Antiplatelet Agents, Coronary Artery Bypass
Conditions
Keywords
CABG, Antiplatelet, Ticagrelor
Brief summary
The study population will include all patients undergoing elective CABG. Consent and randomization will occur before surgery. Total 500 patients undergoing elective CABG will be randomly assigned into three groups with 1:1:1 ratio(167 patients per group) in this open-label study. All the enrolled patients will stop oral antiplatelet drugs according to local protocol before the surgery. Within the first 24 hours after surgery, study medication should be restarted and continued for 12 months. Arm A will restart oral antiplatelet drugs by giving aspirin 100mg qd, Arm B will also restart oral antiplatelet drugs by giving ticagrelor 90mg bid plus aspirin 100mg qd and Arm C will also restart oral antiplatelet drugs by giving ticagrelor 90mg bid. Treatment will continue for 12 months, at which time patients will undergo a multislice computed tomography angiography to assess vein graft patency. This study is designed to show the superiority of ticagrelor and ticagrelor plus aspirin as compared with aspirin monotherapy respectively for the 1-year primary efficacy end point of vein graft patency.
Detailed description
The study is designed to show the superiority of ticagrelor and ticagrelor plus aspirin as compared with aspirin monotherapy respectively for the 1-year primary efficacy end point of vein graft patency. The primary comparison includes two separate parts. One is to demonstrate T+A better than A and the other is T better than A. One year rate of vein graft patency in the aspirin group is estimated as 80%. The assumed rate of ticagrelor plus aspirin is 90%. With a two-sided alpha level 0.05 and 80% power, 199 grafts to each group are required. On the other hand, if we assume the rate of ticagrelor monotherapy has the 1-year vein graft patency rate of 87%, under the same two-sided 0.05 alpha 441 grafts in each arm will offer 80% power to show the superiority of ticagrelor along for the primary efficacy end point. Combined the above two assumptions, if the allocation rate is 1:1:1, this study needs to recruit 1,323 grafts in total (441 in each) to achieve the pre-specified power for both the two comparisons (T+A vs. A and T vs. A). The principle investigator assumes that the average number of the vien grafts in one patient is 2.7-3.0. With this assumption, 500 patients are to be recruited, which will provide us a total of 1350 - 1500 grafts. According to the above, this study will be a confirmatory clinical trial to the primary endpoint.
Interventions
DRUGAspirin
DRUGTicagrelor
Sponsors
Ruijin Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients able to provide written informed consent * Provision of informed consent prior to any study specific procedures * Female and male patients aged 18-80 years * Indication for CABG surgery
Exclusion criteria
* Cardiogenic shock, haemodynamic instability * Need for urgent revascularization within 5 days from presentation * Single vessel disease * Two vessel disease with normal left ventricular function (\> 50%) * Need for concomitant other cardiac surgery (e.g. valve replacement) * Need for dual antiplatelet treatment for the patients undergoing CABG after acute coronary syndrome(ACS) * Contraindication for aspirin and ticagrelor use(e.g. known allergy) * History of bleeding diathesis within 3 months prior presentation * History of significant GI bleed within 1 year prior presentation * History of peptic ulcer without GI bleeding in past 3 years * History of intracranial hemorrhage * History of moderate to severe liver impairment * Patient requires dialysis * Patient with an increased risk of bradycardic events (as patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree arteriolar-venular block or bradycardic-related syncope) * Need vitamin K antagonist therapy after bypass surgery eg. persistent atrial fibrillation, mechanical valves * Known, clinically important thrombocytopenia(i.e. \< 100\*109/L) * Known, clinically important anaemia (i.e. \<100g/L) * Participation in another investigational drug or device study in the last 30 days * Pregnancy or lactation(for premenopausal women 2 methods of reliable contraception, one of which must barrier method, are required) * Concomitant oral or intravenous therapy with strong cytochrome P450 3A4(CYP3A4) inhibitors, CYP3A4 substrates with narrow therapeutic indices, or strong CYP3A4 inducers which cannot be stopped for the course of the study (strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, over 1 litre daily of grapefruit juice. Substrates with narrow therapeutic index: cyclosporine, quinidine. Strong inducers: rifampin, phenytoin, carbamazepine. ) * Any other condition such as active cancer * Life expectancy less than 12 months that may result in protocol non-compliance or a risk for being lost to follow up * Indication for major surgery(e.g. cancer treatment, carotid surgery, cerebral surgery, major vascular surgery)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Patency of Saphenous Vein Grafts | up to 12 months | assessed by multislice computed tomography angiography (MSCTA) or coronary angiography(CAG). FitzGibbon grade A (stenosis \<50%) is defined as patency. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Patency of Saphenous Vein Grafts | up to 7 days | assessed by MSCTA or CAG. FitzGibbon grade A (stenosis \<50%) is defined as patency. |
| The Rate of Post-operative Atrial Fibrillation After CABG. | up to 7 days | Number of Participants with Post-operative Atrial Fibrillation after CABG |
| The Number of Major Adverse Cardiovascular Event (MACE) | up to 12 months | MACE, composite of CV death, myocardial infarction or stroke (ischaemic or unknown etiology) |
| Number of the Major Bleeding Events | up to 12 months | According to modified TIMI criteria, the Major Bleeding Events is defined as the combination of CABG-related bleeding and non-CABG-related major bleeding(Intracranial bleeding, Clinically overt signs of hemorrhage with hemoglobin drop ≥5 g/dL and Fatal bleeding). |
| The Rate of Freedom From Angina According to Canadian Cardiovascular Society (CCS) Classification | up to 12 months | Number of Participants Free of Angina per CCS Classification |
Other
| Measure | Time frame | Description |
|---|---|---|
| The Rate of Gastroduodenal Injury Assessed by Esophagogastroduodenoscopy (EGD) | at 12 months | Not all but the patients recruited in Ruijin Hospital |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aspirin aspirin 100mg tablet by mouth daily for 12 months
Aspirin | 166 |
| Ticagrelor Plus Aspirin ticagrelor 90mg tablet by mouth twice daily and aspirin 100mg tablet by mouth daily for 12 months
Aspirin
Ticagrelor | 168 |
| Ticagrelor ticagrelor 90mg tablet by mouth twice daily for 12 months
Ticagrelor | 166 |
| Total | 500 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 3 | 2 | 0 |
| Overall Study | Protocol Violation | 10 | 8 | 10 |
Baseline characteristics
| Characteristic | Aspirin | Ticagrelor Plus Aspirin | Ticagrelor | Total |
|---|---|---|---|---|
| Age, Continuous | 64.0 years STANDARD_DEVIATION 8.1 | 63.5 years STANDARD_DEVIATION 8.2 | 63.3 years STANDARD_DEVIATION 8.3 | 63.6 years STANDARD_DEVIATION 8.2 |
| Region of Enrollment China | 166 participants | 168 participants | 166 participants | 500 participants |
| Sex: Female, Male Female | 25 Participants | 34 Participants | 32 Participants | 91 Participants |
| Sex: Female, Male Male | 141 Participants | 134 Participants | 134 Participants | 409 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 166 | 2 / 168 | 0 / 166 |
| other Total, other adverse events | 78 / 166 | 91 / 168 | 74 / 166 |
| serious Total, serious adverse events | 9 / 166 | 3 / 168 | 3 / 166 |
Outcome results
Primary
The Patency of Saphenous Vein Grafts
assessed by multislice computed tomography angiography (MSCTA) or coronary angiography(CAG). FitzGibbon grade A (stenosis \<50%) is defined as patency.
Time frame: up to 12 months
Population: ITT analysis, Patients with missing data were considered to have occluded saphenous vein grafts.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | The Patency of Saphenous Vein Grafts | 76.5 percentage of patent SV grafts |
| Ticagrelor Plus Aspirin | The Patency of Saphenous Vein Grafts | 88.7 percentage of patent SV grafts |
| Ticagrelor | The Patency of Saphenous Vein Grafts | 82.8 percentage of patent SV grafts |
Secondary
Number of the Major Bleeding Events
According to modified TIMI criteria, the Major Bleeding Events is defined as the combination of CABG-related bleeding and non-CABG-related major bleeding(Intracranial bleeding, Clinically overt signs of hemorrhage with hemoglobin drop ≥5 g/dL and Fatal bleeding).
Time frame: up to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | Number of the Major Bleeding Events | 0 events |
| Ticagrelor Plus Aspirin | Number of the Major Bleeding Events | 3 events |
| Ticagrelor | Number of the Major Bleeding Events | 2 events |
Secondary
The Number of Major Adverse Cardiovascular Event (MACE)
MACE, composite of CV death, myocardial infarction or stroke (ischaemic or unknown etiology)
Time frame: up to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | The Number of Major Adverse Cardiovascular Event (MACE) | 9 events |
| Ticagrelor Plus Aspirin | The Number of Major Adverse Cardiovascular Event (MACE) | 4 events |
| Ticagrelor | The Number of Major Adverse Cardiovascular Event (MACE) | 3 events |
Secondary
The Patency of Saphenous Vein Grafts
assessed by MSCTA or CAG. FitzGibbon grade A (stenosis \<50%) is defined as patency.
Time frame: up to 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin | The Patency of Saphenous Vein Grafts | 91.1 percentage of patent SV grafts |
| Ticagrelor Plus Aspirin | The Patency of Saphenous Vein Grafts | 94.9 percentage of patent SV grafts |
| Ticagrelor | The Patency of Saphenous Vein Grafts | 94.3 percentage of patent SV grafts |
Secondary
The Rate of Freedom From Angina According to Canadian Cardiovascular Society (CCS) Classification
Number of Participants Free of Angina per CCS Classification
Time frame: up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aspirin | The Rate of Freedom From Angina According to Canadian Cardiovascular Society (CCS) Classification | 154 Participants |
| Ticagrelor Plus Aspirin | The Rate of Freedom From Angina According to Canadian Cardiovascular Society (CCS) Classification | 158 Participants |
| Ticagrelor | The Rate of Freedom From Angina According to Canadian Cardiovascular Society (CCS) Classification | 155 Participants |
Secondary
The Rate of Post-operative Atrial Fibrillation After CABG.
Number of Participants with Post-operative Atrial Fibrillation after CABG
Time frame: up to 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aspirin | The Rate of Post-operative Atrial Fibrillation After CABG. | 23 Participants |
| Ticagrelor Plus Aspirin | The Rate of Post-operative Atrial Fibrillation After CABG. | 20 Participants |
| Ticagrelor | The Rate of Post-operative Atrial Fibrillation After CABG. | 13 Participants |
Other Pre-specified
The Rate of Gastroduodenal Injury Assessed by Esophagogastroduodenoscopy (EGD)
Not all but the patients recruited in Ruijin Hospital
Time frame: at 12 months