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

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.

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