Coronary Artery Disease, Diabetes Mellitus
Conditions
Keywords
Diabetes mellitus, Coronary artery disease, prasugrel, ticagrelor
Brief summary
Patients with diabetes mellitus (DM) have an increased risk of adverse atherothrombotic events. This may be in part attributed to the fact that these patients have reduced response to oral antiplatelet medications, in particular the P2Y12 receptor inhibitor clopidogrel, used for secondary prevention of ischemic events. Prasugrel and ticagrelor are recently approved P2Y12 receptor inhibitors which, compared with clopidogrel, have more potent antiplatelet effects. Head-to-head comparisons between the two drugs are lacking.
Detailed description
Patients with diabetes mellitus (DM) have an increased risk of adverse atherothrombotic events. This may be in part attributed to the fact that these patients have reduced response to oral antiplatelet medications, in particular the P2Y12 receptor inhibitor clopidogrel, used for secondary prevention of ischemic events. Upregulation of platelet P2Y12 receptor mediated signaling has been shown in DM patients and may contribute to these pharmacodynamic observations, suggesting the need for more potent P2Y12 inhibiting strategies in these patients. Prasugrel and ticagrelor are recently approved P2Y12 receptor inhibitors which, compared with clopidogrel, have more potent antiplatelet effects. Therefore, prasugrel and ticagrelor represent attractive treatment options for patients with DM. This is also supported by the DM sub-group analysis of the pivotal TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction) and PLATO (Platelet Inhibition and Patient Outcomes) trials, which have led to approval of prasugrel and ticagrelor, respectively. Although results of these sub-group analysis suggest that prasugrel is associated with an enhanced benefit in DM patients, while ticagrelor effects in DM patients are consistent with the overall study population, only head-to-head comparisons between the two drugs can elucidate if these exert differential effects on platelets from DM patients. However, the pharmacodynamic studies comparing prasugrel with ticagrelor in DM patients are lacking. The ever growing DM population at high risk of recurrent atherothrombotic events underscores the need to define antiplatelet treatment strategies leading to more optimal platelet inhibition in these patients.
Interventions
DRUGPrasugrel
Patients receiving prasugrel will be treated with 60mg loading dose and 10mg maintenance dose
DRUGTicagrelor
Patients receiving ticagrelor will be treated with a 180mg loading dose and 90mg bid maintenance dose
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Patients with known (angiographically documented) CAD. * On maintenance treatment with aspirin (81 mg per day) for at least 1-month as per standard of care. * Type 2 DM on treatment with oral hypoglycemic agents and/or insulin. * Age between 18 and 74 years old.
Exclusion criteria
* History of stroke, transient ischemic attack or intracranial bleeding. * On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor). * Known allergies to aspirin, ticlopidine, clopidogrel, prasugrel, ticagrelor. * Weight \<60kg. * On treatment with oral anticoagulant (Vitamin K antagonists, dabigatran). * Blood dyscrasia or bleeding diathesis. * Platelet count \<80x106/mL. * Hemoglobin \<10 g/dL. * Active bleeding or hemodynamic instability. * Creatinine Clearance \<30 mL/minute. * Baseline ALT \>2.5 times the upper limit of normal. * Hb A1c ≥ 10 mg/dL within 3 months. * Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker protection. * Drugs interfering CYP3A4 metabolism (to avoid interaction with Ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromizycin. * 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 |
|---|---|---|
| P2Y12 Reaction Units | 1 week | The primary endpoint is the comparison of the P2Y12 reaction units (PRU) values determined by VerifyNow between both treatments (ticagrelor or prasugrel). Treatment effects were evaluated comparing PRU observed in the overall patient population after prasugrel treatment with those achieved after ticagrelor regardless of the sequence. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| P2Y12 Reaction Units | 2 hours | Comparison of the P2Y12 reaction units (PRU) values determined by VerifyNow between both treatments (ticagrelor or prasugrel) |
| Platelet Reactivity Index | 1 week | The comparison of the platelet reactivity index (PRI) values determined by vasodilator-stimulated phosphoprotein (VASP) between both treatments (ticagrelor or prasugrel). VASP was measured by quantitative flow cytometry using commercially available labelled monoclonal antibodies. A low PRI is indicative of high platelet inhibition. |
Countries
United States
Participant flow
Recruitment details
Between February 2013 and July 2015, a total of 61 subjects agreed to participate in the study; 11 subjects were excluded and thus a total of 50 subjects were randomized (prasugrel first n=26; ticagrelor first n=24).
Pre-assignment details
11 subjects were excluded before randomization: withdrawn of consent (n=4), screen failure (n=4), unable to draw blood (n=3).
Participants by arm
| Arm | Count |
|---|---|
| Overall Population Subjects with type 2 diabetes mellitus and coronary artery disease | 46 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 1 | 2 |
| Period 1 | Withdrawal by Subject | 0 | 1 |
| Washout Period | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Overall Population |
|---|---|
| Age, Continuous | 59 years STANDARD_DEVIATION 8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 33 Participants |
| Type of diabetes Insulin-dependent | 26 participants |
| Type of diabetes Non-insulin-dependent | 20 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 46 | 10 / 49 |
| serious Total, serious adverse events | 0 / 46 | 0 / 49 |
Outcome results
Primary
P2Y12 Reaction Units
The primary endpoint is the comparison of the P2Y12 reaction units (PRU) values determined by VerifyNow between both treatments (ticagrelor or prasugrel). Treatment effects were evaluated comparing PRU observed in the overall patient population after prasugrel treatment with those achieved after ticagrelor regardless of the sequence.
Time frame: 1 week
Population: All analyses of platelet function conducted on all randomized subjects who received study drug, successfully completed at least one treatment period of the study and had valid data for the primary end point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Prasugrel | P2Y12 Reaction Units | 83 PRU |
| Ticagrelor | P2Y12 Reaction Units | 52 PRU |
p-value: 0.022Mixed Models Analysis
Secondary
P2Y12 Reaction Units
Comparison of the P2Y12 reaction units (PRU) values determined by VerifyNow between both treatments (ticagrelor or prasugrel)
Time frame: 2 hours
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Prasugrel | P2Y12 Reaction Units | 97 PRU |
| Ticagrelor | P2Y12 Reaction Units | 75 PRU |
p-value: 0.086Mixed Models Analysis
Secondary
Platelet Reactivity Index
The comparison of the platelet reactivity index (PRI) values determined by vasodilator-stimulated phosphoprotein (VASP) between both treatments (ticagrelor or prasugrel). VASP was measured by quantitative flow cytometry using commercially available labelled monoclonal antibodies. A low PRI is indicative of high platelet inhibition.
Time frame: 1 week
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Prasugrel | Platelet Reactivity Index | 36 PRI |
| Ticagrelor | Platelet Reactivity Index | 36 PRI |
Secondary
Platelet Reactivity Index
The comparison of the platelet reactivity index (PRI) values determined by vasodilator-stimulated phosphoprotein (VASP) between both treatments (ticagrelor or prasugrel). VASP was measured by quantitative flow cytometry using commercially available labelled monoclonal antibodies. A low PRI is indicative of high platelet inhibition.
Time frame: 2 hours
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Prasugrel | Platelet Reactivity Index | 35 PRI |
| Ticagrelor | Platelet Reactivity Index | 37 PRI |