Electrical Cardioversion of Recent Onset Atrial Fibrillation - Silent Thromboembolic Events, Reverse Atrial Remodeling
Condition: Intracranial Embolism
MeSH terms: Intracranial Embolism; Atrial Fibrillation; Embolism; Thromboembolism
Study type: Observational

Summary: 
      The purpose of this study is to study the effects of transthoracic electrical cardioversion
      for restoration of sinus rhythm in patients who present with recent onset atrial
      fibrillation, with regard to new silent cerebral thrombo-embolic lesions and cognitive
      function, as well as electrical and functional/structural reverse remodelling, and its
      effects on inflammatory changes / specific cardiac biomarkers, vasoactive peptides,
      coagulation activity, and active fibrinolysis.
    

Detailed description: 
      Working plan This study will give information about the incidence of silent cerebral
      thrombo-embolic events in patients with recent onset AF, a population which is expected to
      consist mostly of paroxysmal AF patients.

      Patients with atrial fibrillation (AF) duration less than 48 hours and fulfilling inclusion
      and not exclusion criteria will be included in the study by a cardiologist on the day of
      cardioversion, and study nurse will be notified to plan for the investigations. The patient
      will undergo clinical examination, clinical history will be taken and blood sampling. Once 12
      lead ECG, echocardiography, questionnaires, telemetry and MR have been done the patient will
      be electrically cardioverted After the cardioversion the patient will be subject to
      echocardiography of the heart again, blood-sampling, 12 lead ECG, and MR brain. The patient
      is discharged but will be studied by echocardiography of the heart and MR brain again on day
      7 - 10. Thereafter the patient will be followed for 30 days - see flowchart.

      The day of cardioversion is defined as Day 0.

      3.1. ASSESSMENT OF REMODELING/REVERSE REMODELING 3.1.1. Electrical remodeling Standard
      12-Lead electrocardiography (ECG) at every health care visit. (Day -1, Day 0 before and
      immediately after DCC, Day 0 at discharge, Day 7-10 and 30). Recorded with automatic analysis
      of intervals, Paper speed 50 mm/sec.

      O Data to be collected: Rhythm, heart rate, P wave duration and amplitude.

      3.1.2. Functional remodeling (Echocardiographic analysis) - App. 1. Left and right atrial
      dimensions and volumes 53. Global left atrial function, left atrial ejection fraction:
      (assessed by 2D and speckle tracking )53, 54 Left ventricular ejection fraction and left
      ventricular diastolic function (transmitral velocities, E/E' index)53-56 O Echocardiographic
      data will be collected and stored in the routinely used database of the department of
      Clinical Physiology and as raw images in a separate database dedicated for the study (in the
      care of the investigators) for offline review and measurements. The Core lab in Uppsala will
      do all analysis.

      O Time of collection: prior to cardioversion, within 24 h after cardioversion and at day 7 -
      10 after cardioversion.

      3.1.3.Neurohormonal - inflammatory indices, cardiac biomarkers, vasoactive peptides.

      High-sensitivity cardiac troponin T (hsTnT) and N-terminal pro-brain natriuretic peptide
      (Nt-proBNP) will be measured as sensitive and specific markers of cardiac injury ⁄ strain ⁄
      filling pressures and B-type natriuretic peptide levels correlate with AF burden in patients
      with lone AF and is a strong predictor of recurrent arrhythmia after ablation. (A stable
      fragment of vasoactive peptide, C-terminal -proendothelin-1 will be measured because of its
      relation recurrence of AF, which may be a risk factor for embolism and because of its
      possible role in the pathogenesis and recurrence of AF, and the association with atrial
      dilatation, fibrosis, and hypertrophy, which may contribute to AF persistence and embolism)
      C-Reactive protein (CRP) Interleukin-662-65 Routine blood tests: (Hb, Platelets, White blood
      cell count, Na, K, Creatinine, international normalized ratio (INR), thyroid-stimulating
      hormone (TSH), free-T4): only once before cardioversion.

      O Blood sampling test: Day 0 before (sample 1) and 4 + 1 hours after cardioversion at time
      for MRI no 2 before discharge (sample 2) and day 7-10 (sample 3). The core lab in Uppsala
      will do all analysis.

      3.2. RHYTHM MONITORING O Continuous ECG monitoring O During and after cardioversion to be
      printed from cardioverter or telemetry or 7 - 10 day Holter.

      O 7-day Holter monitoring. To be initiated on Day 0 prior to cardioversion for 7 days. The
      Core lab in Uppsala will do all analysis.

      12 lead ECG recording As above and at symptoms indicating recurrence of AF.

      Data to be collected:

      Time to first P-wave to assess sinus node recovery after DC and time for immediate recurrence
      of AF.

      AF burden (defined as total time in AF during the first 7 days) Time to first AF recurrence
      (sustained AF; duration >30 seconds during first 7 days, then at first symptom of AF
      confirmed on ECG) Number of sustained and non-sustained AF episodes during the first 7 days
      Mean, median - range of duration of AF episodes during the first 7 Days

      3.3. ASSESSMENT OF THROMBOEMBOLIC BIOMARKERS, MENTAL TESTS AND CEREBRAL ISCHEMIC EVENTS

      3.3.1. Biomarkers Coagulation activity by analysing plasma markers for thrombin activity
      (P-selectin, d-dimer, and prothrombin fragment 1+2, von Willebrand factor antigen (vWF-Ag))
      and factor VIII:C.

      Active fibrinolysis (plasmin-alpha 2-plasmin inhibitor complex: PIC) P-fibrinogen och
      P-Fibrin Platelet activity (platelet factor 4: PF4). Brain damage markers: S100 Blood
      sampling test as above.

      3.3.2. Neurological / Cognitive assessment National Institute of Health Stroke Scale (NIHSS):
      Standardized assessment of neurological deficit66.

      To be performed: Day 0 prior to cardioversion, Day 7-10, Day 30 and when clinically evident
      cerebrovascular event.

      Mini-Mental-Test (Mini Mental State Examination, MMSE) and Trail Making Test A och B (TMT A
      och B) To be performed: Day 0 prior to cardioversion, Day 7-10, Day 30 and if clinically
      evident cerebrovascular event.

      3.3.3. Brain magnetic resonance imaging. MRI is performed for the assessment of silent
      thromboembolism, which is defined as 2-3 mm or larger lesion with restricted diffusion on MRI
      with diffusion weighted sequence.51,71-75 Silent or clinically evident cerebrovascular events
      occurring during cardioversion will be detected and eventually not counted as late coming
      emboli in relation to reverse remodeling.

      To be performed: Prior to and within 24 hours after DCC, on Day 0, and on Day 7 - 10 after
      DCC.

      Data to be collected: presence, size, number, and vascular distribution of any focal
      abnormality consistent with embolic lesion.

      Technique for MRI without contrast injection:

      Sag T2 or T1 to position and obtain transversal slices with high reproducibility.

      "DWI" transversal, 5 mm slices, b=0 och b=1000, calculation of "ADC" maps, usually automatic
      by scanner T2 tse/fse transversal, 5 mm slices T2 FLAIR transversal, 5 mm slices

      4. Statistical analysis, sample size, data handling This pilot study will give information
      about the incidence of silent cerebral thromboembolic events and associated clinical
      variables that may affect the outcome, in patients with recent onset AF who are expected to
      mainly suffer from paroxysmal AF.

      Based on previous reports of patients undergoing MRI before and after AF ablations, the % of
      patients with chronic cerebral lesions detected on MRI at baseline varies widely from 4 to 79
      %, with 10 % being the most representative figure for patients with paroxysmal AF. Previous
      observations have reported varying frequencies of new silent cerebral lesions on MRI after AF
      ablation (4-38 %), coronary angiography (10 %) and retrograde aortic catheterisation of
      patients with aortic valve stenosis (22 %). New asymptomatic cerebral ischemic lesions in
      patients undergoing AF ablation have been reported after the use of irrigated radiofrequency
      (RF) catheters (7-11 %), the most common routine ablation procedure, and even a higher
      frequency of lesions (37 %) using a specialized circular RF ablation catheter. Based on these
      observations the investigators argued that a 20 % increase in incidence of new asymptomatic
      cerebral ischemic lesions in patients undergoing DC cardioversion would be clinically
      significant and warrant alternative routines for cardioversions.

      Determination of sample size Considering a 20% increase (i.e. from 10% at baseline to 30%) in
      incidence of silent cerebral lesions following electrical cardioversion, the required number
      of patients to reject the null-hypothesis with 90% power and at the 0.05 significance level
      (two-sided) is 35. To allow for drop-outs, 40 patients will be included in the study. The
      sample size calculations were performed in the software "nQuery Advisor" version 7.0.

      It is reasonable to perform a pilot study of 40 patients, in order to get an indication of
      the number of silent cerebral events. A total of 70 patients will be screened to ensure that
      40 patients will remain in sinus rhythm at least 7 days after cardioversion.

      Categorical variables will be reported as counts and percentages, whereas continuous
      variables as means and standard deviations (SD) or medians and interquartile ranges, as
      applicable.

      The relationship between clinical variables (qualifying history duration of AF, AF duration,
      CHADS2VASC score, biomarkers, conversion to sinus rhythm, left atrial function and left
      atrial volume), confounding variables and incidence of new silent cerebral ischemic lesions
      at Day 1 and 7-10 post MR will be tested in a multiple logistic regression model, using a
      stepwise selection procedure (p<0.05). The model will be validated using bootstrapping.

      The number of new silent cerebral ischemic lesions will be modelled as poisson or negative
      binomial regression models, as applicable.

      Median concentrations of the biomarkers will be compared with baseline levels by
      nonparametric Wilcoxon rank-sum test or Kruskal- Wallis test when appropriate.

      The association between biomarker concentrations and new embolic lesion will be evaluated
      over a follow up period 7 -10 days. The association between baseline concentration of each
      biomarker and new embolic lesion will be assessed by univariable Cox proportional hazards
      models. Biomarkers will be modelled as continuous variables (expressed as 1 SD increment) as
      linearity of the hazard will be tested by appropriate transformation using restricted cubic
      splines to account for possible nonlinear relationships. Cox multivariable models will be
      performed to evaluate the independent prognostic value of each biomarker separately;
      adjusting for baseline covariates emerged as statistically significant from a stepwise
      selection procedure (p < 0.05). The investigators will also investigate whether the addition
      of different combinations of the biomarkers improve the discrimination of the model. The
      independent prognostic value of each biomarker on new embolic lesion will be assessed by
      univariable and multivariable Cox models.

      Each biomarker measured at baseline, Day 1 before and immediately after DCC, at discharge,
      after 7 - 10 days, and 1 months will be analysed graphically over time at the patient level
      as well as by summary statistics.

      All probability values are two-tailed, and 95% confidence intervals (CIs) will be calculated.
      Because of the exploratory nature of this study, adjustments for the multiplicity of
      statistical analyses will not be made.

      A 2-sided P-value <0.05 will be considered statistically significant.

      5. Clinical Significance It is of paramount importance to assess if electrical cardioversion
      performed within 48 hours after AF onset, without preceding oral anticoagulation, results in
      silent strokes, as it is the present clinical routine and no scientific data is available.

      A 20 % increase in incidence of new asymptomatic cerebral ischemic lesions in patients
      undergoing DC cardioversion is in this study defined as clinically significant. If other
      cardioversion strategies can be identified that result in 10 % lower incidence of events,
      that figure may then be regarded as clinically significant.
    

Intervention name(s): Electrical cardioversion
Intervention type(s): Procedure
Intervention description(s): Transthoracic direct current electrical cardioversion
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Patients who present to the emergency department or the outpatient clinic with recent onset
        atrial fibrillation (defined as atrial fibrillation duration less than 48 hours), are
        eligible for the study.
      
Biospecimen description: 
      CRP P- von Willebrandfaktor- antigen P- Interleukin-6 [IL-6] P- Fibrin, D-dimer S-
      N-terminalt pBNP P- Troponin I Pt(Lkc)- Faktor V, genotyp S- Heparin/PF4-antikroppar
      P-Protrombinfragment 1+2 P-selectin factor VIII:C Brain marker S100
    
Keywords: silent brain embolism; atrial fibrillation; cardioversion