SOAR: Study Observing Antiarrhythmic Remodelling Using LGE-MRI

Atrial Fibrillation Clinical Trial

— SOAR  

Official title:

SOAR: Study Observing Antiarrhythmic Remodelling Using LGE-MRI

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01182376
• Other study ID #: IRB_00040931
• Status: Completed
• Phase: Phase 3
• First received: August 11, 2010
• Last updated: January 22, 2016
• Start date: November 2010
• Est. completion date: December 2012

Study information

• Verified date: January 2016
• Source: University of Utah
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to demonstrate how dronedarone (Multaq®) may aid in the slowing of progression of left atrial and ventricular fibrosis in patients with atrial fibrillation as assessed by late gadolinium enhanced magnetic resonance imaging.

Description:

BACKGROUND AND INTRODUCTION:

Atrial fibrillation (AF) arises as a result of a complex interaction between triggers, perpetuators and substrate. As early as 1995, Morillo et al have demonstrated that AF is associated with ultrastructural changes in myocytes. In animal models, alterations in myocytes after sustained AF resemble those of myocardial hybernation with a phenotypical adaptation towards a more fetal stage. Ultimately, these structural changes would lead to Calcium overload and metabolic stress, similar changes have been observed in humans. However, in humans, atrial dilatation and degenerative changes have been observed. Interstitial fibrosis (caused by deposits of collagen and fibronectin) is the prime cause of structural remodeling in left atrium (Boldt et al., 2004). It has been well established that fibrosis is a confounding clinical factor in causing AF (Kostin et al., 2002). But AF itself promotes fibrosis, which in turn leads to increased conduction heterogeneity within the atrial substrate resulting in further progression of AF (Everett,and Olgin, 2007).

The recent introduction of Late Gadolinium enhancement magnetic resonance imaging (LGE-MRI) sequence now allows for non-invasive assessment of the location and extent of arrhythmia related fibrosis.

Contrast enhancement occurs as a result of altered washout kinetics of gadolinium relative to normal surrounding tissue, which may reflect increased fibrosis or tissue remodeling of the myocardium. Our group has demonstrated the feasibility of a new LGE-MRI acquisition and processing protocol to detect fibrosis in the LA.

To date, no controlled trials evaluating the effect of antiarrhythmic drugs (AAD) and regression of left atrial fibrosis as assessed by LGE-MRI has been performed. We propose to use LGE-MRI to evaluate the effects of dronedarone vs. placebo on atrial and ventricular fibrosis. It has been shown that the success of catheter ablation procedure (which has been shown to be superior in terms of maintaining sinus rhythm in AF patients when compared to anti-arrhythmic drugs) is dependent upon the extent of fibrosis (Akoum et al., in prep). In AF patients with greater than 35% enhancement (percent left atrial fibrosis), the success of catheter ablation in reducing AF recurrence is greatly reduced. Hence for these patients, a drug that can control the progression of fibrosis and simultaneously provide respite from AF recurrence would be an extremely desirable prescription.

Multaq® is the chosen drug in this study because clinical trials (Hohnloser et al., 2009) have shown that it has the potential to reduce incidence of hospitalizations due to cardiovascular events by 25.5% and death in AF patients by 45%. We acknowledge the information that Dronedarone may be more prone to AF recurrence, however, it has a better safety profile with regards to thyroid and neurologic events and does not interfere with oral anticoagulants (Le Heuzey et al., 2010), which make dronedarone a more preferred antiarrhythmic drug to be used for this study. Furthermore, in patients who took dronedarone post cardioversion procedure to revert arrhythmia back to normal sinus rhythm (NSR), dronedarone has been shown to decrease AF recurrences (Le Heuzey et al., 2010).

OBJECTIVES:

Primary:

The primary objective of this study is to demonstrate how dronedarone may aid in the regression or slowing of progression of left atrial and ventricular fibrosis in patients with atrial fibrillation as assessed by LGE-MRI, using longitudinal data from a double-blinded, prospective study of patients diagnosed with atrial fibrillation over a twelve month follow up period.

Secondary:

• To study the effects of dronedarone in global parameters of myocardial remodeling such as right and left atrial volumes and right and left ventricular volumes.

• To study correlation between AF burden expressed as percentage of AF measured by an 8-day Holter Monitoring at three, six and twelve months post initiation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: December 2012
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients age 18 and older

• Must carry a diagnosis of Paroxysmal Atrial Fibrillation for 1 months or longer prior to being enrolled.

• AAD: Multaq® (dronedarone) candidate

• Patients have given informed consent

Exclusion Criteria:

• Patients who are unavailable to continue follow-up at the University of Utah outpatient clinic.

• Patients weighing >200 lbs (MR image efficacy decreases due to density)

• Prior RF Ablation treatment for atrial fibrillation

• Severe renal failure manifested by a chronic GFR of < 30 mL/min, or acute renal failure regardless of the GFR, until the renal function has stabilized. (Gadolinium contraindication)

• Enrollment in any other investigational trial for anti-arrhythmic therapy

• Any health related Gadolinium/MRI contraindications: Pacemaker devices, etc.

• Pregnant women

• Individuals with cognitive impairments who are unable to give informed consent

• Multaq® (dronedarone) contraindications:

• NYHA Class IV heart failure or NYHA Class II - III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic

• Second- or third-degree atrioventricular (AV) block or sick sinus syndrome

• Bradycardia < 50 bpm

• Concomitant use of strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir

• Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics

• QTc Bazett interval = 500 ms or PR interval > 280 ms

• Severe hepatic impairment

• Pregnant women

• Nursing mothers

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

Drug:
• dronedarone
Dronedarone will be prescribed by the patient's team according to established guidelines.
• Placebo
Placebo will be administered by the patient's team according to established guidelines.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
University of Utah	Sanofi

References & Publications (15)

Badger TJ, Adjei-Poku YA, Marrouche NF. MRI in cardiac electrophysiology: the emerging role of delayed-enhancement MRI in atrial fibrillation ablation. Future Cardiol. 2009 Jan;5(1):63-70. doi: 10.2217/14796678.5.1.63. Review. — View Citation

Badger TJ, Oakes RS, Daccarett M, Burgon NS, Akoum N, Fish EN, Blauer JJ, Rao SN, Adjei-Poku Y, Kholmovski EG, Vijayakumar S, Di Bella EV, MacLeod RS, Marrouche NF. Temporal left atrial lesion formation after ablation of atrial fibrillation. Heart Rhythm. 2009 Feb;6(2):161-8. doi: 10.1016/j.hrthm.2008.10.042. Epub 2008 Nov 6. — View Citation

Lee SH, Tai CT, Hsieh MH, Tsai CF, Lin YK, Tsao HM, Yu WC, Huang JL, Ueng KC, Cheng JJ, Ding YA, Chen SA. Predictors of early and late recurrence of atrial fibrillation after catheter ablation of paroxysmal atrial fibrillation. J Interv Card Electrophysiol. 2004 Jun;10(3):221-6. — View Citation

Lo LW, Tai CT, Lin YJ, Chang SL, Wongcharoen W, Hsieh MH, Tuan TC, Udyavar AR, Hu YF, Chen YJ, Tsao HM, Chen SA. Mechanisms of recurrent atrial fibrillation: comparisons between segmental ostial versus circumferential pulmonary vein isolation. J Cardiovasc Electrophysiol. 2007 Aug;18(8):803-7. Epub 2007 May 14. — View Citation

O'Donnell D, Furniss SS, Dunuwille A, Bourke JP. Delayed cure despite early recurrence after pulmonary vein isolation for atrial fibrillation. Am J Cardiol. 2003 Jan 1;91(1):83-5. — View Citation

Oakes RS, Badger TJ, Kholmovski EG, Akoum N, Burgon NS, Fish EN, Blauer JJ, Rao SN, DiBella EV, Segerson NM, Daccarett M, Windfelder J, McGann CJ, Parker D, MacLeod RS, Marrouche NF. Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrillation. Circulation. 2009 Apr 7;119(13):1758-67. doi: 10.1161/CIRCULATIONAHA.108.811877. Epub 2009 Mar 23. — View Citation

Oral H, Knight BP, Ozaydin M, Tada H, Chugh A, Hassan S, Scharf C, Lai SW, Greenstein R, Pelosi F Jr, Strickberger SA, Morady F. Clinical significance of early recurrences of atrial fibrillation after pulmonary vein isolation. J Am Coll Cardiol. 2002 Jul 3;40(1):100-4. — View Citation

Oral H, Pappone C, Chugh A, Good E, Bogun F, Pelosi F Jr, Bates ER, Lehmann MH, Vicedomini G, Augello G, Agricola E, Sala S, Santinelli V, Morady F. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med. 2006 Mar 2;354(9):934-41. — View Citation

Pappone C, Oreto G, Rosanio S, Vicedomini G, Tocchi M, Gugliotta F, Salvati A, Dicandia C, Calabrò MP, Mazzone P, Ficarra E, Di Gioia C, Gulletta S, Nardi S, Santinelli V, Benussi S, Alfieri O. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation. 2001 Nov 20;104(21):2539-44. — View Citation

Riley MJ, Marrouche NF. Ablation of atrial fibrillation. Curr Probl Cardiol. 2006 May;31(5):361-90. Review. — View Citation

Sinha AM, Schmidt M, Marschang H, Gutleben K, Ritscher G, Brachmann J, Marrouche NF. Role of left ventricular scar and Purkinje-like potentials during mapping and ablation of ventricular fibrillation in dilated cardiomyopathy. Pacing Clin Electrophysiol. 2009 Mar;32(3):286-90. doi: 10.1111/j.1540-8159.2008.02233.x. — View Citation

Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev. 1999 Jan;79(1):215-62. Review. — View Citation

Vasamreddy CR, Lickfett L, Jayam VK, Nasir K, Bradley DJ, Eldadah Z, Dickfeld T, Berger R, Calkins H. Predictors of recurrence following catheter ablation of atrial fibrillation using an irrigated-tip ablation catheter. J Cardiovasc Electrophysiol. 2004 Jun;15(6):692-7. — View Citation

Wazni OM, Marrouche NF, Martin DO, Verma A, Bhargava M, Saliba W, Bash D, Schweikert R, Brachmann J, Gunther J, Gutleben K, Pisano E, Potenza D, Fanelli R, Raviele A, Themistoclakis S, Rossillo A, Bonso A, Natale A. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA. 2005 Jun 1;293(21):2634-40. — View Citation

Weber KT, Weglicki WB, Simpson RU. Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium. Cardiovasc Res. 2009 Feb 15;81(3):500-8. doi: 10.1093/cvr/cvn261. Epub 2008 Oct 3. Review. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	LA Fibrosis	The change in left atrial fibrosis percentage, as measured on a scale, using MRI imaging, from baseline to the end of treatment.	baseline, 1 year	No