Cavotricuspid Isthmusblock and Circumferential Pulmonary Vein Isolation in Patients With Atrial Fibrillation
Condition: Atrial Fibrillation
MeSH terms: Atrial Fibrillation
Study type: Interventional
Phase: Phase 4

Summary: 
      Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pulmonary vein isolation
      (PVI) in the left atrium using radiofrequency energy is a new and promising non-medical
      treatment in patients with symptomatic AF with reported success rates of 65 % to 90 %
      depending on AF classification and ablation procedure. However, the risk of recurrence has
      led to suggestions of how to improve the clinical outcome by tailoring a more efficient
      ablation procedure. A prospective, randomised study with 150 patients with symptomatic AF
      referred for PVI has been initiated and patients are allocated to PVI alone (75 patients) or
      PVI with additional ablation in the right atrium (75 patients). Patients undergo extensive
      monitoring of the heart rhythm during follow-up to document symptomatic or asymptomatic AF or
      atrial flutter. The presence of asymptomatic AF after PVI could potentially affect the
      management of the anticoagulation therapy in these patients. The structural and functional
      changes in the atria after PVI is characterized by new imaging techniques (Tissue Doppler
      Imaging(TDI))of the atria and cardiac neurohormones. TDI may be an effective tool for
      characterising changes in the left atrial function after PVI. Neurohormones may provide new
      information regarding the changes in left atrial function and clinical outcome after PVI in
      patients with AF.

      We hypothesize that:

        -  Among patients with predominant atrial fibrillation, PVI with additional ablation in the
           right atrium is associated with better outcome, i.e. freedom of symptomatic AF/atrial
           flutter overall.

        -  Asymptomatic AF and atrial flutter occur frequently after PVI.

        -  Left atrial volume and systolic function correlates to AF recurrence after PVI.

        -  Neurohormones levels correlates to AF recurrence after PVI.
    

Detailed description: 
      BACKGROUND:

      Atrial fibrillation (AF) is the most common cardiac arrhythmia. Medical treatment is often
      inefficient or associated with side effects. Pulmonary vein isolation (PVI) in the left
      atrium using radiofrequency energy is a new and promising non-medical treatment in patients
      with symptomatic AF with reported success rates of 65 % to 90 % depending on AF
      classification and ablation procedure (1).

      Circumferential PVI appears to be the superior ablation technique in patients with AF (2).
      However, the risk of recurrence has led to suggestions of how to improve the clinical outcome
      by tailoring a more efficient ablation procedure. Patients with AF often have coexisting
      atrial flutter (3), but it is uncertain if patients referred for PVI can benefit from
      additional cavotricuspid isthmusblock (CTI) which is the traditional ablation treatment of
      atrial flutter. A recent study indicates that PVI reduces both AF and atrial flutter by
      eliminating sharing triggers in the pulmonary veins (4). Other investigators showed that
      patients with AF and atrial flutter prior or during PVI had high risk of recurrent atrial
      flutter during follow-up, and that successful PVI did not reduce the risk of recurrent atrial
      flutter (3). The current approach in our lab is to perform additional CTI in cases of
      documented atrial flutter, but CTI may potentially improve the overall outcome (freedom of
      symptomatic arrhythmia) in patients without documented atrial flutter, especially since most
      symptomatic periods are undocumented.

      A prospective, randomised study with 150 patients with symptomatic AF referred for PVI has
      been initiated and patients are allocated to PVI alone (75 patients) or PVI with additional
      CTI (75 patients). Patients undergo extensive Holter monitoring during follow-up to document
      symptomatic or asymptomatic AF or atrial flutter. Patients with AF have a high incidence of
      asymptomatic AF which correlates to an increased risk of tromboembolic complications (5). The
      presence of aymptomatic AF after PVI could potentially affect the management of the
      anticoagulation therapy in these patients.

      The structural and functional changes in the atria after PVI have been described in few
      studies. To our knowledge, Tissue Doppler Imaging (TDI) and neurohormones (NT-pro-BNP and
      ANP) have not previously been used in characterising the left atrial function after PVI. New
      echocardiographic modalities such as TDI have been introduced in the characterisation of the
      left ventricle systolic function in ischemic heart disease and congestive heart failure. TDI
      has been used for characterising the global and segmental atrial systolic function in healthy
      individuals (6), and TDI may be an effective tool for characterising changes in the left
      atrial function after PVI.

      Neurohormones are produced in the left ventricle/atrium, and patients with AF have elevated
      levels due to atrial stretch. Cardioversion from AF to sinus rhythm is associated with
      normalisation of the BNP/ANP levels (7), and BNP is an independent risk factor of developing
      AF in patients with mild congestive heart failure (8). Neurohormones may therefore provide
      new information regarding the changes in left atrial function and clinical outcome after PVI
      in patients with AF.

      PURPOSE:

        -  To investigate the effect of additional cavotricuspid isthmusblock in patients with AF
           referred for circumferential pulmonary vein isolation.

        -  To investigate the incidence of asymptomatic AF and atrial flutter after ablation by
           extensive Holter monitoring.

        -  To characterise left atrial volume and function before and after PVI by
           echocardiographic assessment (TDI) and measurements of neurohormones (NT-pro-BNP and
           ANP).

      HYPOTHESIS:

        -  Among patients with predominant AF, PVI with additional cavotricuspidal isthmusblock is
           associated with better outcome, i.e. freedom of symptomatic AF/atrial flutter overall.

        -  Asymptomatic AF and atrial flutter occur frequently after PVI.

        -  Left atrial volume and systolic function correlates to AF recurrence after PVI.

        -  ANP/NT-pro-BNP levels correlates to AF recurrence after PVI.

      DESIGN AND MATERIALS:

      A prospective, randomised study with 150 patients referred to PVI due to symptomatic
      paroxysmal or persistent AF. Patients are randomised to circumferential PVI with (75
      patients) or without (75 patients) cavotricuspid isthmusblock in the right atrium. Follow up
      period of 12 months.

      Eighty of the included patients (40 with paroxysmal and 40 with persistent AF) undergo
      TDI-echocardiography and neurohormonal measurements.

      METHOD:

      Admission:

        -  History, physical examination, medication.

        -  Echocardiographic characterisation of left atrial function and volume and left ventricle
           systolic and diastolic function (TDI in 80 patients).

        -  NT-pro-BNP/ANP measurements (in 80 patients).

        -  Questionnaire (SF-36).

        -  Circumferential PVI. Patients are randomised to PVI with or without cavotricuspid
           isthmusblock.

      Ablation:

      One quadripolar 5-F catheter (St. Jude Medical) is placed in the right ventricular apex and a
      decapolar catheter (Biosense Webster) in the coronary sinus. Transseptal access to the left
      atrium is achieved by the use of a SL1 sheath (St. Jude Medical). Three-dimensional maps of
      the left atrium are constructed with a quadripolar D-curve mapping catheter (3.5-mm Navistar,
      Biosense Webster) with the use of a non-fluoroscopic navigation system (CARTO,
      Biosense-Webster). Patients are heparinized using an initial dose of 100 IE/kg with an
      additional 1000 IE/hour. Radiofrequency energy is delivered via the 4-mm mapping catheter.
      Ablation lines are deployed circumferentially around the pulmonary veins (PV) approximately
      0.5 cm from the ostia. After ablation, remapping is performed during sinus rhythm or pacing
      from the coronary sinus. In case of AF during ablation, patients are cardioverted to sinus
      rhythm before remapping. The criteria of successful ablation is the elimination of potentials
      > 0.1 mV within the lesions determined by voltage maps.

      Ultimately, the cavotricuspid ishtmusblock is performed with the ablation catheter. The
      position of the catheter is established using fluoroscopy or CARTO-mapping. Ishtmusblock is
      verified by double potentials during coronary sinus (CS) pacing, an activation detour by
      pacing either side of the line, and differential pacing techniques.

      Follow-up:

        -  24 hours heart rhythm monitoring.

        -  Clinical control after 3,6 and 12 months

        -  1 week Holter monitoring after 3, 6 and 12 months

        -  NT-pro-BNP/ANP measurements after 3 and 12 months

        -  Echocardiography after 3 and 12 months 2D Echocardiography M-mode of the left ventricle
           and atrium in parasternal view Left atrium enddiastolic and endsystolic volume using
           Simpson biplane in apical 4 and 2-chamber view Left ventricle enddiastolic and
           endsystolic volume using Simpson biplane in apical 4 and 2-chamber view Color M-mode
           Transmitral flow (Pulsed Wave Doppler) E- og A-peak velocity, E/A ratio og
           E-decelerationtime Atrial emptying fraction = A velocity time integral (VTI)/total
           velocity time integral (VTI)

      Tissue Doppler echocardiography (TDI) Segmental atrial velocity and amplitude of right and
      left atrium Framerate over 100 fps

      Five points in the apical 4-chamber projection:

        -  2 in the right atrium (lateral annular and superior)

        -  3 in the left atrium (septal annular, superior and lateral annular) Three points in the
           apical 2 chamber view in the left atrium (posterior annular, superior and annular
           anterior)

      STATISTICS:

      The sample size is calculated on the basis of the following assumptions:

      A type 1 error and type 2 error of 5 % and 20 %, respectively, are accepted. The statistical
      power is 80%. Thirty-five percent of patients with AF had coexisting atrial flutter in a
      population who were referred to PVI (3). Patients undergoing CTI due to atrial flutter have
      10 % risk of recurrence. During follow-up, 90 % versus 70 % (without CTI) of the patients are
      expected to be free of symptoms related to atrial flutter. Based on these parameters, the
      sample size is 72 patients included in each group. Overall, 150 patients are included due to
      expected loss of patients during follow-up.

      In 2003, ninety-five patients were treated with PVI in Skejby Hospital which has increased to
      150 patients in 2004. The production is expected to increase further during the following
      years.

      PRACTICAL CONSIDERATIONS:

      The PhD protocol has been approved by The Faculty of Health Science at the University of
      Aarhus and the Local Committee of Ethics in Aarhus. The study was initiated in December 2004
      and at he moment 8 patients have been included. The Institute of Clinical Experimental
      Research at the University Hospital of Aarhus has donated 6 months salary to Dr. Jacob
      Pontoppidan.

      The inclusion period is 12 months. Patients are followed 12 months. Finally, 12 months are
      expected for dataprocessing and publications. At least 3 publications in international
      peer-reviewed journals are expected.

      The measurements of neurohormones are performed by the Department of Clinical Biochemistry
      and the biochemical laboratory at the Department of Nephrology, Skejby Hospital. The
      echocardiographic analyses including TDI are performed by Dr. Pontoppidan, who is experienced
      in this technique. The electrophysiologists in the Department of Cardiology, Skejby
      University Hospital of Aarhus, perform the ablation procedures as described above.
    

Intervention name(s): Pulmonary vein isolation and cavotricuspid ishtmusblock
Intervention type(s): Procedure
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Atrial fibrillation; Pulmonary vein isolation; Tissue Doppler echocardiography