Coronary Artery Disease
Conditions
Brief summary
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. More potent P2Y12 receptor inhibitors, such as 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 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. Therefore, the aim of this investigation is to evaluate the PD effects of switching from ticagrelor to clopidogrel.
Detailed description
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.
Interventions
DRUGClopidogrel
Swiching from ticagrelor to clopidogrel
DRUGTicagrelor
Continue treatment with ticagrelor
Sponsors
University of Florida
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
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. Severe hepatic impairment (ALT \>2.5 times the upper limit of normal) 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 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 \[women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study\].
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity Unit | 48 hours after switch | PRU assessed by VerifyNow at 48 hours after switching of clopidogrel 600 mg LD administered 24 hours after the last ticagrelor MD vs. clopidogrel 75 mg MD given 24 hours after the last ticagrelor MD |
Countries
United States
Participant flow
Pre-assignment details
87 patients entered a run-in phase. Of these, 7 withdrew during run in.
Participants by arm
| Arm | Count |
|---|---|
| A) Clopidogrel 600 mg LD 24 Hours After Last MD of Ticagrelor 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
Clopidogrel: Swiching from ticagrelor to clopidogrel | 20 |
| B) Clopidogrel 600 mg LD 12 Hours After Last MD of Ticagrelor 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
Clopidogrel: Swiching from ticagrelor to clopidogrel | 20 |
| C) Clopidogrel 75mg MD 24 Hours After Last MD of Ticagrelor 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
Clopidogrel: Swiching from ticagrelor to clopidogrel | 20 |
| D) Continue Ticagrelor MD 90mg Twice Daily 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
Ticagrelor: Continue treatment with ticagrelor | 20 |
| Total | 80 |
Baseline characteristics
| Characteristic | A) Clopidogrel 600 mg LD 24 Hours After Last MD of Ticagrelor | Total | D) Continue Ticagrelor MD 90mg Twice Daily | C) Clopidogrel 75mg MD 24 Hours After Last MD of Ticagrelor | B) Clopidogrel 600 mg LD 12 Hours After Last MD of Ticagrelor |
|---|---|---|---|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 7 | 62 years STANDARD_DEVIATION 8 | 58 years STANDARD_DEVIATION 9 | 63 years STANDARD_DEVIATION 9 | 65 years STANDARD_DEVIATION 8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 28 Participants | 6 Participants | 7 Participants | 5 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 | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 51 Participants | 14 Participants | 13 Participants | 14 Participants |
| Region of Enrollment United States | 20 participants | 20 participants | 20 participants | 20 participants | 20 participants |
| Sex: Female, Male Female | 9 Participants | 29 Participants | 8 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Male | 11 Participants | 51 Participants | 12 Participants | 13 Participants | 15 Participants |
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 / 20 | 0 / 20 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 1 / 20 | 0 / 20 | 0 / 20 | 2 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 20 |
Outcome results
Primary
Platelet Reactivity Unit
PRU assessed by VerifyNow at 48 hours after switching of clopidogrel 600 mg LD administered 24 hours after the last ticagrelor MD vs. clopidogrel 75 mg MD given 24 hours after the last ticagrelor MD
Time frame: 48 hours after switch
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| A) Clopidogrel 600 mg LD 24 Hours After Last MD of Ticagrelor | Platelet Reactivity Unit | 177 PRU | Standard Error 27 |
| B) Clopidogrel 600 mg LD 12 Hours After Last MD of Ticagrelor | Platelet Reactivity Unit | 164 PRU | Standard Error 24 |
| C) Clopidogrel 75mg MD 24 Hours After Last MD of Ticagrelor | Platelet Reactivity Unit | 174 PRU | Standard Error 24 |
| D) Continue Ticagrelor MD 90mg Twice Daily | Platelet Reactivity Unit | 26 PRU | Standard Error 25 |
p-value: >0.05985% CI: [-38, 24]ANCOVA