Pharmacodynamic Effects of Dabigatran in Patients on Dual Antiplatelet Therapy

Pharmacodynamic Effects of Dabigatran in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy With Aspirin and Clopidogrel

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.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Placebo; Drug: Dabigatran

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.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Not Applicable

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Matching placebo tablets
Experimental: Dabigatran; Dabigatran 150mg	Drug: Dabigatran; Dabigatran 150mg; Other Names: Pradaxa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TRAP-induced Platelet Aggregation	TRAP-induced platelet aggregation measured by light transmittance aggregometry (LTA) was similar between groups	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet Reactivity Measured by LTA	Multiple measures of platelet reactivity evaluating purinergic and non-purinergic signaling pathways were assessed by light transmittance aggregometry (LTA).	1-week
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.	1-week
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.	1-week
Clot Kinetic: Clot Stength	Clot strength (maximal amplitude:MA) was assessed by thromboelastography.	1-week

Collaborators and Investigators

• Sponsor: University of Florida

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: May 8, 2013
• First Submitted That Met QC Criteria: May 10, 2013
• First Posted (Estimate): May 13, 2013

Study Record Updates

• Last Update Posted (Estimate): March 17, 2015
• Last Update Submitted That Met QC Criteria: March 10, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Coronary artery disease; anticoagulant therapy; antiplatelet therapy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Dabigatran
• Other Study ID Numbers: UFJ 2011-112