Coronary Artery Disease
Conditions
Brief summary
Guideline recommendations on the use of dual antiplatelet therapy have been formulated that ticagrelor 90 mg twice daily plus aspirin in preference to clopidogrel 75mg daily plus aspirin for ACS patients. Recent study found that ticagrelor 90mg twice a day orally could significantly reduce the occurrence of clopidogrel resistance and adverse cardiovascular events. The previous studies have reported that half-dose ticagrelor had the similar inhibitory effect on platelet aggregation as the standard-dose ticagrelor, which was significantly stronger than that in the clopidogrel group. One-quarter standard-dose ticagrelor provided greater degree of platelet inhibition than standard dose clopidogrel in Chinese patients with stable CAD. But large-scale clinical trials are still needed to confirm the effects of low-dose ticagrelor on platelet function in Chinese patients with coronary heart disease.
Detailed description
Dual Antiplatelet Therapy (DAPT) with aspirin and P2Y12 receptor inhibitor remains a cornerstone in the secondary prevention of coronary artery disease (CAD). Clopidogrel is one of the most commonly used antithrombotic agent that inhibits the platelet P2Y(12) adenosine diphosphate (ADP) receptor. Ticagrelor is an oral, reversibly-binding, direct-acting P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Guideline recommendations on the use of dual antiplatelet therapy have been formulated that ticagrelor 90 mg twice daily plus aspirin in preference to clopidogrel 75mg daily plus aspirin for ACS patients. Recent study found that ticagrelor 90mg twice a day orally could significantly reduce the occurrence of clopidogrel resistance and adverse cardiovascular events. The previous studies have reported that half-dose ticagrelor had the similar inhibitory effect on platelet aggregation as the standard-dose ticagrelor, which was significantly stronger than that in the clopidogrel group. One-quarter standard-dose ticagrelor provided greater degree of platelet inhibition than standard dose clopidogrel in Chinese patients with stable CAD. But large-scale clinical trials are still needed to confirm the effects of low-dose ticagrelor on platelet function in Chinese patients with coronary heart disease.
Interventions
DRUGTicagrelor
ticagrelor 45 mg twice daily for 5 consecutive days at least.
DRUGticagrelor
ticagrelor 90 mg once daily for 5 consecutive days at least.
DRUGclopidogrel
clopidogrel 75 mg once daily for 5 consecutive days at least.
Sponsors
Beijing Anzhen Hospital
The First Affiliated Hospital of Dalian Medical University
The Central Hospital of Jia Mu Si City
First Affiliated Hospital of Kunming Medical University
RenJi Hospital
Tianjin Medical University General Hospital
Weifang People's Hospital
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Shengjing Hospital
Shaanxi Provincial People's Hospital
First Affiliated Hospital of Harbin Medical University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with coronary artery disease
Exclusion criteria
* younger than 18 years of age; * anti-platelet therapy with clopidogrel or ticagrelor for less than 5 days; * previous or current treatment with any other potentially confounding drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ADP-induced Inhibition of Platelet Aggregation | up to 5 days | The venous blood samples for platelet function test were drawn after an overnight fast, at 12 hours post-last study-drug dose for subjects receiving twice-daily administrations, and at 24 hours post-last study-drug dose for subjects treated with once-daily regimens. The blood was collected in an evacuated vacuum tube containing 3.2% trisodium citrate and lithium heparin. Then the samples were processed within two hours of blood draw according to standard operating procedure. The physical properties of samples were analyzed using Thromboelastography (TEG) Hemostasis Analyzer (CFMS LEPU-8800, Lepu Medical Technology Co., Ltd, Beijing, China) and automated analytical software. TEG test used four channels to detect the effects of anti-platelet therapy via the arachidonic acid (AA) and ADP pathways. TEG test results were expressed in terms of ADP-induced inhibition of platelet aggregation (IPA, range 0% - 100%), with higher values indicating greater platelet inhibition. |
| Number of Participants With Bleeding (Major or Minor Bleeding) | up to 5 days | Major bleeding was defined as type ≥ 3 and minor bleeding as types 1 and 2, in accordance to the Bleeding Academic Research Consortium classification. (Mehran R et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449.) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ADP-induced Platelet-fibrin Clot Strength (MA) | up to 5 days | The physical properties of samples were analyzed using Thromboelastography (TEG) Hemostasis Analyzer (CFMS LEPU-8800, Lepu Medical Technology Co., Ltd, Beijing, China) and automated analytical software. TEG test used four channels to detect the effects of anti-platelet therapy via the arachidonic acid (AA) and ADP pathways. TEG test results were expressed in terms of ADP-induced platelet-fibrin clot strength (MA). A MA\>47mm was shown to have a high predictive value for 3-year post-PCI ischemic events during dual antiplatelet therapy. Moreover, ROC curve and quartile analysis suggested MA\<31 mm as a predictive value for post-PCI bleeding events (J Am Coll Cardiol. 2013;62(24):2261-73. doi: 10.1016/j.jacc.2013.07.101.). |
| Number of Participants With High On-Treatment Platelet Reactivity (HTPR) | up to 5 days | HTPR was defined as IPA ≤ 30% and MA ≥ 47 mm. |
| Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | up to 5 days | Cardiovascular death was defined as sudden cardiac death, fatal myocardial infarction, death due to heart failure, or death due to other cardiovascular causes. Stroke was defined as the focal loss of neurologic function caused by an ischemic or a hemorrhagic event with residual symptoms lasting at least 24 hours or eventually leading to death. |
| Number of Participants With New-onset Dyspnea | up to 5 days | New-onset dyspnea in patients without previous history of dyspnea |
Countries
China
Participant flow
Recruitment details
3,737 CAD patients who received either clopidogrel or ticagrelor therapy and underwent TEG test from 11 medical centers. Among these patients, 1,725 subjects were treated with clopidogrel and 2,012 subjects were treated with different ticagrelor regimens.
Participants by arm
| Arm | Count |
|---|---|
| Clopidogrel 75mg Qdpo. To observe the efficacy and safety of clopidogrel 75mg qdpo. in patients with coronary artery disease.
clopidogrel: clopidogrel 75 mg once daily for 5 consecutive days at least. | 1,511 |
| Ticagrelor 90mg Bidpo. To observe the efficacy and safety of ticagrelor 90mg bidpo. in patients with coronary artery disease.
ticagrelor: ticagrelor 90 mg twice daily for 5 consecutive days at least. | 501 |
| Ticagrelor 45mg Bidpo. To observe the efficacy and safety of ticagrelor 45mg bidpo. in patients with coronary artery disease.
Ticagrelor: ticagrelor 45 mg twice daily for 5 consecutive days at least. | 525 |
| Ticagrelor 90mg Qdpo. To observe the efficacy and safety of ticagrelor 90mg qdpo. in patients with coronary artery disease.
ticagrelor: ticagrelor 90 mg once daily for 5 consecutive days at least. | 506 |
| Total | 3,043 |
Baseline characteristics
| Characteristic | Clopidogrel 75mg Qdpo. | Total | Ticagrelor 90mg Qdpo. | Ticagrelor 45mg Bidpo. | Ticagrelor 90mg Bidpo. |
|---|---|---|---|---|---|
| acute myocardial infarction | 568 Participants | 895 Participants | 49 Participants | 98 Participants | 180 Participants |
| Age, Continuous | 63 years | 62 years | 62 years | 62 years | 61 years |
| aspirin use | 1429 Participants | 2793 Participants | 443 Participants | 475 Participants | 446 Participants |
| chronic kidney disease | 60 Participants | 111 Participants | 13 Participants | 25 Participants | 13 Participants |
| coronary artery bypass grafting | 12 Participants | 17 Participants | 1 Participants | 2 Participants | 2 Participants |
| creatinine | 71 μmol/L | 69.9 μmol/L | 67.7 μmol/L | 68.7 μmol/L | 69.7 μmol/L |
| diabetes mellitus | 426 Participants | 830 Participants | 117 Participants | 161 Participants | 126 Participants |
| high density lipoprotein | 1.1 mmol/L | 1.1 mmol/L | 1.2 mmol/L | 1.1 mmol/L | 1.1 mmol/L |
| Hypertension | 879 Participants | 1741 Participants | 287 Participants | 332 Participants | 243 Participants |
| low density lipoprotein | 2.6 mmol/L | 2.68 mmol/L | 2.9 mmol/L | 2.7 mmol/L | 2.8 mmol/L |
| percutaneous coronary intervention | 1056 Participants | 1802 Participants | 179 Participants | 241 Participants | 326 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1511 Participants | 3043 Participants | 506 Participants | 525 Participants | 501 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 1511 participants | 3043 participants | 506 participants | 525 participants | 501 participants |
| Sex: Female, Male Female | 532 Participants | 1129 Participants | 237 Participants | 201 Participants | 159 Participants |
| Sex: Female, Male Male | 979 Participants | 1914 Participants | 269 Participants | 324 Participants | 342 Participants |
| smoking | 736 Participants | 1398 Participants | 202 Participants | 226 Participants | 234 Participants |
| total cholesterol | 4.2 mmol/L | 4.24 mmol/L | 4.7 mmol/L | 4.3 mmol/L | 3.9 mmol/L |
| triglyceride | 1.6 mmol/L | 1.67 mmol/L | 1.6 mmol/L | 1.7 mmol/L | 1.9 mmol/L |
| uric acid | 330 μmol/L | 328.4 μmol/L | 320 μmol/L | 323 μmol/L | 338 μmol/L |
| Weight | 70 kg | 70 kg | 70 kg | 70 kg | 70 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1,511 | 0 / 501 | 0 / 525 | 0 / 506 |
| other Total, other adverse events | 0 / 1,511 | 0 / 501 | 0 / 525 | 0 / 506 |
| serious Total, serious adverse events | 0 / 1,511 | 0 / 501 | 0 / 525 | 0 / 506 |
Outcome results
Primary
ADP-induced Inhibition of Platelet Aggregation
The venous blood samples for platelet function test were drawn after an overnight fast, at 12 hours post-last study-drug dose for subjects receiving twice-daily administrations, and at 24 hours post-last study-drug dose for subjects treated with once-daily regimens. The blood was collected in an evacuated vacuum tube containing 3.2% trisodium citrate and lithium heparin. Then the samples were processed within two hours of blood draw according to standard operating procedure. The physical properties of samples were analyzed using Thromboelastography (TEG) Hemostasis Analyzer (CFMS LEPU-8800, Lepu Medical Technology Co., Ltd, Beijing, China) and automated analytical software. TEG test used four channels to detect the effects of anti-platelet therapy via the arachidonic acid (AA) and ADP pathways. TEG test results were expressed in terms of ADP-induced inhibition of platelet aggregation (IPA, range 0% - 100%), with higher values indicating greater platelet inhibition.
Time frame: up to 5 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clopidogrel 75mg Qdpo. | ADP-induced Inhibition of Platelet Aggregation | 54.9 percentage of inhibition of platelet agg |
| Ticagrelor 90mg Bidpo. | ADP-induced Inhibition of Platelet Aggregation | 80.6 percentage of inhibition of platelet agg |
| Ticagrelor 45mg Bidpo. | ADP-induced Inhibition of Platelet Aggregation | 73.6 percentage of inhibition of platelet agg |
| Ticagrelor 90mg Qdpo. | ADP-induced Inhibition of Platelet Aggregation | 66 percentage of inhibition of platelet agg |
Primary
Number of Participants With Bleeding (Major or Minor Bleeding)
Major bleeding was defined as type ≥ 3 and minor bleeding as types 1 and 2, in accordance to the Bleeding Academic Research Consortium classification. (Mehran R et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449.)
Time frame: up to 5 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Clopidogrel 75mg Qdpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | Minor bleeding | 15 Participants |
| Clopidogrel 75mg Qdpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | No bleeding | 1496 Participants |
| Clopidogrel 75mg Qdpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | Major bleeding | 0 Participants |
| Ticagrelor 90mg Bidpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | Minor bleeding | 30 Participants |
| Ticagrelor 90mg Bidpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | No bleeding | 471 Participants |
| Ticagrelor 90mg Bidpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | Major bleeding | 0 Participants |
| Ticagrelor 45mg Bidpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | Major bleeding | 0 Participants |
| Ticagrelor 45mg Bidpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | Minor bleeding | 14 Participants |
| Ticagrelor 45mg Bidpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | No bleeding | 511 Participants |
| Ticagrelor 90mg Qdpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | Minor bleeding | 9 Participants |
| Ticagrelor 90mg Qdpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | No bleeding | 497 Participants |
| Ticagrelor 90mg Qdpo. | Number of Participants With Bleeding (Major or Minor Bleeding) | Major bleeding | 0 Participants |
Secondary
ADP-induced Platelet-fibrin Clot Strength (MA)
The physical properties of samples were analyzed using Thromboelastography (TEG) Hemostasis Analyzer (CFMS LEPU-8800, Lepu Medical Technology Co., Ltd, Beijing, China) and automated analytical software. TEG test used four channels to detect the effects of anti-platelet therapy via the arachidonic acid (AA) and ADP pathways. TEG test results were expressed in terms of ADP-induced platelet-fibrin clot strength (MA). A MA\>47mm was shown to have a high predictive value for 3-year post-PCI ischemic events during dual antiplatelet therapy. Moreover, ROC curve and quartile analysis suggested MA\<31 mm as a predictive value for post-PCI bleeding events (J Am Coll Cardiol. 2013;62(24):2261-73. doi: 10.1016/j.jacc.2013.07.101.).
Time frame: up to 5 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clopidogrel 75mg Qdpo. | ADP-induced Platelet-fibrin Clot Strength (MA) | 40.3 mm |
| Ticagrelor 90mg Bidpo. | ADP-induced Platelet-fibrin Clot Strength (MA) | 28.4 mm |
| Ticagrelor 45mg Bidpo. | ADP-induced Platelet-fibrin Clot Strength (MA) | 32.3 mm |
| Ticagrelor 90mg Qdpo. | ADP-induced Platelet-fibrin Clot Strength (MA) | 34.05 mm |
Secondary
Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke)
Cardiovascular death was defined as sudden cardiac death, fatal myocardial infarction, death due to heart failure, or death due to other cardiovascular causes. Stroke was defined as the focal loss of neurologic function caused by an ischemic or a hemorrhagic event with residual symptoms lasting at least 24 hours or eventually leading to death.
Time frame: up to 5 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Clopidogrel 75mg Qdpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with stroke | 0 Participants |
| Clopidogrel 75mg Qdpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with cardiovascular death | 0 Participants |
| Clopidogrel 75mg Qdpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants without cardiovascular events | 1511 Participants |
| Clopidogrel 75mg Qdpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with new-onset myocardial infarction | 0 Participants |
| Ticagrelor 90mg Bidpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants without cardiovascular events | 501 Participants |
| Ticagrelor 90mg Bidpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with new-onset myocardial infarction | 0 Participants |
| Ticagrelor 90mg Bidpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with cardiovascular death | 0 Participants |
| Ticagrelor 90mg Bidpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with stroke | 0 Participants |
| Ticagrelor 45mg Bidpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants without cardiovascular events | 525 Participants |
| Ticagrelor 45mg Bidpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with cardiovascular death | 0 Participants |
| Ticagrelor 45mg Bidpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with new-onset myocardial infarction | 0 Participants |
| Ticagrelor 45mg Bidpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with stroke | 0 Participants |
| Ticagrelor 90mg Qdpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with cardiovascular death | 0 Participants |
| Ticagrelor 90mg Qdpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants without cardiovascular events | 506 Participants |
| Ticagrelor 90mg Qdpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with stroke | 0 Participants |
| Ticagrelor 90mg Qdpo. | Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke) | Participants with new-onset myocardial infarction | 0 Participants |
Secondary
Number of Participants With High On-Treatment Platelet Reactivity (HTPR)
HTPR was defined as IPA ≤ 30% and MA ≥ 47 mm.
Time frame: up to 5 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Clopidogrel 75mg Qdpo. | Number of Participants With High On-Treatment Platelet Reactivity (HTPR) | HTPR | 317 Participants |
| Clopidogrel 75mg Qdpo. | Number of Participants With High On-Treatment Platelet Reactivity (HTPR) | Non-HTPR | 1194 Participants |
| Ticagrelor 90mg Bidpo. | Number of Participants With High On-Treatment Platelet Reactivity (HTPR) | Non-HTPR | 488 Participants |
| Ticagrelor 90mg Bidpo. | Number of Participants With High On-Treatment Platelet Reactivity (HTPR) | HTPR | 13 Participants |
| Ticagrelor 45mg Bidpo. | Number of Participants With High On-Treatment Platelet Reactivity (HTPR) | HTPR | 23 Participants |
| Ticagrelor 45mg Bidpo. | Number of Participants With High On-Treatment Platelet Reactivity (HTPR) | Non-HTPR | 502 Participants |
| Ticagrelor 90mg Qdpo. | Number of Participants With High On-Treatment Platelet Reactivity (HTPR) | HTPR | 32 Participants |
| Ticagrelor 90mg Qdpo. | Number of Participants With High On-Treatment Platelet Reactivity (HTPR) | Non-HTPR | 474 Participants |
Secondary
Number of Participants With New-onset Dyspnea
New-onset dyspnea in patients without previous history of dyspnea
Time frame: up to 5 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Clopidogrel 75mg Qdpo. | Number of Participants With New-onset Dyspnea | Participants without new-onset dyspne | 1477 Participants |
| Clopidogrel 75mg Qdpo. | Number of Participants With New-onset Dyspnea | Participants with new-onset dyspnea | 34 Participants |
| Ticagrelor 90mg Bidpo. | Number of Participants With New-onset Dyspnea | Participants without new-onset dyspne | 472 Participants |
| Ticagrelor 90mg Bidpo. | Number of Participants With New-onset Dyspnea | Participants with new-onset dyspnea | 29 Participants |
| Ticagrelor 45mg Bidpo. | Number of Participants With New-onset Dyspnea | Participants with new-onset dyspnea | 32 Participants |
| Ticagrelor 45mg Bidpo. | Number of Participants With New-onset Dyspnea | Participants without new-onset dyspne | 493 Participants |
| Ticagrelor 90mg Qdpo. | Number of Participants With New-onset Dyspnea | Participants without new-onset dyspne | 478 Participants |
| Ticagrelor 90mg Qdpo. | Number of Participants With New-onset Dyspnea | Participants with new-onset dyspnea | 28 Participants |