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

This study is currently recruiting participants.
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

February 15, 2012
September 17, 2013
February 2012
December 2015   (final data collection date for primary outcome measure)
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.
Same as current
Complete list of historical versions of study NCT01546883 on ClinicalTrials.gov Archive Site
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Not Provided
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Dabigatran's Effect on Changes in Atrial Fibrosis in Patients With Atrial Fibrillation
Dabigatran-related Effect on Progression of Atrial Fibrosis in Patients With Atrial Fibrillation

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.

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.

Interventional
Phase 4
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Atrial Fibrillation
Drug: Dabigatran etexilate (Pradaxa)
150mg bid or 75mg bid for a period of one year
Other Name: Pradaxa
Experimental: Dabigatran
Patients with Atrial fibrillation taking Dabigatran etexilate as the anti-coagulant
Intervention: Drug: Dabigatran etexilate (Pradaxa)
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
30
January 2016
December 2015   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact: Marci Fjelstad, MPH, MBA, CCRP 8012133775 Marci.Fjelstad@carma.utah.edu
Contact: Holly Johnson, MBA 8015873889 holly.johnson@carma.utah.edu
United States
 
NCT01546883
IRB # 43119
Yes
Nassir F. Marrouche, MD, University of Utah
University of Utah
Not Provided
Principal Investigator: Nassir F Marrouche, MD, FHRS University of Utah, CARMA center
University of Utah
September 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP