Pharmacodynamic Evaluation of Switching From Ticagrelor to Clopidogrel in Patients With Coronary Artery Disease
Phase: PHASE4
Conditions: Coronary Artery Disease
Sponsor: University of Florida

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Pharmacodynamic evaluation of switching from ticagrelor to clopidogrel in patients 
with coronary artery disease 
 
 
 
 
 
 
Dominick J Angiolillo, MD, PhD, FACC, FESC, FSCAI 
Director of Cardiovascular Research 
Associate Professor of Medicine 
Division of Cardiology 
University of Florida College of Medicine - Jacksonville 
655 West 8th Street 
Jacksonville, FL – 32209 
Tel: 904-2443933, Fax: 904-2443102 
dominick.angiolillo@jax.ufl.edu 

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Project overview 
The recommended antiplatelet treatment regimen for patients affected by acute coronary 
syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI) consists in the 
combination of aspirin and a P2Y12 receptor inhibitor. Currently, three P2Y12 receptor inhibitors 
are available for clinical use (clopidogrel, prasugrel, and ticagrelor). Among these, clopidogrel 
remains the most widely used. However, recent studies have shown that there is a broad 
variability in platelet-inhibitory response induced by clopidogrel, which in turn is associated with 
worse outcomes. More potent P2Y12 receptor inhibitors (prasugrel and ticagrelor) have been 
developed which are associated with less response variability than clopidogrel and better clinical 
outcomes. Ticagrelor use has increased significantly because of its more expanded Food and 
Drug Administration (FDA) indications compared with prasugrel. However, despite the evidence 
for sustained efficacy and safety, many physicians limit treatment duration with ticagrelor to the 
early phases following an ACS (early weeks or months, rather than one-year) mostly due to cost 
issues and concerns about increased bleeding. Therefore, it is very common in clinical practice to 
switch patients while on maintenance dosing (MD) with ticagrelor to treatment with clopidogrel. 
However, the pharmacodynamic (PD) effects of switching from ticagrelor to clopidogrel remain 
unknown. In addition, it is unknown whether switching from ticagrelor to clopidogrel should 
occur with or without a loading dose (LD).  Therefore, the aim of this investigation is to evaluate 
the PD effects of switching from ticagrelor to clopidogrel with and without a LD. The present 
study has a prospective, randomized, open-label design, in which patients will be treated with 4 
different strategies to assess PD profiling after switching. This study will provide important 
insights on PD effects of switching from ticagrelor to clopidogrel. 

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Background and Significance: 
The currently recommended antiplatelet treatment regimen for patients affected by acute 
coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI) 
consists in the combination of aspirin and a P2Y12 receptor inhibitor [1-3]. Currently, three 
P2Y12 receptor inhibitors are available for clinical use (clopidogrel, prasugrel, and ticagrelor). 
Among these, clopidogrel remains the most widely used to reduce recurrent ischemic events [1, 
4,5,6]. However, several studies have shown that there is a broad variability in platelet-inhibitory 
response induced by clopidogrel, which in turn is associated with worse outcomes [7]. 
Variability in clopidogrel response is a multifactorial process [7]. Clopidogrel is a prodrug that 
requires bioactivation into its active metabolite before targeting the P2Y12 receptor on blood 
platelets. In vivo bioactivation of the drug is a 2-step process that is closely linked to the 
cytochrome P450 (CYP) system [8]. The most prominent and best established genetic factor is 
located within the CYP2C19 gene, as the polymorphically expressed isoenzyme CYP2C19 is 
involved in both metabolic steps of clopidogrel’s active metabolite generation [8,9]. In 
particular, a single-nucleotide polymorphism located within the CYP2C19 gene is a major 
determinant of clopidogrel responsiveness [9]. The presence of CYP2C19*2 and CYP2C19*3 
LOF allelic variants is associated with a loss of enzyme function and comes along with an 
attenuated response to clopidogrel leading to higher risk for ischemic events [10]. CYP2C19 *2 
allele is the most common LOF variant with allele frequencies of ~15% in Caucasians and 
Africans, and 29-35% in Asians [11]. 
More potent P2Y12 receptor inhibitors (prasugrel and ticagrelor) have been developed and 
are associated with less response variability than clopidogrel and better clinical outcomes in 

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patients with ACS [12,13,14,15]. Ticagrelor use has increased significantly because of its more 
expanded Food and Drug Administration (FDA) indications compared with prasugrel 
[1,4,5,14,15]. However, despite the evidence for consistent and sustained efficacy and safety of 
ticagrelor with up to one-year of treatment, many physicians limit treatment duration with 
ticagrelor to the early phases following an ACS (early weeks or months) rather than one-year 
mostly due to cost issues and concerns about increased bleeding [14,16]. The PD profiles after 
discontinuation of ticagrelor indicate faster recovery of platelet-inhibitory effects than 
clopidogrel [17], suggesting the need for early overlap of treatment among ticagrelor-treated 
patients in case of switching antiplatelet therapy. In the SWAP-2 (Switching AntiPlatelet-2) 
study in which patients were switched from ticagrelor to prasugrel, a loading-dose (LD) appeared 
to be essential to mitigate a rebound in platelet reactivity due to a drug-interaction after 
switching [18]. This study also hypothesized that this potential drug-drug interaction could have 
been attributed to the presence of ticagrelor or its metabolite still on the P2Y12 receptor when 
prasugrel was administered after 12 hours from the last maintenance dose (MD) of ticagrelor. 
This also suggested that switching should occur after a later time frame (e.g. 24 hours) to enable 
more time for the receptor to be unbounded by ticagrelor or its metabolite to allow a better 
switching approach [18]. However, to date, the PD effect of switching from ticagrelor to 
clopidogrel, and how this may be affected by administering a LD prior to initiating a standard 
MD regimen, as well as how this may be affected by timing of administration from last MD, has 
not been explored. Moreover, if such PD response profiles can be affected by CYP2C19 LOF 
genetic status also remains unknown. 
 

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Study aim 
The aim of this investigation is to evaluate the PD effects of switching from ticagrelor to 
clopidogrel with and without a LD., and to evaluate how this might be affected by CYP2C19 
LOF genetic status.  
 
Study Population 
Patients with known coronary artery disease (CAD) on maintenance aspirin (<100mg qd) and 
clopidogrel therapy (75mg qd) as a part of their standard-of-care will be screened for this study. 
Details of inclusion and exclusion criteria are described below: 
Inclusion Criteria 
1) Patients with angiographically documented CAD 
2) On therapy with aspirin(<100mg/day) and clopidogrel (75mg/day) for at least 30 
days per standard of care 
3) Age between 18 and 80 years old  
 
Exclusion Criteria 
1) History of intracranial bleeding 
2) Known hepatic impairment (based on clinical judgment)  
3) Active bleeding or propensity to bleed or blood dycrasia 
4) Platelet count <80x106/mL 
5) Hemoglobin <10g/dL 
6) Hemodynamic instability 
7) Estimated glomerular filtration rate (eGFR) <30 mL/min 
8) On treatment with oral anticoagulants 
9) Patients with sick sinus syndrome (SSS) or II or III degree AV block without 
pacemaker protection 

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10) Drugs interfering CYP3A4 metabolism (to avoid interaction with ticagrelor): 
ketoconazole, itraconazole, voriconazole, clarithromicin, nefazodone, ritonavir, 
saquinavir, nelfinavir, indinavir, atazanavir and telithromizycin 
11) Pregnant females [women of childbearing age must use reliable birth control (i.e. 
oral contraceptives) while participating in the study]. 
 
Research design 
Patients meeting inclusion criteria will be enrolled in this prospective, randomized, open-
label study. Baseline labs obtained within the past 180 days will be considered valid for 
screening purposes. If baseline labs are not available, these will need to be obtained prior to 
considering a patient eligible for study entry (patients will have 90 days to enter the study). 
Eligible patients will undergo a 7±2 day run-in phase with ticagrelor after switching from 
clopidogrel 75mg/day to ticagrelor 180mg LD followed by 90mg bid MD. Ticagrelor dosing in 
this study is line with FDA recommendations [15]. After this run-in phase, patients will be 
randomized (1:1:1:1) into one of the four following groups: A) clopidogrel 600 mg LD 24 hours 
after last MD of ticagrelor, followed by 75mg daily MD; B) clopidogrel 600 mg LD 12 hours 
after last MD of ticagrelor, followed by 75mg daily MD; C) clopidogrel 75mg daily MD 24 
hours after last MD of ticagrelor; D) continue ticagrelor MD 90mg twice daily. The FDA 
approved dose for clopidogrel is 300 mg loading dose and 75 mg/qd maintenance dose; however 
standard of care loading dose is 600 mg which is in line with practice guidelines [1-5]. 
 
Blood sampling: Peripheral venous blood samples (20 mL) will be drawn through a short venous 
catheter inserted into a forearm vein and collected in citrate, EDTA, and serum tubes as 
appropriate for assessments. The first 2-4 mL of blood will be discarded to avoid spontaneous 

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platelet activation. Blood sampling for PD will be performed at the following time points: prior 
to run-in baseline visit (24 hours after last clopidogrel dose in order to assess trough levels of 
platelet reactivity), after run-in (12 hours after last ticagrelor maintenance dose of run-in period), 
24 hours after washout (groups A and C only), and 2, 24, 48, 72 hours and 10±3 days after 
randomization. For patients randomized to groups A and C, both requiring 24 hours washout 
from last MD, they will take their morning MD of ticagrelor after blood sample collection for 
their post-run-in phase and return the following morning to receive the randomized treatment 
(these groups will have a total of 8 blood sampling time points). Patients randomized to groups B 
and D will initiate their randomized treatment the same morning of the post-run-in phase visit 
(these groups will have a total of 7 blood sampling time points). CYP2C19 genetic status will be 
evaluated at baseline visit. PD assessment will include VerifyNow point-of-care testing (VN-
P2Y12), light-transmittance aggregometry (LTA) and whole blood vasodilator-stimulated 
phosphoprotein (VASP) as described below. Time points will have a ±10% window. Results of 
genetic testing will not be used for clinical decision makings on choice of antiplatelet treatment 
regimen to be used at the end of the study. This is because we are studying patients in stable 
clinical conditions who have already on maintenance clopidogrel therapy without experiencing 
ischemic events, which are more likely to occur in the earlier phases of treatment in the setting of 
PCI [10]. Moreover, routine genetic testing and modification of treatment based on results of 
genetic testing is a class III recommendation in practice guidelines [1,2]. An illustration of the 
study design is provided below. A study table summarizing protocol procedures is provided as an 
appendix.  
 

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This study will be performed at the University of Florida Health Science Center at UF 
Health - Division of Cardiology. Patients will be recruited and consented at the inpatient and 
outpatient services in the UF Health system. Patients will be screened by cardiology research, 
who will verify that all candidates meet inclusion criteria. Subjects will be identified with a 
number and data collection sheets will all be stored in a locked area. Data will be kept for 6 years 
after enrollment ends to comply with HIPAA regulations. Patients will receive a copy of the 
consent with the names and telephone numbers of the doctors involved in the study. 
 
Study Medications 
Study medications will include the ticagrelor doses needed for the run-in phase for all patients 
enrolled in the study, the clopidogrel 600mg LD needed for Groups A and B, and the ticagrelor 
MD needed for Groups A and C and D. Study supplies will be obtained by the Department of 
Cardiology. 

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Patients will be continued on their prescribed clopidogrel 75mg standard of care dosing at the 
following time points: 
Group A: On the Day after Visit 3 
Group B: On the Day after Visit 2 
Group C: At Visit 3 
Group D: On the Day after Visit 7 
 
Laboratory assessments 
1. VerifyNow P2Y12 point-of-care testing (VN-P2Y12) 
2. Light-transmittence aggregometry (LTA) 
3. Whole blood vasodilator-stimulated phosphoprotein (VASP) 
4. CYP 2C19 Genetic testing 
 
Description of laboratory assays 
1) VerifyNow point-of-care testing (VN-P2Y12): The VN-P2Y12 is currently the most widely 
used point-of-care testing to evaluate platelet aggregation, because is rapid, easy to 
perform and uses whole blood [19]. The VerifyNow System is a turbidimetric based 
optical detection system which measures platelet induced aggregation as an increase in 
light transmittance (Accumetrics, San Diego, CA) and will be utilized according to 
manufacturer’s instructions, as previously described [19]. The assay is based on 
microbead agglutination and uses specific reagents for the pathways of interest. The VN-
P2Y12 assay, by combining ADP+PGE1, measures changes in platelet function specific to 

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P2Y12 receptor inhibitors. The assay is based upon the ability of activated platelets to 
bind fibrinogen. Fibrinogen-coated microparticles aggregate in proportion to the number 
of GP IIb/IIIa receptors expressed. Microbead aggregation is more rapid and reproducible 
if platelets are activated; therefore the reagents are incorporated into the assay channel to 
induce platelet activation without fibrin formation. Light transmittance increases as 
activated platelets bind and aggregate fibrinogen-coated beads. The instrument measures 
this change in optical signal and reports results in P2Y12 Reaction Units (PRU). 
2) Light transmittance aggregometry (LTA): Platelet aggregation will be measured using 
LTA according to standard protocols. Blood will be collected in citrated (3.8%) tubes. 
LTA will be assessed using platelet rich plasma (PRP) by the turbidimetric method in a 
2-channel aggregometer (Chrono-Log 490 Model, Chrono-Log Corp., Havertown) as 
previously described [19]. Platelet agonists will include 5 and 20 µM ADP. PRP will be 
obtained as a supernatant after centrifugation of citrated blood at 1000 rpm for 10 
minutes. The isolated PRP will be kept at 37° C before use. Platelet poor plasma (PPP) 
will be obtained by a second centrifugation of the blood fraction at 2800 rpm for 10 
minutes. Light transmission will be adjusted to 0% with the PRP and to 100% for the PPP 
for each measurement. Curves will be recorded for 6 minutes and platelet aggregation 
will be determined as the maximal percent change (MPA) in light transmittance from 
baseline using PPP as a reference. 
3) Whole blood vasodilator-stimulated phosphoprotein (VASP):  VASP phosphorylation 
(VASP-P) is a marker of P2Y12 receptor reactivity, which is the target for ticagrelor. 
VASP will be assessed according to standard protocol using labeled monoclonal 

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antibodies by flow cytometry with the Platelet VASP-FCM kit (Biocytex Inc., Marseille, 
France) as previously described [19]. PGE1 increases VASP-P levels by stimulation of 
adenylate cyclase. Binding of ADP to P2Y12 leads to Gi-coupled inhibition of adenylate 
cyclase. Therefore, the addition of ADP to PGE1-stimulated platelets reduces PGE1-
induced VASP-P levels. If P2Y12 receptors are successfully inhibited by inhibitors, 
addition of ADP will not reduce the PGE1-stimulated VASP-P levels. The platelet 
reactivity ratio (PRI) will be calculated after measuring VASP-P levels after stimulation 
with PGE1 (MFI PGE1) and also PGE1 + ADP (MFI PGE1 + ADP). The P2Y12 
reactivity ratio = ([MFI PGE1] – [MFI PGE1 + ADP]/[MFI PGE1]) x 100%. 
4) CYP 2C19 Genetic testing: CYP2C19 genetic status will be performed with the Spartan 
RX point-of-care rapid genotyping device. Spartan RX (Spartan Bioscience Inc., Ontario, 
Canada) is a point-of-care determining the CYP2C19 (*1,*2,*3,*17) allele status within 1 
hour [20]. This test consisted of four separate steps intended to be done in less than 8 
minutes: acquisition of a buccal swab; insertion of the swab into the cartridge; insertion 
of the reaction solution into the device; and analysis of CYP2C19 genotype triggered by a 
button on the device. In particular, this point-of-care assay enables assessment of the 
following alleles: *1,*2,*3 and *17. The most common LOF alleles are *2 and *3. 
Therefore, carriers of *2 or *3 LOF carrier status can be homozygotes (*2/*2, *3/*3 or 
*2/*3) or heterozygotes (*1/*2, *1/*3, *2/*17, *3/*17). Non-carriers of LOF alleles 
include the following: *1/*1, *1/*17 or *17/*17. 
 
 

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Definitions of high on treatment platelet reactivity 
High on-treatment platelet reactivity (HPR) will be defined according to updated expert 
consensus as following: PRU higher than 208 or 235, MPA-ADP (5 µM) >46%, MPA-ADP (20 
µM) >59% and VASP-PRI >50% [21,22]. 
 
Study endpoints and sample size calculation 
The primary endpoint is the comparison of PRU assessed by VN- P2Y12 at 48 hours after 
switching from ticagrelor 90 mg bid to clopidogrel 600 mg LD given 24 hours after last 
ticagrelor MD (group A) vs. clopidogrel 75 mg MD given 24 hours after last ticagrelor MD 
(group C). We hypothesize that switching from ticagrelor to clopidogrel with a loading dose will 
have less increase in platelet reactivity than that without loading dose and the sample size was 
determined based on the objective of establishing superiority of this approach. Superiority will 
be assessed using a 95% confidence interval (CI) of the difference in mean PRU between these 
two groups. Under the assumption of a mean difference of 60 PRU between groups and a 
common standard deviation of 50 PRU, a sample size of 16 per group allows for the 95% CI 
with a 95% power and alpha=0.05. Considering 4 arms of treatment and a possible invalid data 
in 20-25% of patients due to technical issues or drop-outs, we will randomize up to a total of 80 
patients to ensure complete data. We anticipate screening 100 patients to identify these 80 
patients to be randomized. Secondary endpoints include comparison of PRU (other than primary 
endpoint) assessed by VN-P2Y12, 5 and 20 µM ADP aggregation assessed by LTA and VASP-
PRI in all four groups at each time points; rates of HPR according to each platelet function assay 

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(VN-P2Y12, LTA, and VASP-PRI) in all four groups at each time point; impact of CYP2C19 
LOF genetic status on PD parameters. 
 
Statistical analysis plan  
Continuous variables will be expressed as a mean ± SD when are normally distributed or 
median [IQR] when are not normally distributed. Categorical variables will be expressed as 
frequencies and percentages. The Kolmogorov-Smirnov test will be used to examine data 
distribution normality. Comparisons between categorical variables will be performed using two-
tailed Fisher’s exact test or the Pearson's chi-square test. Student´s t test, Mann-Whitney U-test 
and Wilcoxon test will be used to compare continuous variables when appropriate. A repeated 
measures analysis of variance (ANOVA) model will be used to evaluate intra-group comparisons 
and the overall difference between groups. An analysis of covariance (ANCOVA) method with a 
general linear model, using the baseline value of platelet reactivity as a covariate, will be used to 
evaluate all between-groups comparisons. Missing data will not be imputed. A 2-tailed p value of 
< 0.05 is considered to indicate a statistically significant difference for all the analyses 
performed. Statistical analysis will be performed by our group using SPSS v22.0 software (SPSS 
Inc. Chicago, IL).  
 
Possible Discomforts and Risk 
The study entails blood draws at multiple time points as indicated above. The risks of the 
blood draw may include faintness, inflammation of the vein, pain, bruising or bleeding at the site 
of the puncture. There is also a slight risk of infection from the blood draw. In clinical trials, the 

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most common clinical side effects of ticagrelor were dyspnea (13.8%), headache (6.5%), cough 
(4.9%), dizziness (4.5%), nausea (4.3%), bradycardia (4.4%) principally. Infrequent events 
included intracranial hemorrhage (0.3%) and severe bradycardia requiring pacemaker insertion 
(0.9%). Patients considered to be at high risk of bradyarrhythmic events will be excluded. The 
most important adverse effect associated with the use of ticagrelor is bleeding. The risk of major 
spontaneous bleeding with ticagrelor is 2.8% [9]. However, such bleeding prevalence occurred in 
the setting of long-term (12 months) trials, while our study is limited only to approximately 1-
week of ticagrelor therapy, thus reducing the risk of bleeding complications. All clinical events 
described above, if they were to occur, as well as death, myocardial infarction, stroke, and urgent 
revascularization procedure with PCI or coronary artery bypass grafting will be recorded. 
Bleeding data will be collected using PLATO definitions [14]. Clinical events will be evaluated 
by a local committee, comprised of 2 faculty members (2 cardiologists), not directly involved in 
the research. In the event of a report of a serious adverse event (major bleeding – defined as life-
threatening: fatal, symptomatic intracranial hemorrhage, leading to a drop in hemoglobin of at 
least 5 g/dL, significant hypotension requiring intravenous inotropes, requiring surgical 
intervention, or requiring transfusion of 4 or more units of blood; non–life-threatening: 
substantially disabling, intraocular bleeding leading to vision loss, or requiring at least 2 units of 
blood; thrombocytopenia <50,000 ) the local committee will meet and antiplatelet treatment 
management will be managed according to physician recommendation. 
 
 
 

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Definition of Adverse Events 
An adverse event is any unintended or undesirable experience that occurs during the 
course of the clinical investigation whether or not it is considered to be therapy related.  This 
includes any newly occurring event or previous condition that has increased in severity or 
frequency since the initiation of study treatment.  Adverse events will be followed until 
resolution while the patient remains on-study.  Once the patient is removed from study, events 
thought to be related to the study therapy will be followed until resolution or until the patient 
starts a new treatment regimen. 
Serious Adverse Events (SAE): An adverse event occurring while on study and 
considered related (reasonable possibility that the study treatment caused the adverse experience) 
to the study treatment that results in any of the following outcomes: 
- Death 
- A life-threatening adverse experience. 
- A persistent or significant disability, incapacity, or is a congenital anomaly, or birth defect. 
- Requires inpatient hospitalization, or prolongation of existing hospitalization. 
The definition of serious adverse event also includes ‘important medical event’.  Medical 
and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient and/or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
definition above.  These should also usually be considered serious.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 

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dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
 
 
Possible benefits 
The present investigation is aimed to evaluate the PD effects of switching from ticagrelor 
to clopidogrel. This study is not designed to evaluate differences in clinical benefit. However, 
differences in antiplatelet profiles may potentially prompt further investigation of the clinical 
implication of this difference by means of a larger scale clinical study. 
   
Potential Financial Risks or Benefits 
 
None 
 
Conflict of Interest 
Dr. Angiolillo is a consultant for Astra Zeneca, the maker of ticagrelor.  

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22. Aradi D, Storey RF, Komócsi A, et al. Expert position paper on the role of platelet 
function testing in patients undergoing percutaneous coronary intervention. Eur Heart J. 
2014;35(4):209-215. 

Version 6 
August 21, 2017 
NCT02287909 
20 
 
Table S1. Summary of protocol procedures  
 
Screening 
V1 
Run-in Baseline 
V2 
After 7±2 days Run-in$ 
V3 
After 24 hours wash-out$$ 
V4 
V5 
V6 
V7 
 
Consent 
Baseline 
Labs* 
PD 
testing 
Genetic 
Testing 
 
Study 
drug^ 
Baseline 
PD 
Randomi-
zation 
Study 
drug 
2 hrs 
PD† 
Baseline 
PD† 
Study 
drug 
2 hrs 
PD† 
24 hrs 
PD† 
48 hrs 
PD† 
72 hrs 
PD† 
10±3 
days 
PD† 
Group 
A 
X 
X 
X 
X 
 
X 
X 
X 
X** 
 
X 
X*** 
X 
X 
X 
X 
X 
Group 
B 
X 
X 
X 
X 
 
X 
X 
X 
X*** 
X 
 
 
 
X 
X 
X 
X 
Group 
C 
X 
X 
X 
X 
 
X 
X 
X 
X** 
 
X 
 
X 
X 
X 
X 
X 
Group 
D 
X 
X 
X 
X 
 
X 
X 
X 
X++ 
X 
 
 
 
X 
X 
X 
X 
* Baseline labs obtained within the past 180 days will be considered valid for screening purposes. If baseline labs are not available, these will need to 
be obtained prior to considering a patient eligible for study entry and start the run-in phase (patients will have 90 days to enter the study). 
^ Ticagrelor LD 180mg followed by 90mg BID MD for 7+2 days 
† After Study Drug administration. 
$ 12 hours after last ticagrelor 90-mg dose. 
$$ 24 hours after last ticagrelor 90-mg dose. 
Screening visit, V1, V2 and V4-V7 are common for all groups.  
**At V2, group A and C will receive a 90-mg maintenance dose of ticagrelor.  
*** Clopidogrel 600 LD 
++  Ticagrelor 90mg BID for 10+3days 
V3 will be needed only for group A and group C. 
 
Group A: clopidogrel 600mg LD 24 hours after last MD of ticagrelor, followed by 75mg daily MD;  
Group B: clopidogrel 600mg LD 12 hours after last MD of ticagrelor, followed by 75mg daily MD;  
Group C: clopidogrel 75mg daily MD 24 hours after last MD of ticagrelor; 
Group D: continue ticagrelor MD 90mg twice daily. 
PD: pharmacodynamic; V: visit.