Early Versus Late DC-cardioversion of Persistent Atrial Fibrillation. Effect on Atrial Remodeling,Inflammatory and Neurohumoral Markers and Recurrence of Atrial Fibrillation
Condition: Atrial Fibrillation
MeSH terms: Atrial Fibrillation; Recurrence; Atrial Remodeling
Study type: Interventional

Summary: 
      Atrial fibrillation (AF) is the most common arrhythmia present in 1% of population under 60
      years of age and reaching up to 15% at 80 years. AF is associated with reduced quality of
      life, increased morbidity, mortality and health economic costs.

      Presentation of AF differs substantially among patients ranging from self-limiting short
      episodes (paroxysmal AF), longstanding episodes (persistent AF) where direct current (DC)
      cardioversion is needed, to chronic atrial fibrillation. Treatment of AF is individually
      tailored in accordance to symptoms, type of AF and thromboembolic risk. The standard
      treatment of symptomatic persistent AF is DC-cardioversion preceded by anticoagulant
      treatment with Warfarin. According to guidelines DC-cardioversion can be performed when
      anticoagulation treatment has been in therapeutic range for at least 4 weeks. However
      introduction of Pradaxa (Dabigatran) has enabled an earlier DC cardioversion, reducing time
      to cardioversion to a 3 week period. During anticoagulation treatment persistence of AF
      contributes to left atrial remodeling and increases in inflammatory and neurohumoral
      biomarkers. The prolonged duration of AF and the remodeling of the left atrium increase the
      risk of AF recurrence after DC-cardioversion.

      Early cardioversion of patients with persistent AF is possible if preceded by transesophageal
      echocardiography (TEE). The TEE guided DC- cardioversion, as demonstrated in the ACUTE study,
      is a safe and efficient alternative to conventional treatment. This treatment regime is not
      routinely used in clinical practice.

      The aim of this study is to compare early DC-cardioversion (within 72 hours) to conventional
      treatment (Pradaxa prior to DC-cardioversion). 140 patients with persistent AF will be
      randomized to early cardioversion preceded by TEE in accordance with guidelines or
      conventional treatment with Pradaxa for 4 weeks prior to DC-cardioversion.

      The investigators will determine the outcome in the two groups regarding:

        -  Left atrial function and size assessed by left atrial strain, left atrial ejection
           fraction and left atrial volume.

        -  Inflammatory and neurohumoral biomarkers including ANP, BNP,IL6 and CRP.

        -  Time to recurrence of AF (AF documented by ECG or Holter monitoring)

      Comprehensive transthoracic echocardiography, 12 lead ECG, biomarkers and Holter monitoring
      will be performed at the time of randomization, 4 weeks, 3 month and 6 month post
      DC-cardioversion. Furthermore all patients will be followed for symptomatic AF recurrence for
      a period of one year. AF recurrence will be documented by 12 lead ECG.
    

Detailed description: 
      Background:

      Atrial fibrillation (AF) is the most common arrhythmia, present in about 1 % of the
      population under 60 years of age and significantly higher among the older population,
      reaching up to 15 % in patients at 80 years. Worldwide, the proportion of people aged over 60
      years is growing faster than any other age group. This will inevitably result in an increased
      prevalence of AF in the overall population. This is supported by the fact that the incidence
      of AF has increased over the past two decades. Furthermore a number of diseases which are
      associated with a higher prevalence of AF, such as ischemic heart disease (IHD), valvular
      heart disease, diabetes and hypertension are also expected to increase in prevalence due to
      the aging population. This again will contribute to an increased incidence of AF. Atrial
      fibrillation is associated with significant increase in mortality, morbidity and a reduction
      in quality of life.

      The mechanisms behind AF including proliferation of fibroblasts, enhanced connective tissue
      deposition and fibrosis, all play an important part in structural remodeling of the left
      atrium. The structural remodeling leads to electrical deterioration which is fundamental for
      initiation of AF. The persistence of AF induces further electrophysiological remodeling,
      shortening of atrial refractoriness and in the end persistence of AF. The vicious cycle can,
      be reversed by restoration of sinus rhythm.

      The treatments available today range from DC cardioversion, pharmacological rhythm and rate
      control, radiofrequency ablation to anticoagulation treatment.

      If rhythm control is desired, cardioversion to sinus rhythm is achievable by
      DC-cardioversion. If AF is present less than 48 hours DC-cardioversion can be performed
      without further precautions. If AF is present more than 48 hours, DC cardioversion should be
      preceded by anticoagulation treatment with Warfarin for a minimum of 4 weeks or alternatively
      Pradaxa for 3 weeks prior to DC-cardioversion. Early cardioversion of patients with
      persistent AF > 48 hours is possible if preceded by transesophageal echocardiography (TEE)
      and exclusion of thrombus as demonstrated in the ACUTE trial.

      Discrepancy of the results and the limitations of the earlier studies lead to inconclusive
      results. Tendencies favouring early DC-cardioversion and an increase in haemorrhages in the
      conventional treatment group underline the need for a randomized study with a primary aim to
      asses' differences in effect of conventional vs. early DC-cardioversion treatment.

      To the investigators knowledge no randomised study has assessed the effect of early versus
      late DC-cardioversion in patients with persistent AF.

      Hypothesis:

      Early DC-cardioversion of persistent AF will improve left atrial function and remodeling,
      decrease inflammatory /neurohumoral markers and increase time to recurrence of AF compared to
      conventional treatment.

      Aims:

        1. To determine, if there is difference in function and size of the left atrium, prior to
           and post cardioversion comparing early cardioversion to conventional treatment group.
           The data for comparison will be acquired echocardiographically.

        2. To determine, if there is difference in levels of inflammatory (IL-6 & CRP) and
           neurohumoral markers (ANP & BNP) prior to and post cardioversion, when comparing early
           cardioversion to conventional treatment group.

        3. To determine, if there is difference in time to recurrence of, ECG or Holter verified
           AF, when comparing early cardioversion to conventional treatment.

      Descriptive aims:

        1. To determine whether there is any difference in correlation between left atrial size and
           function and neurohumoral or inflammatory biomarker levels pre/post cardioversion, when
           comparing early cardioversion to conventional treatment group.

        2. To determine, whether there is any difference in strain when analyzing TEE versus
           transthoracic echocardiography (TTE) images of the left atrium, in patient's receiving
           early cardioversion.

      Methods :

      Inclusion criteria

      Patients admitted to department of cardiology OUH Svendborg Hospital or referred to
      outpatient clinic with symptomatic persistent AF, duration more than 48 hours and indication
      for DC cardioversion. Atrial fibrillation must be verified by a 12 lead ECG. All patients
      must be over 18 years of age, and must provide written informed consent prior to inclusion.

      Exclusion criteria

      Reversible causes for AF (thyrotoxicosis, infection, pulmonary embolism), acute coronary
      syndrome and absolute contraindications of TEE (oesophageal spasm, stricture, perforation and
      diverticula). Patients with diminished mental capability will not be included.

      Study design

      The patients will undergo unblinded randomization in two groups with PROBE design which
      includes blinded analysis of echocardiography, Holter monitoring and biomarker results.

      Group one will receive conventional treatment with Pradaxa for a period of minimum 3 weeks
      prior to DC cardioversion. Group two will undergo TEE followed by early DC cardioversion
      within 72 hours. Post cardioversion treatment with Pradaxa will be applied according to
      guidelines for a minimum of 4 weeks.

      Comprehensive transthoracic echocardiography, 12 lead ECG, biomarkers and Holter monitoring
      will be performed at the time of randomization, 4 weeks, 3 month and 6 month post
      DC-cardioversion. Furthermore all patients will be followed for symptomatic AF recurrence for
      a period of one year, AF recurrence will be documented by 12 lead ECG.

      Procedures :

      Transesophageal echocardiography Patients will be examined in the fasting state, after the
      application of topical pharyngeal anaesthesia. Left atrium and left atrial appendage will be
      viewed in order to exclude thrombus and dynamic spontaneous echo contrast. Tissue Doppler and
      2D images of the left atrium from 0,30,60 and 90 degrees will be acquired for the offline
      strain analysis.

      Transthoracic echocardiography Two dimensional images and tissue doppler images (TDI) of the
      left atrium and the left ventricle will be acquired for offline strain analysis. Standard
      evaluation of systolic function (EF, WMSI); diastolic function (E/a, DT, e', s', atrial
      volume) and evaluation of mitral and aortic valves will be performed. Blinded offline strain
      analysis will be performed with commercially available software. "Time to peak standard
      deviation"(TPSD)a reliable measurement of overall left atrial dyssynchrony, peak strain and
      global atrial strain will all be computed during the offline analysis.

      Blood specimen Will be drawn prior to cardioversion and 4 weeks post cardioversion. The blood
      samples will be stored immediately after the collection in a - 80°C refrigerator.
      Neurohumoral and inflammatory markers (IL 6, ANP, BNP, CRP, ect.) will be analyzed en bloc.

      Holter monitoring /12 lead ECG 48 hour Holter monitoring and a 12 lead ECG will take place 4
      weeks, 3 month and 6 month post cardioversion. A recurrence of AF will be defined as AF for a
      period of minimum 30 seconds on Holter or AF verified by 12 lead ECG.

      Sample size Based on previous studies of changes in peak strain following DC cardioversion
      the investigators expect a mean change in peak strain of 5.8 in the control group. The
      investigators expect a minimum relevant difference (MIREDIF) between the two groups of ½
      standard deviation ( 4.05 %). With an α of 0.05 and a β of 0.80 the investigators must
      include a minimum of 63 patients in each treatment group. With an expected dropout of 10% the
      total sample size is 140 patients included. A thorough review of medical records for a period
      of 01/01/2010 - 01/10/2010 show that DC-cardioversions has been performed 121 times at OUH,
      Svendborg Hospital during a period of 10 month. Based on the number of previous
      DC-cardioversions the investigators expect an inclusion period of approximately 18 month.

      Data Analysis Outcome and explanatory variables will be tested for normality and transformed
      when appropriate. Univariate analyses of changes in atrial strain and neurohumeral response
      between the two groups will be performed using unpaired t-test and simple regression.
      Multivariate regression analysis will be used to analyze significant covariates. Analysis of
      repeated measures will be performed in a Mixed Model approach. Time to recurrence will be
      analysed using log-rank test and Cox Proportional Hazards Model.

      Ethical Considerations This clinical trial will be performed in accordance with ethical
      principles based on the Declaration of Helsinki and will be approved by the ethics comity.
      Prior to inclusion all patients will receive a thorough explanation of this trials nature;
      participation will be based on signing of an informed consent. The patients may, at any given
      time withdraw from the trial. The trial itself will be approved by ethical and scientific
      counsels. Furthermore both patient groups will receive an already established and approved
      treatment, and patients will therefore not be submitted to experimental treatments and/or
      risks that such treatments may present.
    

Intervention name(s): Pradaxa; TEE; Compare TEE guided cardioversion to Dabigatran + DC cardioversion
Intervention type(s): Drug; Procedure; Other
Intervention description(s): Pradaxa for 3 weeks prior to DC; Transesophageal echo to exclude LAA thrombus, followed by early DC.; compare the two groups, TEE followed by early DC cardioversion with Dabigatran for 3 weeks followed by DC cardioversion.
Intervention MeSH terms: Dabigatran
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Atrial Fibrillation; TEE; Early versus late DC cardioversion.