Pharmacodynamic Effects of Dabigatran in Patients on Dual Antiplatelet Therapy - Full Text View

Purpose

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.

Condition	Intervention
Coronary Artery Disease	Drug: Dabigatran Drug: Placebo


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacodynamics Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	Pharmacodynamic Effects of Dabigatran in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy With Aspirin and Clopidogrel

Resource links provided by NLM:

MedlinePlus related topics: Coronary Artery Disease

Drug Information available for: Dabigatran Dabigatran etexilate Dabigatran etexilate mesylate

U.S. FDA Resources

Further study details as provided by University of Florida:

Primary Outcome Measures:

TRAP-induced Platelet Aggregation [ Time Frame: 1 week ] [ Designated as safety issue: No ]
TRAP-induced platelet aggregation measured by light transmittance aggregometry (LTA) was similar between groups

Secondary Outcome Measures:

Platelet Reactivity Measured by LTA [ Time Frame: 1-week ] [ Designated as safety issue: No ]
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. [ Time Frame: 1-week ] [ Designated as safety issue: No ]
Multiple measures of platelet reactivity evaluating purinergic and non-purinergic signaling pathways were assessed by multiple electrode aggregometry.
Clot Kinetic: Thrombin Activity [ Time Frame: 1-week ] [ Designated as safety issue: No ]
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 [ Time Frame: 1-week ] [ Designated as safety issue: No ]
Clot strength (maximal amplitude:MA) was assessed by thromboelastography.


Enrollment:	35
Study Start Date:	February 2012
Study Completion Date:	February 2014
Primary Completion Date:	January 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Dabigatran Dabigatran 150mg	Drug: Dabigatran Dabigatran 150mg Other Name: Pradaxa
Placebo Comparator: Placebo Placebo	Drug: Placebo Matching placebo tablets

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.

Eligibility


Ages Eligible for Study:	18 Years to 80 Years (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01852162

Locations


United States, Florida
University of Florida
Jacksonville, Florida, United States, 32209

Sponsors and Collaborators

University of Florida

Investigators


Principal Investigator:	Dominick Angiolillo, MD, PhD	University of Florida

More Information


Responsible Party:	University of Florida
ClinicalTrials.gov Identifier:	NCT01852162 History of Changes
Other Study ID Numbers:	UFJ 2011-112
Study First Received:	May 8, 2013
Results First Received:	February 3, 2015
Last Updated:	March 10, 2015
Health Authority:	United States: Institutional Review Board

Keywords provided by University of Florida:


Coronary artery disease antiplatelet therapy anticoagulant therapy

Additional relevant MeSH terms:


Coronary Artery Disease Myocardial Ischemia Coronary Disease Heart Diseases Cardiovascular Diseases Arteriosclerosis Arterial Occlusive Diseases Vascular Diseases	Dabigatran Antithrombins Serine Proteinase Inhibitors Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anticoagulants

ClinicalTrials.gov processed this record on September 23, 2016