Coronary Artery Disease, Diabetes Mellitus
Conditions
Keywords
coronary artery disease, diabetes mellitus, chronic kidney disease, ticagrelor
Brief summary
Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events. Importantly, DM is a key risk factor for the development of chronic kidney disease (CKD), which further enhances atherothrombotic risk. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor. However, despite its clinical benefit, patients with DM and CKD frequently experience recurrent atherothrombotic events. Ticagrelor is an oral, reversible, non-competitive P2Y12 receptor inhibitor with more potent and consistent platelet inhibition than clopidogrel. In large-scale clinical investigation, ticagrelor significantly reduced ischemic events to a greater extent than clopidogrel, a finding that was consistent also among DM patients. To date there has been no analysis on the efficacy of ticagrelor in DM patients according to CKD status. Moreover, although pharmacodynamic (PD) studies showed enhanced platelet inhibition associated with ticagrelor, it is unknown how this may be affected by CKD status. Ultimately, how PK/PD profiles of different ticagrelor dosing regimens may be affected by DM and CKD status is also unknown. The proposed study is aimed to show the impact of CKD status among patients with DM and coronary artery disease) CAD on PD and PK profiles of ticagrelor used at 2 doses (90mg bid and 60mg bid) in the setting of a prospective, randomized, cross-over trial.
Detailed description
Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events. Importantly, DM is a key risk factor for the development of chronic kidney disease (CKD), which further enhances atherothrombotic risk. These observations underscore the importance of antiplatelet therapy for prevention of atherothrombotic recurrences in these high-risk patients. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor. However, despite its clinical benefit, patients with DM and CKD frequently experience recurrent atherothrombotic events. This may be in part due to the impaired pharmacokinetic (PK) and pharmacodynamic (PD) effects of clopidogrel in patients with DM and CKD. Since both DM and CKD represent pandemic public health problems, the prevalence of which will double over the next 20 years, identifying antiplatelet agents with more favorable PK/PD profiles is of key importance. Ticagrelor is an oral, reversible, non-competitive P2Y12 receptor inhibitor with more potent and consistent platelet inhibition than clopidogrel. In large-scale clinical investigation, ticagrelor significantly reduced ischemic events to a greater extent than clopidogrel, a finding that was consistent also among DM patients. In patients with CKD, ticagrelor led to an even greater relative risk reduction of ischemic events, including cardiovascular mortality, compared to patients without CKD. However, to date there has been no analysis on the efficacy of ticagrelor in DM patients according to CKD status. Moreover, although PD studies showed enhanced platelet inhibition associated with ticagrelor, it is unknown how this may be affected by CKD status. Ultimately, how PK/PD profiles of different ticagrelor dosing regimens may be affected by DM and CKD status is also unknown. The proposed study is aimed to show the impact of CKD status among patients with DM and CAD on PD and PK profiles of ticagrelor used at 2 doses (90mg bid and 60mg bid) in the setting of a prospective, randomized, cross-over trial.
Interventions
DRUGticagrelor
Diabetic patients with or without chronic kidney disease will be randomized 1:1 to either (A) standard dose (90mg twice daily of ticagrelor) for 7-10 days and then cross-over to low dose (60mg twice daily of ticagrelor) for 7-10 days; (B) low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2).
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \>18 years. * Type 2 DM, defined according to World Health Organization (WHO) definition, on treatment with oral hypoglycemic agents and/or insulin for at least 2 months without any changes in treatment regimen; * Angiographically documented CAD. * On treatment with low-dose aspirin (81mg/day) and clopidogrel (75mg/day) for at least 30 days as part of standard of care.
Exclusion criteria
* Patients with end-stage renal disease on hemodialysis. * Use of any antiplatelet therapy (except aspirin and clopidogrel) in past 30 days. * Use of parenteral or oral anticoagulation in past 30 day. * Active pathological bleeding. * History of intracranial hemorrhage with prior hemorrhage stroke. * Blood dyscrasia or bleeding diathesis. * Any active malignancy. * Platelet count \< 80x106/µl. * Hemoglobin \<10 g/dl. * Known hepatic dysfunction (known moderate and severe hepatic dysfunction). * Hemodynamic instability. * Known allergy or hypersensitivity to ticagrelor or any excipients. * Pregnant / lactating females (women of childbearing age must use reliable birth control while in the study). * Strong inhibitors of cytochrome CYP3A4 and potent inducers of cytochrome CYP3A4 (to avoid interaction with ticagrelor): ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin. * Patients with sick sinus syndrome (SSS) or high degree atrio-ventricular block without pacemaker protection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity Measured by Vasodilator Stimulated Phosphoprotein (VASP) Platelet Reactivity Index (PRI %) | 7 days | The primary end point of the study was platelet reactivity assessed by VASP-PRI following treatment with ticagrelor 90mg between DM-CKD and DM-non-CKD cohorts. PRI % is a measure of platelet reactivity, where higher PRI levels represent higher platelet reactivity and lower effect of antiplatelet medications. PRI greater than 50% represents inadequate response to antiplatelet medications. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity Measured by VerifyNow P2Y12 | 7 days | Platelet reactivity assessed by VerifyNow P2Y12 following treatment with ticagrelor 90mg or 60 mg between DM-CKD and DM-non-CKD cohorts. Results are expressed in P2Y12 reaction units (PRU). PRU is a measure of platelet reactivity, where higher PRU levels represent higher platelet reactivity and lower effect of antiplatelet medications. PRU greater than 208 represents inadequate response to antiplatelet medications. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited between February 2016 and November 2019 at the outpatient clinics of University of Florida Health - Jacksonville (Jacksonville, Florida, USA).
Pre-assignment details
101 patients were consented and enrolled in the study; 9 patients were not eligible for randomization due to the presence of exclusion criteria. A total of 92 patients (non-CKD, n=48; CKD, n=44) were randomized and exposed to at least one dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| DM-Non-CKD (All Participants Regardless of Sequence) Patients with diabetes mellitus (DM) and coronary artery disease (CAD) were stratified according to chronic kidney disease (CKD) status. Non-CKD was defined by a glomerular filtrate rate (GFR) ≥ 60 ml/min/1.73m2.
Non-CKD patients were randomized 1:1 to a) standard dose ticagrelor (90mg twice daily) for 7-10 days or b) low dose ticagrelor (60mg twice daily) for 7-10 days (phase 1). After 7-10 days of randomized treatment patients were crossed over to the alternative treatment, which was maintained for additional 7-10 days (phase 2).
This is a crossover study where participants in each cohort received both treatments but in difference sequences. Therefore, baseline characteristics are presented for the two separate cohorts but combining patients together regardless of treatment sequence. | 39 |
| DM-CKD (All Participants Regardless of Sequence) Patients with diabetes mellitus (DM) and coronary artery disease (CAD) were stratified according to chronic kidney disease (CKD) status. CKD was defined by a glomerular filtrate rate (GFR) \< 60 ml/min/1.73m2.
CKD patients were randomized 1:1 to a) standard dose ticagrelor (90mg twice daily) for 7-10 days or b) low dose ticagrelor (60mg twice daily) for 7-10 days (phase 1). After 7-10 days of randomized treatment patients were crossed over to the alternative treatment, which was maintained for additional 7-10 days (phase 2).
This is a crossover study where participants in each cohort received both treatments but in difference sequences. Therefore, baseline characteristics are presented for the two separate cohorts but combining patients together regardless of treatment sequence. | 38 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase 1 Pre-crossover | Adverse Event | 3 | 3 | 2 | 1 |
| Phase 1 Pre-crossover | Protocol Violation | 0 | 0 | 0 | 2 |
| Phase 1 Pre-crossover | Withdrawal by Subject | 2 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | DM-CKD (All Participants Regardless of Sequence) | Total | DM-Non-CKD (All Participants Regardless of Sequence) |
|---|---|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 9 | 64 years STANDARD_DEVIATION 8 | 62 years STANDARD_DEVIATION 8 |
| GFR | 46 ml/min/1.73m^2 STANDARD_DEVIATION 9 | 67 ml/min/1.73m^2 STANDARD_DEVIATION 25 | 88 ml/min/1.73m^2 STANDARD_DEVIATION 17 |
| Prior myocardial infarction | 23 Participants | 41 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 27 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 46 Participants | 20 Participants |
| Sex: Female, Male Female | 15 Participants | 29 Participants | 14 Participants |
| Sex: Female, Male Male | 23 Participants | 48 Participants | 25 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 / 38 | 0 / 38 | 0 / 38 | 0 / 38 |
| other Total, other adverse events | 9 / 38 | 6 / 38 | 9 / 39 | 7 / 39 |
| serious Total, serious adverse events | 1 / 38 | 1 / 38 | 0 / 39 | 1 / 39 |
Outcome results
Primary
Platelet Reactivity Measured by Vasodilator Stimulated Phosphoprotein (VASP) Platelet Reactivity Index (PRI %)
The primary end point of the study was platelet reactivity assessed by VASP-PRI following treatment with ticagrelor 90mg between DM-CKD and DM-non-CKD cohorts. PRI % is a measure of platelet reactivity, where higher PRI levels represent higher platelet reactivity and lower effect of antiplatelet medications. PRI greater than 50% represents inadequate response to antiplatelet medications.
Time frame: 7 days
Population: The pharmacodynamic (PD) population included all patients with any PD data on study drug and without a major protocol deviation thought to affect significantly the PD findings. The PD population was used for analysis of all primary and secondary PD variables.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CKD - Ticagrelor 90 | Platelet Reactivity Measured by Vasodilator Stimulated Phosphoprotein (VASP) Platelet Reactivity Index (PRI %) | 25 PRI% | Standard Deviation 14 |
| CKD - Ticagrelor 60 | Platelet Reactivity Measured by Vasodilator Stimulated Phosphoprotein (VASP) Platelet Reactivity Index (PRI %) | 32 PRI% | Standard Deviation 13 |
| Non-CKD - Ticagrelor 90 | Platelet Reactivity Measured by Vasodilator Stimulated Phosphoprotein (VASP) Platelet Reactivity Index (PRI %) | 31 PRI% | Standard Deviation 20 |
| Non-CKD - Ticagrelor 60 | Platelet Reactivity Measured by Vasodilator Stimulated Phosphoprotein (VASP) Platelet Reactivity Index (PRI %) | 38 PRI% | Standard Deviation 20 |
p-value: 0.10595% CI: [-1.1, 14.3]t-test, 2 sided
p-value: 0.11295% CI: [-1.5, 13.7]t-test, 2 sided
Secondary
Platelet Reactivity Measured by VerifyNow P2Y12
Platelet reactivity assessed by VerifyNow P2Y12 following treatment with ticagrelor 90mg or 60 mg between DM-CKD and DM-non-CKD cohorts. Results are expressed in P2Y12 reaction units (PRU). PRU is a measure of platelet reactivity, where higher PRU levels represent higher platelet reactivity and lower effect of antiplatelet medications. PRU greater than 208 represents inadequate response to antiplatelet medications.
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CKD - Ticagrelor 90 | Platelet Reactivity Measured by VerifyNow P2Y12 | 39 PRU | Standard Deviation 57 |
| CKD - Ticagrelor 60 | Platelet Reactivity Measured by VerifyNow P2Y12 | 59 PRU | Standard Deviation 56 |
| Non-CKD - Ticagrelor 90 | Platelet Reactivity Measured by VerifyNow P2Y12 | 51 PRU | Standard Deviation 52 |
| Non-CKD - Ticagrelor 60 | Platelet Reactivity Measured by VerifyNow P2Y12 | 74 PRU | Standard Deviation 65 |