Dabigatran's Effect on Changes in Atrial Fibrosis in Patients With Atrial Fibrillation (DEPAF)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by University of Utah
Sponsor:
Information provided by (Responsible Party):
Nassir F. Marrouche, MD, University of Utah
ClinicalTrials.gov Identifier:
NCT01546883
First received: February 15, 2012
Last updated: September 17, 2013
Last verified: September 2013
  Purpose

This study includes treating patients with atrial fibrillation (AF) with Dabigatran, an anti-coagulant for a period of one year to see if there are any significant changes in the degree of left atrial structural remodeling in these patients. The investigators hypothesize that there will be a significant decrease in the degree of left atrial structural remodeling (fibrosis) in AF patients treated with dabigatran.


Condition Intervention Phase
Atrial Fibrillation
Drug: Dabigatran etexilate (Pradaxa)
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Dabigatran-related Effect on Progression of Atrial Fibrosis in Patients With Atrial Fibrillation

Resource links provided by NLM:


Further study details as provided by University of Utah:

Primary Outcome Measures:
  • Percentage of fibrosis [ Time Frame: MRI at baseline and MRI at 12 months post-enrollment ] [ Designated as safety issue: No ]
    We will measure the change in percentage of fibrosis over a one-year period when drug is taken. We will calculate the results as percentage of fibrosis measured using MRI at 12 months minus the percentage of fibrosis measured using MRI at baseline to clarify if there is a decrease in fibrosis in the one year period.


Estimated Enrollment: 30
Study Start Date: February 2012
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dabigatran
Patients with Atrial fibrillation taking Dabigatran etexilate as the anti-coagulant
Drug: Dabigatran etexilate (Pradaxa)
150mg bid or 75mg bid for a period of one year
Other Name: Pradaxa

  Hide Detailed Description

Detailed Description:

Atrial fibrillation (AF) is one of the most common cardiac arrhythmia in medical practice in both the clinical and hospital settings. In addition to a three-fold increase in the risk of mortality 1, AF patients are at an increased risk of developing a stroke 2. This risk increased from 6.7% for those who are 50-59 years of age to 36.2% for those between 80-89 years of age 3. One of the most serious complications of AF is thromboembolism (TE) 4, including both Transient Ischemic Attack (TIA) and stroke, which can be fatal or disabling in many patients and is associated with either type of AF - recurrent or persistent. Image-based methods of risk-stratification and clinical scoring systems, such as the CHADS2 score 5, have the potential to advance our understanding of the mechanisms governing AF recurrence as well as thrombus formation and can improve our ability to prevent these potentially devastating complications.

Treatments for AF include antiarrhythmic drug therapy, anticoagulation, catheter ablation, and cardioversion 6, all of which have been thoroughly studied. Anticoagulation is undisputably effective in preventing strokes in patients with AF 7, reducing the incidence of stroke by 3 fold in high-risk patients 8. Pradaxa® (Dabigatran etexilate) is a new oral anticoagulant that was approved by the FDA on October 19, 2010 for reducing the risk of stroke and systemic embolism in patients with non-valvular AF. Pradaxa is a direct and reversible inhibitor of thrombin, the penultimate protease in the coagulation process. Thrombin converts fibrinogen to fibrin9, which participates in forming the matrix of blood clots. Pradaxa® inhibits formation of thrombus by inhibiting the conversion of fibrinogen to fibrin. Prior to approval of Pradaxa®, warfarin has been the only other oral anticoagulant available in the US for reducing the risk of stroke associated with AF, but its use is limited because of a number of undesirable characteristics10. Recently, the RE-LY study showed Pradaxa® 150mg bid was statistically significantly superior to warfarin in reducing the risk of strokes in patients with AF 11, although there was no statistically significant difference in risk of hemorrhage between warfarin and Pradaxa®. Pradaxa® will be used for its approved indication in this study.

The link between AF and stroke is complex but remodeling of the left atrium (LA) may play a central role. Atrial remodeling refers to any persistent change in atrial structure and function12. Fibrosis, an extensive deposition of extracellular matrix components (specifically collagen and fibronectin)13, is the major causative component of structural remodeling of LA14. AF promotes fibrosis15 and this structural remodeling in turn leads to increased heterogeneity of electrical conduction in the LA which can contribute to AF progression14. Late gadolinium enhancement magnetic resonance imaging (LGE-MRI), is a noninvasive technique that allows us to detect and quantify structural remodeling of the LA tissue in patients with AF 16. Changes in the composition of LA tissue is detected by LGE-MRI based on the delayed enhancement property of the gadolinium-based contrast agent, whose slow washout kinetics relative to normal surrounding tissue17, can be quantified as increased fibrosis16(structural remodeling of myocardium prior to any ablation) or scar18 (inflammation and tissue remodeling post ablation). Preliminary findings from our lab demonstrate a significantly larger amount of atrial remodeling / fibrosis detected using LGE-MRI in those patients with strokes compared to those without (22.7±16.4% vs. 15.6±9.5%, P<0.05)19.

Thrombin (the protease inhibited by Pradaxa®), also is a potent mitogen for connective-tissue producing cells which are prone to developing fibrosis20 and a chemoattractant for fibroblasts, thus playing an important role in development of tissue fibrosis21. Bogatkevich et al. 200922 recently demonstrated Pradaxa restrained fibrotic events in lung fibroblasts, suggesting that thrombin inhibition could be an effective strategy for inhibiting fibrosis in other organs, including the heart.

We suggest the characteristics of the fibrosis that we quantify in the left atrium will be similar to the fibrosis seen in the other organs such as lungs, skin and kidney. We hypothesize that Pradaxa will inhibit left atrial structural remodeling (measured as percent fibrosis) associated with AF.

In this study, we plan to study the effect of Pradaxa on remodeling of left atrial structure (measured as percent fibrosis) as detected by LGE-MRI.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with all types of non-valvular AF (includes paroxysmal, persistent and permanent AF)
  2. Candidate for anticoagulation therapy
  3. No contra-indication for LGE-MRI
  4. Patients age 18 and older
  5. Patients who are able to provide informed consent to participate in the study

Exclusion Criteria:

  1. Patients who have already undergone an atrial fibrillation ablation procedure.
  2. Patients with active contra-indications to any anticoagulant agent.
  3. Other major bleeding disorders or risk factors that would place the patient at risk of bleeding.
  4. Recent surgery (within 30 days).
  5. Renal insufficiency, severe kidney disorders/diseases, GFR < 30mg/dL (Gadolinium contraindication).
  6. Advanced liver disease.
  7. Any health related Gadolinium/MRI contraindications: Pacemaker devices, etc.
  8. Pregnant, planning to be become pregnant or nursing women
  9. Individuals who are unable to provide informed consent
  10. Contraindicated for Pradaxa® .
  11. Patients the Investigators feel are inappropriate for the study
  12. Patients who cannot give informed consent
  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: NCT01546883

Contacts
Contact: Marci Fjelstad, MPH, MBA, CCRP 8012133775 Marci.Fjelstad@carma.utah.edu
Contact: Holly Johnson, MBA 8015873889 holly.johnson@carma.utah.edu

Locations
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
University of Utah
Investigators
Principal Investigator: Nassir F Marrouche, MD, FHRS University of Utah, CARMA center
  More Information

No publications provided

Responsible Party: Nassir F. Marrouche, MD, Associate Professor, University of Utah
ClinicalTrials.gov Identifier: NCT01546883     History of Changes
Other Study ID Numbers: IRB # 43119
Study First Received: February 15, 2012
Last Updated: September 17, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Utah:
Atrial fibrillation
MRI

Additional relevant MeSH terms:
Atrial Fibrillation
Fibrosis
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Dabigatran
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anticoagulants
Hematologic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 21, 2014