Introduction 1 2 3 5 6 11 12 14 15 19 20 21 22 23 19 24 25 17 26 Methods Patient population Consecutive patients with ongoing symptoms and documented atrial flutter with or without fibrillation were included. At least one recent episode of atrial flutter (within the last 6 months) was documented on a 12 lead ECG and was suggestive for isthmus dependency. Patients with drug-induced flutter (and prior AF) could be included, and had their drug therapy continued after ablation. Patients were excluded if they had undergone a previous flutter ablation, if thrombus was present in the atria, or after previous cardiac surgery for valvular or congenital heart disease. Baseline investigations included a standard echocardiogram, a simple questionnaire asking about clinical wellbeing and a subjective assessment of the arrhythmia burden both in terms of duration and frequency. The study was approved by the ethics committee of our institution. All patients signed written informed consent. Assessment before ablation Antiarrhythmic drugs, except for AV nodal slowing agents, and amiodarone, were discontinued at least five half-lives prior to ablation. Patients were studied in the fasting, post-absorptive state. A coronary sinus (CS) catheter was inserted through the left subclavian vein, and a multipolar circular right atrial catheter with alternating 2–10–2 mm interelectrode distance was positioned from the right groin, with the tip positioned immediately lateral to the planned position of the isthmus line and anterior to the crista terminalis. Heparin 100 U/kg was given and a further 5 U/kg given if the procedure lasted longer than 180 min. If the patient was in sinus rhythm, isthmus conduction was confirmed by pacing. If flutter was present, entrainment was performed to confirm isthmus dependence, and the patient left in flutter. If AF was present, the patient was cardioverted after a transoesophageal echocardiogram, and then isthmus conduction confirmed. Absence of isthmus conduction or non-isthmus dependence was not seen in the selected patients. No induction of arrhythmia was attempted if patients had sinus rhythm. 14 Ablation procedure The catheters were a 9Fr 8 mm tip catheter (FreezorMax, Cryocath Technologies Inc, Kirkland, Canada) with a cryoconsole for the cryoablation group, and a 7Fr 8 mm tip single sensor catheter (EPT Blazer II, Boston Scientific, Natick, MA, USA) with an EPT-1000XP generator for the radiofrequency group. A large curve was initially selected in both groups, with change out of catheter curve during the study only as necessary. Applications of −75°, for 4 min were given with cryothermy, and applications of 60 Watt, for 60 s, targeted at 60°C for RF. Lines were made with discrete applications between the tricuspid valve and the inferior vena cava at an approximately 6 o’clock position in LAO 45°, unless otherwise dictated. If termination of atrial flutter occurred, or if the patient was in sinus rhythm, continuous pacing from the proximal coronary sinus was employed to continually assess isthmus conduction. After the first line, a new assessment of conduction was performed. If conduction over the isthmus remained present, gaps were sought. If there was still isthmus conduction, a slightly more medial or lateral line was made. In no patient was an attempt made to perform a septal ablation line. Final assessment of acute block was confirmed after 30 min waiting. The end point for successful ablation was induction of complete bidirectional isthmus block, defined as the presence of reversal of activation on the lateral and septal wall when pacing the CS os and low lateral RA, the presence of widely split potentials along the isthmus line, by activation mapping across the isthmus, and by differential pacing. All 4 were required before calling the ablation successful. In the case where bidirectional block was not achieved, ablation was stopped when no large, sharp signals could be identified over a broad area of the isthmus. As pain perception was assessed, sedation was standardized. Before venous puncture 5 mg of diazepam was given intravenously, and repeated at the patient’s request. Fentanyl 50 μg intravenously was given when the patient requested pain control and the physician considered this necessary. This was repeated as needed. Dosages of both diazepam and fentanyl were recorded. In the initial 40 patients creatine kinase (CK) and CK-MB were taken before the procedure, 2 and 24 h after the start of the procedure. For the final 22 patients the laboratory had changed the measurement to CK mass. We then modified the protocol to measure CK-MB mass, Troponin T, and Myoglobin at 4 and 24 h after the start of the procedure. No crossover, other than in catheter curve, was allowed in an attempt to remove any possible bias. Change over to an irrigated tip ablation catheter was also not allowed. In patients in whom no block could be induced, a repeat procedure was scheduled not earlier than 6 weeks after the initial ablation, at the physicians’ discretion. The choice of energy source at that time was at the physicians’ discretion. Patients were all questioned with regard to pain perception using a visual analogue score, where patients are shown a line from 0 to 10, where 0 is no pain, and 10 is the highest pain level imaginable, and were asked to point to the position on the line where their pain level during ablation was. Follow-up All patients received an event-recorder for the first 6 weeks after the procedure and were requested to send at least daily strips as well as strips made during symptoms. Patients visited the outpatient clinic 6 weeks after the procedure. After this period all patients were asked to report symptoms and if these were present were given a further event monitor until documentation of symptoms was obtained. If at all possible a 12 lead ECG was also obtained. A second assessment with a questionnaire was performed after 3 months, again asking a question about general clinical well being and also symptom burden in regard to duration and frequency. Clinical files were followed up after 9 months. Statistical analysis p Results Patient data 1 Table 1 Demographics   All Cryo RF p Number 62 32 30  Age (years ± SD) 56 ± 10 55 ± 11 56 ± 9 NS Male/female 27/5 27/5 28/2 NS Atrial fibrillation history 47 (76%) 25 (78%) 22 (73%) NS Cryo NS RF SD Angiographic data Right atrial angiography was not performed in 4 patients because of mild renal dysfunction or allergy to contrast material. The angiogram was of insufficient quality in eight others. The mean isthmus length was 35.2 ± 14.6 mm and its topography was assessed as being flat or only mildly concave in 28, markedly concave in 19 and showed a pit or aneurysm in 10. A clear Eustachian valve was seen on six angiograms. Ablation data 2 Table 2 Procedure data and recurrent arrhythmias   All Cryo RF p Number 62 32 30  Application number 22 ± 13 18 ± 10 25 ± 16 0.05 Ablation time (s) 2,742 ± 1,930 3,792 ± 1,900 1,459 ± 950 <0.001 Acute success 47 (76%) 22 (69%) 25 (83%) NS Single line 47 (76%) 25 (78%) 22 (73%) NS 2 lines 9 (15%) 2 (6%) 7 (24%) 0.073 3 lines 4 (6%) 3 (9%) 1 (3%) NS Reversal of block during application 7 (11%) 6 (19%) 1 (3%) 0,091 Reversal of block during 30 min 6 (10%) 1 (3%) 5 (7%) NS Isthmus length (mm) 35 ± 15 35 ± 17 36 ± 11 NS Sheath usage 7 (11%) 0 (0%) 7 (23%) <0.005 Recurrent arrhythmias Flutter (typical)      After success 1 (2%) 0 (0%) 1 (4%) NS  After failure 11 (73%) 7 (70%) 4 (50%) NS Flutter (atypical) 1 (2%) 0 (0%) 1(3%) NS Atrial tachycardia 5 (8%) 2 (6%) 3 (10%) NS Atrial fibrillation 28 (45%) 13 (41%) 15 (50%) NS The numbers are given with the standard deviation. Cryo NS RF p p p In 22 of 30 in the RF group and 25 of 32 in the cryo group, a single line at approximately 6 o’clock was drawn. In the RF group two lines were drawn in seven, and three in one. In the cryo group two lines were made in four, and three lines in three. The need to draw more than one line was associated with failure of the procedure in four of eight in the RF group and five of seven in the cryo group (NS). p In the RF group the signal was significantly diminished at the end of each application whether isthmus block was present or not, while there tended to be preservation of signals on the cryoablation catheter after ablation across the isthmus until block occurred. Only then were low voltage signals seen. p Procedure data and complications p p 3 3 Table 3 Biomarkers after catheter ablation   All Cryo RF p Procedure values CK (U/l) 141 ± 96 184 ± 102 96 ± 60 0.02 CK-MB (U/l) 27 ± 16 36 ± 17 18 ± 8 0.011 CK-MB mass (μg/l) 18 ± 21 33 ± 24 4.4 ± 1.2 0.004 Troponin T (μg/l) 0.49 ± 0.32 0.54 ± 0.38 0.39 ± 0.27 NS Values after 24 hrs     CK (U/l) 264 ± 245 289 ± 173 136 ± 74 0.022 CK-MB (U/l) 37 ± 28 51 ± 30 18 ± 6 0.011 CK-MB mass (μg/l) 8.4 ± 7.3 12 ± 10 5.16 ± 3.3 0.07 Troponin T (μg/l) 0.44 ± 0.30 0.54 ± 0.36 0.38 ± 0.29 NS The numbers are given with the standard deviation. CK Cryo NS RF p Follow-up results p A total of 6 patients were taking no antiarrhythmic medication prior to ablation and this increased to 13 post isthmus ablation. Recurrent arrhythmias were frequent in both groups of patients. ECG documented recurrent flutter occurred only in one patient from the RF group. A further procedure confirmed recovery of isthmus conduction. This recurrence was seen at 14 months post ablation, whereas he had previously had monthly episodes of flutter. One other patient had symptoms with an apparently non-isthmus dependent flutter documented on ECG on day 1 post ablation and not since, and elected not to have a further procedure. We cannot exclude asymptomatic arrhythmias but at least during the first 6 weeks, patients sent in daily event monitor transmissions, which one would hope would have captured at least some asymptomatic recurrences, particularly of atrial flutter. In 11 of 15 patients in whom the initial procedure failed, a redo procedure was performed after the elected period of 6 weeks because of documented recurrent flutter. The redo procedure required a small number of point touch ups in five patients (three in the RF group and two in the cryo group), while more extensive diffuse isthmus applications were required in six (one in the RF group and five in the cryo group). In those undergoing repeat ablation, success was achieved in all and during follow up no recurrent atrial flutter was noted. Previously undocumented atrial tachycardias were also seen in both groups (three in the RF group, and two in the cryo group). ECG documented AF recurrence occurred in 28 patients, at a similar rate in both groups (15 in the RF group and 13 in the cryo group). The likelihood of asymptomatic recurrences is probably higher for atrial fibrillation but was not the primary focus of this study. Discussion Acute success This study showed an acute success rate of 83% for an 8 mm tip RF catheter vs. 69% for an 8 mm tip cryocatheter. This non significant difference is clearly concerning. However, the cryoablation group required significantly less applications to achieve success, with a similar procedural duration, significantly lower fluoroscopy time, and with a much lower requirement for analgesia with fentanyl. Arrhythmia recurrences in the initially successful patients were similar with a very low flutter recurrence rate. 22 26 17 26 Difficulties during ablation Recurrence during or shortly after ablation occurring more commonly in the cryo group probably relates to a reversible cooling effect at the periphery of the ice ball which recovers during or shortly after termination of ablation, while the central lesion acutely formed is more permanent. The more common recurrence during the waiting period after RF ablation probably relates to a longer reversal time of the acute RF effects (either edema or temperature effect). Cryoablation for flutter 27 28 17 29 30 31 32 32 34 33 35 Higher peak CK levels, confirmed by the high CK-mass in the last patients, suggest that the damage caused by cryotherapy may be more extensive despite the lower number of applications. Several explanations are possible. The first is that the CK levels may be underestimated after RF, which denatures proteins in another way than cryotherapy. Troponin T levels are more accurate in estimation of myocardial damage, but they also tended to be higher, be it not significantly. This may suggest that lesions are equal with both approaches. Future developments 36 Study limitations 37 14 Conclusion 37