Coronary Artery Disease
Conditions
Keywords
Coronary artery disease, antiplatelet therapy, anticoagulant therapy
Brief summary
Dual antiplatelet therapy consisting of aspirin and clopidogrel is the cornerstone of treatment for prevention of atherothrombotic events in patients with coronary artery disease (CAD) undergoing percutaneous coronary interventions (PCI). Many patients on dual antiplatelet therapy in this setting may be affected by other thromboembolic conditions, in particular atrial fibrillation, therefore having an indication to also receive oral anticoagulation for stroke prevention. Thus, a considerable percentage of patients are under triple therapy which consists of aspirin plus clopidogrel plus an oral anticoagulant. The ever raising population with CAD warranting triple therapy and the growing number of patients being treated with dabigatran underscores the importance of understanding the pharmacodynamic effects of this treatment regimen.
Detailed description
Dual antiplatelet therapy consisting of aspirin and clopidogrel is the cornerstone of treatment for prevention of atherothrombotic events in patients with coronary artery disease (CAD) undergoing percutaneous coronary interventions (PCI). Many patients on dual antiplatelet therapy in this setting may be affected by other thromboembolic conditions, in particular atrial fibrillation, therefore having an indication to also receive oral anticoagulation for stroke prevention. Thus, a considerable percentage of patients are under triple therapy which consists of aspirin plus clopidogrel plus an oral anticoagulant. Although this combination therapy allows a reduction of atherothrombotic and thromboembolic events, patients on triple therapy are at an increased risk of bleeding complications. Dabigatran, a synthetic, reversible direct thrombin inhibitor, has been studied as an alternative to warfarin in patients with atrial fibrillation and has been shown to be at least as efficacious with a favorable safety profile. In particular, dabigatran at a dose of 110 mg is associated with rates of stroke and systemic embolism similar to warfarin, with lower rates of major hemorrhage, while a dose of 150 mg is associated with lower thrombotic events with similar rates of bleeding events. These findings have led the Food and Drug Administration (FDA) to approve dabigatran for use in atrial fibrillation patients in December 2011 and this has also been implemented in practice guidelines to be a superior strategy to warfarin. However, the FDA only approved the 150mg formulation. Dabigatran has high affinity and specificity for its target serine protease thrombin, and one small study shows that dabigatran produced potent inhibition of thrombin-induced platelet aggregation in vitro. However, there are no studies assessing the ex vivo pharmacodynamic effects of dabigatran in patients on dual antiplatelet therapy. The ever raising population with CAD warranting triple therapy and the growing number of patients being treated with dabigatran underscores the importance of understanding the pharmacodynamic effects of this treatment regimen.
Interventions
DRUGDabigatran
Dabigatran 150mg
DRUGPlacebo
Matching placebo tablets
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients with known CAD * On maintenance treatment with aspirin (81 to 325mg per day) and clopidogrel (75 mg per day) for at least for at least 4-weeks as per standard of care. * Age between 18 and 80 years old.
Exclusion criteria
* Transient ischemic attack or ischemic stroke in the past 6 months. * Prior hemorrhagic stroke (irrespective of timing). * Known allergies to dabigatran. * On treatment with Coumadin derivate or have an indication to be on Coumadin treatment (atrial fibrillation, prosthetic valve, DVT/pulmonary embolism). * Platelet count \<80x106/mL * Active bleeding or hemodynamic instability. * Creatinine clearance \<30 mL/minute. * Baseline ALT \>2.5 times the upper limit of normal. * Hemoglobin \< 10 gm/dL * 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 |
|---|---|---|
| TRAP-induced Platelet Aggregation | 1 week | TRAP-induced platelet aggregation measured by light transmittance aggregometry (LTA) was similar between groups |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity Measured by LTA | 1-week | Multiple measures of platelet reactivity evaluating purinergic and non-purinergic signaling pathways were assessed by light transmittance aggregometry (LTA). |
| Platelet Reactivity Measured by Multiple Electrode Aggregometry. | 1-week | Multiple measures of platelet reactivity evaluating purinergic and non-purinergic signaling pathways were assessed by multiple electrode aggregometry. |
| Clot Kinetic: Thrombin Activity | 1-week | Parameters related to thrombin activity and velocity of thrombus generation (reaction time: R; time to maximum rate of thrombus generation: TMRTG) were evaluated by thromboelastography. |
| Clot Kinetic: Clot Stength | 1-week | Clot strength (maximal amplitude:MA) was assessed by thromboelastography. |
Countries
United States
Participant flow
Recruitment details
This was a prospective, randomized, double-blind, placebo-controlled PD study conducted in patients with CAD on maintenance DAPT with aspirin and clopidogrel. Patients were screened at the Division of Cardiology of the University Of Florida College Of Medicine - Jacksonville from February 2012 to December 2013.
Participants by arm
| Arm | Count |
|---|---|
| Dabigatran Dabigatran 150mg tablets | 14 |
| Placebo Placebo tablets | 16 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Dabigatran | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 8 | 63 years STANDARD_DEVIATION 9 | 59 years STANDARD_DEVIATION 9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 10 Participants | 21 Participants | 11 Participants |
| Region of Enrollment United States | 14 participants | 30 participants | 16 participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 11 Participants | 24 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 18 | 0 / 17 |
| serious Total, serious adverse events | 1 / 18 | 0 / 17 |
Outcome results
Primary
TRAP-induced Platelet Aggregation
TRAP-induced platelet aggregation measured by light transmittance aggregometry (LTA) was similar between groups
Time frame: 1 week
Population: TRAP-induced platelet aggregation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran | TRAP-induced Platelet Aggregation | 74 percentage of aggregation | Standard Deviation 8 |
| Placebo | TRAP-induced Platelet Aggregation | 77 percentage of aggregation | Standard Deviation 6 |
Comparison: Assuming a 20% relative difference in TRAP induced MPA between dabigatran and placebo with a common standard deviation of 10%, 13 patients with available data needed to be randomized to obtain a 95% power and 2-sided alpha=0.05.p-value: <0.05ANCOVA
Secondary
Clot Kinetic: Clot Stength
Clot strength (maximal amplitude:MA) was assessed by thromboelastography.
Time frame: 1-week
Population: Clot kinetic assessed by citrated-kaolin thromboelastography
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran | Clot Kinetic: Clot Stength | 63.7 mm | Standard Deviation 4.4 |
| Placebo | Clot Kinetic: Clot Stength | 62.9 mm | Standard Deviation 6.7 |
Secondary
Clot Kinetic: Thrombin Activity
Parameters related to thrombin activity and velocity of thrombus generation (reaction time: R; time to maximum rate of thrombus generation: TMRTG) were evaluated by thromboelastography.
Time frame: 1-week
Population: Clot kinetic assessed by citrated-kaolin thromboelastography
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran | Clot Kinetic: Thrombin Activity | R | 12.25 minutes | Standard Deviation 2.6 |
| Dabigatran | Clot Kinetic: Thrombin Activity | TMRTG | 14.32 minutes | Standard Deviation 3 |
| Placebo | Clot Kinetic: Thrombin Activity | R | 6.76 minutes | Standard Deviation 1.1 |
| Placebo | Clot Kinetic: Thrombin Activity | TMRTG | 8.4 minutes | Standard Deviation 1.6 |
Secondary
Platelet Reactivity Measured by LTA
Multiple measures of platelet reactivity evaluating purinergic and non-purinergic signaling pathways were assessed by light transmittance aggregometry (LTA).
Time frame: 1-week
Population: Platelet aggregation measured by LTA
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran | Platelet Reactivity Measured by LTA | ADP-induced platelet aggregation | 49.5 percentage of aggregation | Standard Deviation 16.6 |
| Dabigatran | Platelet Reactivity Measured by LTA | Arachidonic acid-induced platelet aggregation | 6.9 percentage of aggregation | Standard Deviation 18.2 |
| Dabigatran | Platelet Reactivity Measured by LTA | Collagen-induced platelet aggregation | 42.6 percentage of aggregation | Standard Deviation 22.8 |
| Placebo | Platelet Reactivity Measured by LTA | ADP-induced platelet aggregation | 44.6 percentage of aggregation | Standard Deviation 15 |
| Placebo | Platelet Reactivity Measured by LTA | Arachidonic acid-induced platelet aggregation | 6.0 percentage of aggregation | Standard Deviation 1.5 |
| Placebo | Platelet Reactivity Measured by LTA | Collagen-induced platelet aggregation | 34.9 percentage of aggregation | Standard Deviation 22 |
Secondary
Platelet Reactivity Measured by Multiple Electrode Aggregometry.
Multiple measures of platelet reactivity evaluating purinergic and non-purinergic signaling pathways were assessed by multiple electrode aggregometry.
Time frame: 1-week
Population: Platelet aggregation measured by multiple electrode aggregometry.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran | Platelet Reactivity Measured by Multiple Electrode Aggregometry. | TRAP-induced platelet aggregation | 1176.4 arbitrary aggregation units | Standard Deviation 274 |
| Dabigatran | Platelet Reactivity Measured by Multiple Electrode Aggregometry. | ADP-induced platelet aggregation | 482.2 arbitrary aggregation units | Standard Deviation 199 |
| Dabigatran | Platelet Reactivity Measured by Multiple Electrode Aggregometry. | Arachidonic acid-induced platelet aggregation | 238.9 arbitrary aggregation units | Standard Deviation 88 |
| Dabigatran | Platelet Reactivity Measured by Multiple Electrode Aggregometry. | Collagen-induced platelet aggregation | 559.4 arbitrary aggregation units | Standard Deviation 180 |
| Placebo | Platelet Reactivity Measured by Multiple Electrode Aggregometry. | Collagen-induced platelet aggregation | 532.5 arbitrary aggregation units | Standard Deviation 182 |
| Placebo | Platelet Reactivity Measured by Multiple Electrode Aggregometry. | TRAP-induced platelet aggregation | 1210.6 arbitrary aggregation units | Standard Deviation 275 |
| Placebo | Platelet Reactivity Measured by Multiple Electrode Aggregometry. | Arachidonic acid-induced platelet aggregation | 230.1 arbitrary aggregation units | Standard Deviation 115 |
| Placebo | Platelet Reactivity Measured by Multiple Electrode Aggregometry. | ADP-induced platelet aggregation | 454.0 arbitrary aggregation units | Standard Deviation 227 |