Dabigatran's Effect on Changes in Atrial Fibrosis in Patients With Atrial Fibrillation
Information source: University of Utah
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Atrial Fibrillation
Intervention: Dabigatran etexilate (Pradaxa) (Drug)
Phase: Phase 4
Status: Recruiting
Sponsored by: University of Utah Official(s) and/or principal investigator(s): Nassir F Marrouche, MD, FHRS, Principal Investigator, Affiliation: University of Utah, CARMA center
Overall contact: Marci Fjelstad, MPH, MBA, CCRP, Phone: 8012133775, Email: Marci.Fjelstad@carma.utah.edu
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.
Clinical Details
Official title: Dabigatran-related Effect on Progression of Atrial Fibrosis in Patients With Atrial Fibrillation
Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
Primary outcome: Percentage of fibrosis
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
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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
Locations and Contacts
Marci Fjelstad, MPH, MBA, CCRP, Phone: 8012133775, Email: Marci.Fjelstad@carma.utah.edu
University of Utah, Salt Lake City, Utah 84132, United States; Recruiting
Additional Information
Starting date: February 2012
Last updated: September 17, 2013
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