A Prospective Study of Medical Therapy Against Cryoballoon Ablation in Symptomatic Recent Onset Persistent Atrial Fibrilation
Phase: PHASE4
Conditions: Atrial Fibrillation
Sponsor: University Hospital, Ghent

PROSPECTIVE STUDY OF MEDICAL THERAPY VERSUS CRYOBALLOON ABLATION IN PATIENTS WITH RECENT ONSET PERSISTENT 
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PROSPECTIVE STUDY OF MEDICAL THERAPY AGAINST CRYOBALLOON ABLATION IN 
PATIENTS WITH SYMPTOMATIC  RECENT ONSET PERSISTENT ATRIAL FIBRILLATION: 
METACSA   
Frédéric Van Heuverswyn, Jean­Benoît le Polain de Waroux, Peter Goethals, TBD, Gian 
Battista Chierchia and Luc Jordaens 
BACKGROUND 
Atrial fibrillation (AF) is the most common cardiac arrhythmia and causes significant 
morbidity and mortality. AF is not benign, as the mortality risk is doubled and the risk 
for stroke, left ventricular dysfunction and hospitalization are increased. The prevalence 
is 1-2%, and increases with age. [1] The health care burden is substantial. [2] 
Treatment of AF is targeted on prevention of thrombo-embolic complications and the 
reduction of symptoms. Medication includes anticoagulation and anti-arrhythmic drugs 
(AAD) for either rhythm or rate-control. Although AAD are the first line of therapy, they 
have their shortcomings, as most AAD have been shown only to be 40-50% effective in 
maintaining sinus rhythm and may have serious side effects. Only amiodarone performs 
better, but its side effects are substantial, and it is withdrawn of treatment in about 20% 
of patients, which makes its efficacy comparable to that of propafenone. [3,4]  
Ablation of the pulmonary veins (pulmonary vein isolation, further PVI) has proven to 
be a safe and effective treatment for AF with variable success rate, depending on the AF 
type, and the presence or absence of underlying disease. [5,6] Recent data show that 
non-repeated PVI with radiofrequency (RF) ablation, has only a limited effect at one 
year (50-60%).  These results can be improved with a repeated ablation, and seem not 

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be maintained after 5 year. [7-11] These are some of the arguments that alternative 
techniques are still being investigated, inclusive minimal invasive surgical techniques.  
Success rates, at least similar to RF ablation have been reported after 1-year follow-up 
and later with a freedom from AF of 69-77% in patients using a cryoballoon technology 
(CBA).  [12-14]. CBA seems to be a reproducible technique, with the same outcome in 
different centers. It has theoretically less side effects than RF, and its only specific side 
effect is phrenic nerve paresis. 
Results are better in paroxysmal patients, than for persistent AF, also for CBA. [13]  
Nevertheless, persistent patients with normal left atrial dimensions made up an 
important proportion of our group. [15]  Differentiation between paroxysmal and short 
term persistent becomes almost impossible from a clinical point of view, as patients get 
early cardioversion, before they are spontaneously reverted to sinus rhythm. [16] Real 
longstanding persistent patients, however were excluded from our and all previous 
trials, as were patients with very large atria. Larger atria have more recurrences than 
smaller atria. Successful ablation results in a smaller left atrial volume, which was 
shown in several studies with RF, also for paroxysmal patients. [17] This volume 
reduction is antiarhythmic as well. 
 It has been hypothesized that early therapy prevents further progression of the disease. 
[16] This has never been proven for catheter ablation, while some pilot trials were 
promising. [18] Reduction of left atrial volume can be used as a substitute for 
antiarrhythmic efficacy and for less disease progression. 
RATIONALE 

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Limited data indicate that ablation is better than AAD therapy. The 9 small randomized 
clinical trials as recently summarized by health care authorities with a correct 
methodology only  included 971 patients, and only studied radiofrequency ablation. [19] 
However, there was substantial heterogeneity, with a majority of paroxysmal patients, 
but some had mixed groups. Endpoints in these trials were not always clear and variable 
as well. Side effects of ablation were somewhat neglected. Stop-AF only addressed 
paroxysmal patients (but included 22% cardioverted patients) and has recently been  
published. [14] This opens the perspective to organize a prospective trial comparing the 
efficacy and safety of CBA to standardized medication for treatment of paroxysmal AF 
and early onset persistent AF without structural heart disease. As elsewhere a trial is 
launched for first onset paroxysmal AF, we would like to focus in this protocol on early 
onset persistent AF without structural heart disease. The value of CBA in these patients 
has never been studied; the endpoints for persistent patients are much easier than for 
paroxysmal patients. Reduction in LA size can be compared versus patients on drug 
therapy and versus failing patients. 
HYPOTHESIS 
1.  The results of CBA in early onset persistent AF are better compared to standard medical 
therapy  with as endpoint maintenance of sinus rhythm after  1 year and an improved QOL in 
the ablation group. 
2.  Successful CBA results in reduction of the LA volume.  
INCLUSION/EXCLUSION CRITERIA 
The total AF history is regarded for previous episodes, paroxysmal or persistent. should 
be shorter than 24 months. Symptomatic patients can be included if they have had at 

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least 2 episodes in their total history, of which one within the last year.  One episode in 
the entire history should have lasted more than 7 days 48 h, requiring electrical or 
pharmacological cardioversion or stopped spontaneously after more than 7 days. The 
duration of this episode should be shorter than 1 year.   If one episode is paroxysmal it 
should have been lasting minimal 30 sec. 
 
All patients eligible for the study will sign informed consent, have an echocardiogram 
prior to inclusion to exclude severe left ventricular dysfunction, to rule out significant 
valve abnormalities, left ventricular hypertrophy and to assess the left atrial (LA) 
volume and diameter.  
Prior to randomization, and after inclusion it is suggested to the local investigators to 
perform an MRI-scan or CT scan of the  LA and pulmonary veins (in both branches of the 
study ) in eligible patients to assess the anatomy and the left atrial volume.  The results 
should not influence the strategy of treatment.  
Inclusion criteria 
•  > 21 years and legally capable 
•  history of 2 symptomatic AF epiodes more than 30 sec . 
•  At least one  AF episode within the last year  
•  One episode cardioverted after more than 7 days or spontaneously terminated 
after more than 7 days; this episode should have been shorter than one year 
•  Eligible for at least one first step drug therapy (sotalol, propafenone, or 
flecainide) and/or  for amiodarone  

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•  Left ventricular ejection fraction  estimated > 45%   
•  LA diameter < 50 mm (parasternal short axis) and or LA volume less than 100 ml 
(apical view, Area Length method) 
•  No previous CVA or TIA (the latter with documented deficit on CT scan) 
•  CHADS2VASC ≤ XXXX  
•  Failed AAD strategy, or untreated with AAD  
•  No use of Amiodarone in the previous 6 weeks (except IV or oral for 7 days) 
•  Informed consent 
 
Exclusion criteria 
•  Age > = 80 yrs  
•  CHF 
•  Ischemic heart disease as known in the history 
•  (Severe) Left ventricular hypertrophy as shown on  echo (IVSd or PWd > 14 mm) 
•  Uncontrolled Hyperthyroidism 
•  Congenital heart disease 
•  HCM, ARVC,  channelopathies 
•  Contra-indications to AAD 
•  Long QT syndrome 

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•  Received already adequately dosed all level 1 drugs (sotalol, propafenone, and 
flecainide) and >6 weeks amiodarone 
•  Pure (typical) atrial flutter as documented on one occasion 
 
INVESTIGATION DESIGN 
Type 
Randomized study design. Experienced centres/operators with a load of > 50 
cryoablations/year. 
Randomization 
1:1 at the time of inclusion 
 
SAMPLE SIZE 
The maximal expected 1 year success on AAD is 50% and minimal expected success of 
CBA is 72%.[3,14,15,20,21,22]  With a power of 0.8 and a significance of 0,05, 
approximately 76 patients should be included in each arm. A total number of 167 
patients need to be included in the study when anticipating that 10% of the patients will 
not be followed as required. 
 
INTERVENTIONS 
Run-in period (from month -1 till month 0) 
Holter recording in the month after inclusion, preferably directly after inclusion to avoid 
extra visits. 

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MRI or CT scan to measure LA volume and PV sizes and anatomy is encouraged 
(optional – if done it should be done in both branches) 
Ablation arm (at month 0): 
 
 
 
 
 
 
 
 
 
 
 
 
Ablation should be scheduled 4 weeks after cardioversion/inclusion. All patients should  
 
 
The ablation approach should be as standardised as possible, and will be discussed at the investigators 
meeting 
After venous punctures, 5000 IE of heparin is administered and after the transseptal puncture (TSP) this 
is repeated. Hereafter, heparin infusion is started with a target ACT of at least 275-300 s. A multipolar 
catheter will be introducted into the coronary sinus. Single TSP will be performed (guided by X-ray and 
intracardiac echocardiography or transoesophageal echocardiography). The 12 Fr steerable sheath is 
introduced into the LA, and the second generation (large) cryoballoon with the Achieve catheter is 
introduced.   Before ablation is started, the veins are checked for entrance and exit block. If there is 
conduction a balloon application is given during 300 s. The occlusion grade, maximal freezing 
temperature and time to isolation are noted. Every vein with potentials is ablated at least twice with at 
least one grade IV occlusion, except when PNP occurs at the right upper PV. If not isolated, a third 
application can be given. If after the third application the vein is still not occluded it is up to the physican 
to decide to do another balloon application or to use a freezer catheter. 
 If isolated, the veins are checked after 30 minutes again for entrance and exit block. The left sided veins 
are ablated while pacing from the distal CS electrodes and when ablating the right sided veins the 
phrenic nerve is stimulated to prevent phrenic nerve palsy (PNP). When all veins are isolated AF 
induction is preformed, 5 s of pacing with CL 200 ms from the distal CS, LA roof (twice) en the HRA. 
Procedure times , X-ray times, and the radiation dose (mGy) are noted. 

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be anticoagulated for at least 4 weeks prior to ablation. Antiarrhythmic drugs are 
maintained after cardioversion. One day before or the day of ablation a TEE will be made 
to exclude a LAA thrombus. Anticoagulation can be continued if this is the protocol of 
the participating centre, and the local protocol per ablation should be followed.  
 
 
 
 
 
 
 
 
 
 
 
 
Drug arm:  
Anticoagulation should be continued per protocol (4 weeks) after the cardioversion. If 
the CHADS2VASC is 
2,  anticoagulation is left at the discretion of the physician. A first 
level  antiarrhythmic drug regimen is started at the month -1, time of the inclusion and 
Proposed first level: 
 
A:   propafenone 300 mg BID / 150 mg QID if < 70 years and > 70 kg 
 
       propafenone 150 mg TID   if  ≥ 70 years or < 70 kg 
B:  sotalol       120 mg BID if  men ≤70 years, cr ≤ 1,5mg/130 μmol, > 70kg; 
           80 mg TID if  men ≥ 70 years, cr > 1,5mg/130 μmol, < 70kg;  
                                                 if  women ≤ 70 years; cr ≤ 1,2/110 μmol 
 
      
          80 mg  once if women > 70 years or cr > 1,2 mg/110 μmol 
                 C: Flecainide : Apocard Retard 100 mg/day as startdosis 4 to 5 days 
                                                                             Further 200 mg/day 
 
 
            Tambocor 100 mg BID if preferred 
Proposed second level: 
 
Amiodarone: loading 14 days with 600 mg/day 
 
 
 
One week 400 mg/day 
 
 
 
Maintenance 200 mg/day 

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an adequate dosage  is prescribed.  If  the patients` condition requires so, a reduced 
dosage can be used during the first (5-7) days. 
If at month 0, at the first clinical visit, the drug therapy does not look sufficient, another 
 
 
Level 1 treatment can be used. This can be repeated if the clinical condition requests so. 
 The  second slevel  antiarrhythmic drug therapy is only allowed after failure of at least 
one level 1 drug. As this is amiodarone, its final efficacy can only be judged 6 months 
after its initiation. 
 
 
FOLLOW UP : see flow charts 
Is in agreement with proposal in ref 23. 
•  24 hour Holter:  
o  after inclusion (month -1) and repeated at  months  3 .This will be done with the 
study Holter without necessarily influencing the therapy (so called blanking period) 
•  48 hour Holter:  with a clinical device 
o  at the end of 6 months . 
•  7 days Holter: with a clinical device 
       °   at the end of 12 months .  
•  Clinical visits :  

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  should be performed by the study nurses/supervised by the investigators 
o  At months 3, 6, and 12 months after ablation 
o  Additionally at month 0 for the drug arm, while the ablation group is 
admitted 
•  Office ECG ; 
         ° at month 3, 6 and 12 
•  Drug management: 
o  AAD: After 3 months stop AAD in the ablation arm in those patients free of 
AF episodes.   
o  OAC: After 6 months consider stopping oral anticoagulation, or replacing 
them with antithrombotic medication in patients free of AF episodes if the 
scores allow so. 
•  Echocardiogram: 
o  At month 12  a new echocardiogram is obtained to assess the LA volume 
and diameter.  
•  QOL with disease specific questionnaire  (AFQOL 18) 
o  At baseline and at month 12 
•  Blood samples  
o  At baseline and at months 6 and 12  
o  Thyroid tests (TSH), liver function (AP, SGOT, SGPT), creatinine 

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•  Drug diary  
o  At baseline, at month 0 and at months 6 and 12 for all patients in both 
arms 
• 
Cost calculation: data should be prospectively collected in CRF at the time of scheduled and 
unscheduled visits, based on costs as foreseen in the reimbursement of the RIZIV/INAMI and 
additional drug costs. 
CROSS OVER 
Is allowed after 6 months. This implies that at 12 months we will be able to do not only 
ITT but  also OTA.    
SERIOUS ADVERSE EVENTS 
SAE`s are expected to happen in 7% in the ablation arm, and at a rate of 12-15% in the 
drug arm, because of side effects and 3% because of proarrhythmia (20). 
ENDPOINTS 
Primary endpoints 
•  Sinus rhythm at clinical visit at 1 year after the ablation, or with AAD  
•  Freedom of AF with all measurements 
Secundary endpoints 
•  Reduction of LA volume  in successfully treated patients   
•  Number of cardioversions 
•  Percentage of patients on AAD after 6 and 12 months  

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•  Vascular complications 
•  Stroke, TIA 
•  SAE in both groups 
•  Number of cross-overs (with OTA) 
 
 
 
 
Figure 1. AAD : antiarrhythmic drugs;  LA: left atrial; QOL: quality of life; R: randomization 

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STUDY ORGANISATION 
Steering committee : L. Jordaens, GB Chierchia, F. Van Heuverswyn, M. De Pauw 
DMSB  : Dr Duytschaever, Dr. Bhagwandien, L. Deroy 
One central study coordinator (University Hospital Ghent) – Pieter Vervaet 
eCRF: electronic CRF will facilitate on line data management  
Central data analysis of  ECGs, 24 hour , 48 hr and 7 day Holters at central site via 
software based (GEM-MED) 
Analysis of echo in University Hospital Ghent 
QOL data analysis   
Cost efficacy (Belgian data) and MRI substudies will be encouraged. 
STUDY SITES 
Ghent University Hospital as primary Belgian site (METC submission); 
Liege University Hospital 
Sint Jan, Brussels 
UCL - St Luc Brussels 
UZ, VUB 
Roeselare, 
Liège, Citadelle 

PROSPECTIVE STUDY OF MEDICAL THERAPY VERSUS CRYOBALLOON ABLATION IN PATIENTS WITH RECENT ONSET PERSISTENT 
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Luxembourg 
Time line 
METC submission: Sept 2013 (B); approval     3-5-2013  ; First inclusion November 
2015; Inclusion completed April 2018; Follow-up completed April 2019.  
 
Advisors: 
Prof Dr Luc Deroy; Dr J; Schaar; Prof Dr Roland Stroobandt 
 
Dr. Tine De Backer

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