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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01546883
Recruitment Status : Terminated (Not enough patients in time period allotted for study)
First Posted : March 7, 2012
Results First Posted : October 12, 2015
Last Update Posted : October 12, 2015
Information provided by (Responsible Party):
Nassir F. Marrouche, MD, University of Utah

Tracking Information
First Submitted Date  ICMJE February 15, 2012
First Posted Date  ICMJE March 7, 2012
Results First Submitted Date  ICMJE August 11, 2015
Results First Posted Date  ICMJE October 12, 2015
Last Update Posted Date October 12, 2015
Study Start Date  ICMJE February 2012
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 6, 2012)
Percentage of Fibrosis [ Time Frame: MRI at baseline and MRI at 12 months post-enrollment ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01546883 on Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Dabigatran's Effect on Changes in Atrial Fibrosis in Patients With Atrial Fibrillation
Official Title  ICMJE Dabigatran-related Effect on Progression of Atrial Fibrosis in Patients With Atrial Fibrillation
Brief Summary 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.
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, AF patients are at an increased risk of developing a stroke. 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. One of the most serious complications of AF is thromboembolism (TE), 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, 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, all of which have been thoroughly studied. Anticoagulation is undisputably effective in preventing strokes in patients with AF, reducing the incidence of stroke by 3 fold in high-risk patients. 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 fibrin, 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 characteristics. 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, 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 function. Fibrosis, an extensive deposition of extracellular matrix components (specifically collagen and fibronectin), is the major causative component of structural remodeling of LA. AF promotes fibrosis and this structural remodeling in turn leads to increased heterogeneity of electrical conduction in the LA which can contribute to AF progression. 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 . 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 tissue, can be quantified as increased fibrosis (structural remodeling of myocardium prior to any ablation) or scar (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.

Thrombin (the protease inhibited by Pradaxa®), also is a potent mitogen for connective-tissue producing cells which are prone to developing fibrosis and a chemoattractant for fibroblasts, thus playing an important role in development of tissue fibrosis. Bogatkevich et al. 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE Atrial Fibrillation
Intervention  ICMJE Drug: Dabigatran etexilate (Pradaxa)
150mg bid or 75mg bid for a period of one year
Other Name: Pradaxa
Study Arms  ICMJE Experimental: Dabigatran
Patients with Atrial fibrillation taking Dabigatran etexilate as the anti-coagulant
Intervention: Drug: Dabigatran etexilate (Pradaxa)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 10, 2015)
Original Estimated Enrollment  ICMJE
 (submitted: March 6, 2012)
Actual Study Completion Date  ICMJE December 2013
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01546883
Other Study ID Numbers  ICMJE IRB # 43119
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Nassir F. Marrouche, MD, University of Utah
Study Sponsor  ICMJE University of Utah
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Nassir F Marrouche, MD, FHRS University of Utah, CARMA center
PRS Account University of Utah
Verification Date September 2015

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