major role in converting clopidogrel into its active metabolites. In recent years, 2 novel oral antiplatelet medications, namely prasugrel, and ticagrelor, have been demonstrated to be superior to clopidogrel in inhibiting platelet activity.[14,15] In addition, 2 milestone randomized clinical trials also demonstrated that both prasugrel and ticagrelor are better than clopidogrel in reducing cardiovascular events and mortality in ACS patients after PCI treatment.[6,16] Therefore, both the recent ACC/AHA and ESC guidelines have recommended prasugrel and ticagrelor as the preferred anti-platelet medications for patients with ACS.[1,2] However, the expenditure of the novel antiplatelet medications is much higher than clopidogrel and many patients have to switch to clopidogrel for chronic antiplatelet treatment.
Interestingly, in 2013, Kerneis et al  reported that ACS patients treated with prasugrel had low on-treatment platelet reactivity, indicating that early switching prasugrel 10 mg to clopidogrel 75 mg put the patients at increased risk of platelet reactivity rebound. In another study conducted by Franchi et al, they also observed that in patients with coronary artery disease, de-escalation from ticagrelor to clopidogrel is associated with an increase in platelet reactivity. These 2 studies demonstrate that early switching potent antiplatelet medications to clopidogrel results in impaired inhibition of platelet activity. However, whether this pharmacodynamics change is related to cardiovascular outcomes is unclear. Our present study also observed that in the Chinese populations, early switching ticagrelor to clopidogrel is associated with increased platelet activity. Due to the higher prevalence of loss-of-function of CYP450 2C19 gene in the Asians compared to the Caucasians,[17,18] one may anticipate that the percentages of patients with platelet activity rebound might be even higher than that of Caucasians after switching.
Beyond the pharmacodynamics changes, we also observed that antiplatelet medications switching is associated with short-term cardiovascular outcomes. We found that compared to the ticagrelor group, patients in the clopidogrel group have higher incidence of non-fatal MI and stent thrombosis. In the Cox proportional hazards regression model, before adjusted for platelet reactivity, clopidogrel switching is independently associated with 20% higher risk of composite cardiovascular outcomes. However, after adjusted for platelet reactivity, the associated is attenuated to statistical insignificance. These findings suggest that insufficient inhibition of platelet activity after switching is associated with increased risk of cardiovascular events, and short-term pharmacodynamics changes may translate into significant impact on cardiovascular outcomes. One patient in the ticagrelor group has gastrointestinal bleeding which was due to duodenal ulceration and treated with proton pump inhibitor without interruption of ticagrelor treatment.
The prospective design and follow-up for cardiovascular outcomes are the strengths of our present study. However, there are some limitations should be addressed. First, the inherent biases related to the non-randomized and open-label design could influence the association of medication switching and cardiovascular outcomes. Although we have extensively adjusted for potential biases, undetected and unmeasured biases could still exist and future randomized double-blind trials are warranted to corroborate our findings. Second, the relatively small sample size and short-term follow-up could not allow us to observe more cardiovascular events, and whether the pharmacodynamics changes could impact long-term cardiovascular outcomes is unknown. Last but not the least, results from Chinese populations may not be extrapolated to other population group due to the difference in prevalence of loss-of-function of CYP450 2C19 gene.
In summary, our study indicates that in ACS patients after coronary artery stenting, early switching ticagrelor to clopidogrel results in increased platelet reactivity and higher incidence of short-term cardiovascular events.
We appreciate very much for the help Dr. Fang Yang provided to us in critically revising our paper.
Conceptualization: Lin Liu, Chun Xiao.
Data curation: Lin Liu.
Formal analysis: Sigan Zhong.
Funding acquisition: Chun Xiao.
Investigation: Huocheng Liao.
Methodology: Lin Liu, Huocheng Liao, Sigan Zhong.
Project administration: Huocheng Liao.
Resources: Sigan Zhong.
Supervision: Huocheng Liao.
Validation: Lin Liu, Yan Liu.
Writing – original draft: Lin Liu.
Writing – review & editing: Chun Xiao.
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