Coronary Artery Disease, Diabetes Mellitus, Type 2
Conditions
Keywords
diabetes mellitus, ticagrelor, clopidogrel, percutaneous coronary intervention
Brief summary
Recent studies have shown that withdrawing aspirin and maintaining P2Y12 inhibitor monotherapy for up to 12 months post-PCI, after a brief period of DAPT, reduces bleeding without increasing ischemic harm. Such effects have shown to of particular benefit in patients with diabetes mellitus (DM). However, if an aspirin-free approach can be considered after this time frame is a matter of debate. The aim of this study is to assess the PD effects of ticagrelor 60 mg with and without aspirin therapy in CAD patients and to compare this with a standard DAPT regimen of aspirin plus clopidogrel.
Detailed description
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is the standard of care for the prevention of thrombotic complications in patients with coronary artery disease (CAD) undergoing percutaneous coronary interventions (PCI). However, such ischemic benefit occurs at the expense of enhanced bleeding, the risk of which increases in a graded fashion with prolonged exposure to DAPT. Recent studies have shown that withdrawing aspirin and maintaining P2Y12 inhibitor monotherapy for up to 12 months post-PCI, after a brief period of DAPT, reduces bleeding without increasing ischemic harm. Such effects have shown to of particular benefit in patients with diabetes mellitus (DM). However, if an aspirin-free approach can be considered after this time frame is a matter of debate. In fact, current guidelines recommend maintaining P2Y12 inhibiting therapy for high risk patients but which all imply background use of aspirin. P2Y12 inhibitors for long-term (beyond 12 months) secondary prevention mainly include clopidogrel and ticagrelor. In particular, the dosing regimen for clopidogrel remains the standard 75 mg qd, whereas ticagrelor dosing is recommended to be reduced from 90 mg bid to 60 mg bid. However, of these regimens the pharmacodynamics (PD) effects of ticagrelor 60 mg in the absence of aspirin has not yet been tested. Because DM patients are likely to continue with long-term P2Y12 inhibitor therapy, defining the optimal antithrombotic approach for these patients is of critical importance. In light of the above made observations, patients with DM represent an ideal population to define the antiplatelet effects of a ticagrelor 60 mg monotherapy regimen. The aim of this study is to assess the PD effects of ticagrelor 60 mg with and without aspirin therapy in CAD patients and to compare this with a standard DAPT regimen of aspirin plus clopidogrel.
Interventions
Eligible patients will enter a 7-10 day run-in phase with aspirin 81 mg/ qd plus ticagrelor 90 mg bid after which they will discontinue aspirin and maintain ticagrelor 90 mg bid monotherapy for 10±3 days. After this period, patients will be randomized using a randomly generated computer sequence in a 1:1:1 fashion to either: a) ticagrelor 60 mg bid monotherapy; b) aspirin 81 mg qd plus ticagrelor 60 mg bid; c) aspirin 81 mg qd plus clopidogrel 75 mg qd. Randomized treatment will be maintained for 10±3 days.
Eligible patients will enter a 7-10 day run-in phase with aspirin 81 mg/ qd plus ticagrelor 90 mg bid after which they will discontinue aspirin and maintain ticagrelor 90 mg bid monotherapy for 10±3 days. After this period, patients will be randomized using a randomly generated computer sequence in a 1:1:1 fashion to either: a) ticagrelor 60 mg bid monotherapy; b) aspirin 81 mg qd plus ticagrelor 60 mg bid; c) aspirin 81 mg qd plus clopidogrel 75 mg qd. Randomized treatment will be maintained for 10±3 days.
DRUGClopidogrel with aspirin
Eligible patients will enter a 7-10 day run-in phase with aspirin 81 mg/ qd plus ticagrelor 90 mg bid after which they will discontinue aspirin and maintain ticagrelor 90 mg bid monotherapy for 10±3 days. After this period, patients will be randomized using a randomly generated computer sequence in a 1:1:1 fashion to either: a) ticagrelor 60 mg bid monotherapy; b) aspirin 81 mg qd plus ticagrelor 60 mg bid; c) aspirin 81 mg qd plus clopidogrel 75 mg qd. Randomized treatment will be maintained for 10±3 days.
Sponsors
AstraZeneca
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Staff performing PK/PD assessments will remain blinded to treatment assignment.
Intervention model description
Prospective randomized
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For inclusion in the study patients should fulfill the following criteria: 1. Provision of informed consent prior to any study specific procedures 2. Men or women ≥18 years of age 3. Diagnosed with type 2 DM defined by ongoing glucose lowering therapy (oral medications and/or insulin) treatment for at least 1 month 4. Known angiographically defined CAD (including a history of previous PCI, CABG, or \>50% stenosis in a major epicardial vessel) on standard of care antiplatelet therapy\* \*Patients can be treated with any background antiplatelet treatment regimen as part of their standard of care, including aspirin and/or any P2Y12 inhibitor (clopidogrel, ticagrelor, prasugrel).
Exclusion criteria
1. PCI \< 6 months prior 2. Recent (\< 6 months) type I myocardial infarction 3. Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 3A4 (CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices that cannot be stopped for the course of the study: * Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin (but not erythromycin or azithromycin), nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir * CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses \>40 mg daily or lovastatin at doses \>40 mg daily 4. Anticipated concomitant oral or intravenous therapry of strong CYP3A inducers (phenytoin, rifampin, phenobarb, carbamazepine) 5. Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin (at venous thrombosis treatment not prophylaxis doses) 6. Patients with known bleeding diathesis or coagulation disorder 7. History of previous intracerebral bleed at any time, gastrointestinal (GI) bleed within the past 6 months prior to randomization, or major surgery within 30 days prior to randomization 8. Active pathological bleeding 9. Hypersensitivity to aspirin, ticagrelor or clopidogrel 10. Increased risk of bradycardic events (eg, known sick sinus syndrome, second or third degree AV block or previous documented syncope suspected to be due to bradycardia) unless treated with a pacemaker 11. Known severe liver disease 12. Renal failure requiring dialysis 13. Known platelet count \<80x106/mL 14. Known hemoglobin \<9 g/dL 15. Pregnant or breastfeeding women. \*Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| P2Y12 Reaction Units (PRU) | Day 10, pre-dose | The primary end-point of the study is the comparison of the PRU determined by VerifyNow PRU between between aspirin plus ticagrelor 60 mg and ticagrelor 60 mg monotherapy (trough effect pre-dosing). The VerifyNow System is a turbidimetric based optical detection system which measures platelet induced aggregation as an increase in light transmittance. The assay is based on microbead agglutination induced by adenosine diphosphate (ADP). The instrument measures this change in optical signal and reports results in P2Y12 Reaction Units (PRU). |
Other
| Measure | Time frame | Description |
|---|---|---|
| VASP | Day 10, pre-dose | Comparison of the platelet reactivity index (PRI) determined by VASP between between aspirin plus ticagrelor 60 mg and ticagrelor 60 mg monotherapy. VASP phosphorylation (VASP-P) is a marker of P2Y12 receptor signaling. VASP was assessed the ELISA VASP-P kit. Low PRI indicates appropriate platelet inhibition. |
| Comparison of Platelet Aggregation With ADP as Stimuli Determined by Light Transmittance Aggregometry Between Between Aspirin Plus Ticagrelor 60 mg and Ticagrelor 60 mg Monotherapy. | Day 10, pre-dose | Platelet aggregation was stimulated by ADP. Platelet aggregation will be determined as the maximal percent change (MPA%) in light transmittance from baseline. Low MPA% reflects good platelet inhibition. |
| Comparison of Thrombus Formation Measured by T-TAS Between Between Aspirin Plus Ticagrelor 60 mg and Ticagrelor 60 mg Monotherapy | Day 10, pre-dose | T-TAS is an automated microchip flow chamber system for the quantitative analysis of the thrombus formation process under blood flow conditions. In the present study, total platelet-derived thrombus formation is expressed as the area under the flow pressure curve for the first 10 min for the PL-chip tested at a flow rate of 18 μL/min (PL18-AUC10). Results of the assay are reported as PL18-AUC10. Low AUC reflect reduced thrombus growth and rapid breakdown of the thrombus. |
Countries
United States
Participant flow
Pre-assignment details
105 patients consented. * 4 screen failures * 16 withdrawn during run in * 4 lost to follow-up before randomization visit
Participants by arm
| Arm | Count |
|---|---|
| Ticagrelor ticagrelor 60 mg bid monotherapy
Ticagrelor monotherapy: Eligible patients will enter a 7-10 day run-in phase with aspirin 81 mg/ qd plus ticagrelor 90 mg bid after which they will discontinue aspirin and maintain ticagrelor 90 mg bid monotherapy for 10±3 days. After this period, patients will be randomized using a randomly generated computer sequence in a 1:1:1 fashion to either: a) ticagrelor 60 mg bid monotherapy; b) aspirin 81 mg qd plus ticagrelor 60 mg bid; c) aspirin 81 mg qd plus clopidogrel 75 mg qd. Randomized treatment will be maintained for 10±3 days. | 26 |
| Aspirin Plus Clopidogrel aspirin 81 mg qd plus clopidogrel 75 mg qd
Clopidogrel with aspirin: Eligible patients will enter a 7-10 day run-in phase with aspirin 81 mg/ qd plus ticagrelor 90 mg bid after which they will discontinue aspirin and maintain ticagrelor 90 mg bid monotherapy for 10±3 days. After this period, patients will be randomized using a randomly generated computer sequence in a 1:1:1 fashion to either: a) ticagrelor 60 mg bid monotherapy; b) aspirin 81 mg qd plus ticagrelor 60 mg bid; c) aspirin 81 mg qd plus clopidogrel 75 mg qd. Randomized treatment will be maintained for 10±3 days. | 27 |
| Aspirin Plus Ticagrelor aspirin 81 mg qd plus ticagrelor 60 mg bid
Ticagrelor plus aspirin: Eligible patients will enter a 7-10 day run-in phase with aspirin 81 mg/ qd plus ticagrelor 90 mg bid after which they will discontinue aspirin and maintain ticagrelor 90 mg bid monotherapy for 10±3 days. After this period, patients will be randomized using a randomly generated computer sequence in a 1:1:1 fashion to either: a) ticagrelor 60 mg bid monotherapy; b) aspirin 81 mg qd plus ticagrelor 60 mg bid; c) aspirin 81 mg qd plus clopidogrel 75 mg qd. Randomized treatment will be maintained for 10±3 days. | 28 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Randomized Treatment | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 |
| Run-in Phase With Aspirin and Ticagrelor | Adverse Event | 0 | 0 | 0 | 9 | 0 |
| Run-in Phase With Aspirin and Ticagrelor | Lost to Follow-up | 0 | 0 | 0 | 4 | 0 |
| Run-in Phase With Aspirin and Ticagrelor | Physician Decision | 0 | 0 | 0 | 2 | 0 |
| Run-in Phase With Aspirin and Ticagrelor | Withdrawal by Subject | 0 | 0 | 0 | 4 | 0 |
| Run-in Phase With Ticagrelor Monotherapy | Adverse Event | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Ticagrelor | Aspirin Plus Clopidogrel | Aspirin Plus Ticagrelor | Total |
|---|---|---|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 8 | 65 years STANDARD_DEVIATION 8 | 65 years STANDARD_DEVIATION 10 | 64 years STANDARD_DEVIATION 8 |
| Hemoglobin A1c | 8.0 % of glycated hemoglobin STANDARD_DEVIATION 2 | 7.5 % of glycated hemoglobin STANDARD_DEVIATION 2.7 | 7.6 % of glycated hemoglobin STANDARD_DEVIATION 2.4 | 7.7 % of glycated hemoglobin STANDARD_DEVIATION 2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 8 Participants | 4 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 16 Participants | 18 Participants | 23 Participants | 57 Participants |
| Sex: Female, Male Female | 16 Participants | 7 Participants | 13 Participants | 36 Participants |
| Sex: Female, Male Male | 10 Participants | 20 Participants | 15 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 27 | 0 / 28 | 0 / 101 | 0 / 82 |
| other Total, other adverse events | 7 / 26 | 12 / 27 | 7 / 28 | 7 / 101 | 0 / 82 |
| serious Total, serious adverse events | 0 / 26 | 0 / 27 | 0 / 28 | 2 / 101 | 0 / 82 |
Outcome results
Primary
P2Y12 Reaction Units (PRU)
The primary end-point of the study is the comparison of the PRU determined by VerifyNow PRU between between aspirin plus ticagrelor 60 mg and ticagrelor 60 mg monotherapy (trough effect pre-dosing). The VerifyNow System is a turbidimetric based optical detection system which measures platelet induced aggregation as an increase in light transmittance. The assay is based on microbead agglutination induced by adenosine diphosphate (ADP). The instrument measures this change in optical signal and reports results in P2Y12 Reaction Units (PRU).
Time frame: Day 10, pre-dose
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | P2Y12 Reaction Units (PRU) | 47 PRU |
| Aspirin Plus Clopidogrel | P2Y12 Reaction Units (PRU) | 136 PRU |
| Aspirin Plus Ticagrelor | P2Y12 Reaction Units (PRU) | 39 PRU |
Comparison: The primary end point was non-inferiority of Ticagrelor 60 mg monotherapy vs. aspirin plus Ticagrelor 60 mg95% CI: [-23, 38]
Other Pre-specified
Comparison of Platelet Aggregation With ADP as Stimuli Determined by Light Transmittance Aggregometry Between Between Aspirin Plus Ticagrelor 60 mg and Ticagrelor 60 mg Monotherapy.
Platelet aggregation was stimulated by ADP. Platelet aggregation will be determined as the maximal percent change (MPA%) in light transmittance from baseline. Low MPA% reflects good platelet inhibition.
Time frame: Day 10, pre-dose
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | Comparison of Platelet Aggregation With ADP as Stimuli Determined by Light Transmittance Aggregometry Between Between Aspirin Plus Ticagrelor 60 mg and Ticagrelor 60 mg Monotherapy. | 29 MPA% |
| Aspirin Plus Clopidogrel | Comparison of Platelet Aggregation With ADP as Stimuli Determined by Light Transmittance Aggregometry Between Between Aspirin Plus Ticagrelor 60 mg and Ticagrelor 60 mg Monotherapy. | 39 MPA% |
| Aspirin Plus Ticagrelor | Comparison of Platelet Aggregation With ADP as Stimuli Determined by Light Transmittance Aggregometry Between Between Aspirin Plus Ticagrelor 60 mg and Ticagrelor 60 mg Monotherapy. | 26 MPA% |
Other Pre-specified
Comparison of Thrombus Formation Measured by T-TAS Between Between Aspirin Plus Ticagrelor 60 mg and Ticagrelor 60 mg Monotherapy
T-TAS is an automated microchip flow chamber system for the quantitative analysis of the thrombus formation process under blood flow conditions. In the present study, total platelet-derived thrombus formation is expressed as the area under the flow pressure curve for the first 10 min for the PL-chip tested at a flow rate of 18 μL/min (PL18-AUC10). Results of the assay are reported as PL18-AUC10. Low AUC reflect reduced thrombus growth and rapid breakdown of the thrombus.
Time frame: Day 10, pre-dose
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | Comparison of Thrombus Formation Measured by T-TAS Between Between Aspirin Plus Ticagrelor 60 mg and Ticagrelor 60 mg Monotherapy | 258 kPa x minutes |
| Aspirin Plus Clopidogrel | Comparison of Thrombus Formation Measured by T-TAS Between Between Aspirin Plus Ticagrelor 60 mg and Ticagrelor 60 mg Monotherapy | 147 kPa x minutes |
| Aspirin Plus Ticagrelor | Comparison of Thrombus Formation Measured by T-TAS Between Between Aspirin Plus Ticagrelor 60 mg and Ticagrelor 60 mg Monotherapy | 67 kPa x minutes |
Other Pre-specified
VASP
Comparison of the platelet reactivity index (PRI) determined by VASP between between aspirin plus ticagrelor 60 mg and ticagrelor 60 mg monotherapy. VASP phosphorylation (VASP-P) is a marker of P2Y12 receptor signaling. VASP was assessed the ELISA VASP-P kit. Low PRI indicates appropriate platelet inhibition.
Time frame: Day 10, pre-dose
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor | VASP | 77 PRI |
| Aspirin Plus Clopidogrel | VASP | 73 PRI |
| Aspirin Plus Ticagrelor | VASP | 70 PRI |