title: Randomised clinical trial of cryoballoon versus irrigated radio frequency catheter ablation for atrial fibrillation—the effect of double short versus standard exposure cryoablation duration during pulmonary vein isolation (CIRCA-DOSE): methods and rationale Cryoballoon Versus Open Irrigated Radiofrequency Ablation in Patients With Paroxysmal Atrial Fibrillation Cryoballoon versus radiofrequency catheter ablation for paroxysmal atrial fibrillation. Cost-Effectiveness of Radiofrequency Catheter Ablation Compared With Antiarrhythmic Drug Therapy for Paroxysmal Atrial Fibrillation Two-Year Follow-Up after Contact Force Sensing Radiofrequency Catheter and Second-Generation Cryoballoon Ablation for Paroxysmal Atrial Fibrillation: A Comparative Single Centre Study Assessing the Gold Standard--Lessons from the History of RCTs. Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the prospective, multicenter SMART-AF trial. Point-by-Point Radiofrequency Ablation Versus the Cryoballoon or a Novel Combined Approach: A Randomized Trial Comparing 3 Methods of Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation (The Cryo Versus RF Trial). Real-time contact force sensing for pulmonary vein isolation in the setting of paroxysmal atrial fibrillation: procedural and 1-year results. A brief history of the randomized controlled trial. From oranges and lemons to the gold standard. The COR trial: a randomized study with continuous rhythm monitoring to compare the efficacy of cryoenergy and radiofrequency for pulmonary vein isolation. Cellular damage, platelet activation, and inflammatory response after pulmonary vein isolation: a randomized study comparing radiofrequency ablation with cryoablation. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation.
abstract: Introduction Pulmonary vein isolation ( PVI ) is an effective therapy for paroxysmal atrial fibrillation ( AF ) , but it has limitations . The two most significant recent advances have centred on the integration of real-time quantitative assessment of catheter contact force into focal radio frequency ( RF ) ablation catheters and the development of dedicated ablation tools capable of achieving PVI with a single ablation lesion ( A rct ic Front cryoballoon , Medtronic , Minneapolis , MN , USA ) . Although each of these holds promise for improving the clinical success of catheter ablation of AF , there has not been a rigorous comparison of these advanced ablation technologies . Moreover , the optimal duration of cryoablation ( freezing time ) has not been determined . Methods and analysis Patients undergoing an initial PVI procedure for paroxysmal AF will be recruited . Patients will be r and omised 1:1:1 between contact-force irrigated RF ablation , short duration cryoballoon ablation ( 2 min applications ) and st and ard duration cryoballoon ablation ( 4 min applications ) . The primary outcome is time to first documented AF recurrence on implantable loop recorder . With a sample size of 111 per group and a two-sided 0.025 significance level ( to account for the two main comparisons ) , the study will have 80 % power ( using a log-rank test ) to detect a difference of 20 % between contact force RF catheter ablation and either of the two cryoballoon ablation groups . Factoring in a 4 % loss to follow-up , 116 patients per group should be r and omised and followed for a year ( total study population of 348 ) . Ethics and dissemination The study was approved by the University of British Columbia Office of Research ( Services ) Ethics Clinical Research Ethics Board . Results of the study will be su bmi tted for publication in a peer- review ed journal . Trial registration number NCT01913522 ; Pre- Background — There is a lack of data on the comparative efficacy and procedural safety of open irrigated radiofrequency ( RF ) and cryoballoon catheter ( CB ) ablation for pulmonary vein isolation in patients with paroxysmal atrial fibrillation . Methods and Results — In a prospect i ve , noninferiority study , 315 patients were r and omly assigned to RF ( n=159 ) or CB ( n=156 ) ablation . The primary end point was freedom from atrial arrhythmia with absence of persistent complications . Patients were largely comparable between groups with more vascular disease in the RF group ( 8.2 % versus 2.6 % for CB ; P=0.028 ) . The primary end point at 12 months was achieved by 70.7 % with RF and 73.6 % with CB ( multiple procedure success ) , including 31 redo procedures in each group ( 19.5 % of RF versus 19.9 % of CB ; P=0.933 ) . For the intention-to-treat population , noninferiority of CB was revealed for the predefined inferiority margin ( risk difference , 0.029 ; 95 % confidence interval , −0.074 to 0.132 ; P<0.001 ) . Rates at 6 months were 63.1 % and 64.1 % for the RF and CB groups ( single procedure success ) , and noninferiority was confirmed ( risk difference , 0.010 ; 95 % confidence interval , −0.097 to 0.116 ; P=0.002 ) . Periprocedural complications for the index procedure were more frequent in the CB group ( 5.0 % RF , 12.2 % CB ; P=0.022 ) with a significant difference in phrenic nerve palsies ( 0 % RF , 5.8 % CB ; P=0.002 ) . Conclusion — This large , prospect i ve , r and omized , controlled study demonstrates noninferiority of CB ablation versus RF ablation for treating patients with paroxysmal atrial fibrillation . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00774566 BACKGROUND Catheter ablation is an established treatment for atrial fibrillation ( AF ) .  Cryoballoon ablation ( CBA ) has emerged as an alternative to radiofrequency ablation ( RFA ) . However , there are few data comparing these modalities for treatment of paroxysmal AF ( pAF ) in the U.S. POPULATION The purpose of this study was to compare procedural times , safety , and efficacy of CBA against RFA . METHODS A single-center prospect i ve cohort study evaluated patients who underwent catheter ablation for pAF using CBA or RFA between January 1 , 2010 and October 31 , 2013 . Patients with prior ablation and those without rhythm follow-up for at least 3 months were excluded . The primary end point was freedom from AF , atrial flutter , and atrial tachycardia ( FFAF ) > 30 seconds after a 3-month blanking period without requirement for antiarrhythmic drugs . We also compared rates of successful pulmonary vein isolation ( PVI ) , fluoroscopy and procedure times , and major complication rates . RESULTS A total of 201 patients were included ( CBA = 101 , RFA = 100 ) . The rate of successful PVI was 99.3 % in CBA versus 97.4 % in RFA ( P = 0.08 ) . Procedure times were shorter with CBA ( 192.9 ± 44.0 minutes vs 283.7 ± 78.0 minutes , P < 0.001 ) as well as total fluoroscopy times ( 46.0 ± 22.4 minutes vs 73.0 ± 30.1 minutes , P < 0.001 ) . Overall complication rates were equivalent ; however , fewer cardiac perforations occurred with CBA ( 0 % vs 4 % , P = 0.042 ) . The 1-year FFAF rates were 60.3 % for CBA and 61.1 % for RFA ( log rank P = 0.93 ) . CONCLUSION CBA was associated with equivalent 1-year FFAF rate as RFA for pAF . Procedure and fluoroscopy times were shorter for CBA and fewer cardiac perforations occurred Background —Radiofrequency catheter ablation ( RFA ) has emerged as an important treatment strategy for atrial fibrillation ( AF ) . The potential cost-effectiveness of RFA for AF , relative to antiarrhythmic drug ( AAD ) therapy , has not been fully explored from a US perspective . Methods and Results —We constructed a Markov disease simulation model for a hypothetical cohort of patients with drug-refractory paroxysmal AF , treated either with RFA with/without AAD or AAD alone .  Costs and quality -adjusted life-years were projected over 5 years . Model inputs were drawn from published clinical trial and registry data , from new registry and trial data analysis , and from data prospect ively collected from patients with AF treated with RFA at our institution . We assumed no benefit from ablation on stroke , heart failure or death , but did estimate changes in quality -adjusted life expectancy using data from several AF cohorts . In the base case scenario , cumulative costs with the RFA and AAD strategies were $ 26 584 and $ 19 898 , respectively . Over 5 years , quality -adjusted life expectancy was 3.51 quality -adjusted life-years with RFA versus 3.38 for the AAD group . The incremental cost-effectiveness ratio for RFA versus AAD was thus $ 51 431 per quality -adjusted life-year . Model results were most sensitive to time horizon , the relative utility weights of successful ablation versus unsuccessful drug therapy , and to the cost of an ablation procedure . Conclusions —RFA with/without AAD for symptomatic , drug-refractory paroxysmal AF appears to be reasonably cost-effective compared with AAD therapy alone from the perspective of the US health care system , based on improved quality of life and avoidance of future health care costs Background . There are little comparative data on catheter ablation of paroxysmal atrial fibrillation ( AF ) using the contact force radiofrequency ( CF-RF ) catheter versus the second-generation cryoballoon ( CB2 ) . Methods and results . This is a single center , retrospective , nonr and omized study of 98 patients with symptomatic , drug-refractory paroxysmal AF who underwent their first PVI ablation using either the CB2 ( n = 40 ) or CF-RF ( n = 58 ) . The mean age was 60 years with 63 % men , a mean LA size of 42 mm . The procedure duration ( 74 ± 17 versus 120 ± 49 minutes p < 0.05 ) was shorter for CB2 group ; the fluoroscopy time ( 14 ± 17 versus 16 ± 5 minutes , p = 0.45 ) was similar . Complete PVI was achieved in 96 % of patients with RF-CF and 98 % with CB2 . Phrenic nerve palsies ( 2 transient and 1 persistent ) occurred exclusively in the CB2 group and 1 severe , nonlethal complication ( pericardial tamponade ) occurred in the CF-RF group . At 24-month follow-up , the success rate , defined as freedom from AF/atrial tachycardia ( AT ) after a single procedure without antiarrhythmic drug , was comparable in CF-RF group and CB2 group ( 65.5 % versus 67 % , resp . , log rank p = 0.54 ) . Conclusion . Both the CB2 and the RF-CF ablation appeared safe ; the success rate at 2 years was comparable between both technologies R and omized , controlled trials have become the gold st and ard of medical knowledge . Yet their scientific and political history offers lessons about the complexity of medicine and disease and the economic and political forces shaping the production and circulation of knowledge BACKGROUND Catheter ablation is important for treatment of paroxysmal atrial fibrillation ( PAF ) . Limited animal and human studies suggest a correlation between electrode-tissue contact and radiofrequency lesion generation . OBJECTIVES The study sought to assess the safety and effectiveness of an irrigated , contact force (CF)-sensing catheter in the treatment of drug refractory symptomatic PAF . METHODS A prospect i ve , multicenter , nonr and omized study was conducted . Enrollment criteria included : ≥3 symptomatic episodes of PAF within 6 months of enrollment and failure of ≥1 antiarrhythmic drug ( Class I to IV ) . Ablation included pulmonary vein isolation with confirmed entrance block as procedural endpoint . RESULTS A total of 172 patients were enrolled at 21 sites , where 161 patients had a study catheter inserted and 160 patients underwent radiofrequency application . Procedural-related serious adverse events occurring within 7 days of the procedure included tamponade ( n = 4 ) , pericarditis ( n = 3 ) , heart block ( n = 1 , prior to radiofrequency application ) , and vascular access complications ( n = 4 ) . By Kaplan-Meier analyses , 12-month freedom from atrial fibrillation/atrial flutter/atrial tachycardia recurrence was 72.5 % . The average CF per procedure was 17.9 ± 9.4 g. When the CF employed was between investigator selected working ranges ≥80 % of the time during therapy , outcomes were 4.25 times more likely to be successful ( p = 0.0054 ; 95 % confidence interval : 1.53 to 11.79 ) . CONCLUSIONS The SMART-AF trial demonstrated that this irrigated CF-sensing catheter is safe and effective for the treatment of drug refractory symptomatic PAF , with no unanticipated device-related adverse events . The increased percent of time within investigator-targeted CF ranges correlates with increased freedom from arrhythmia recurrence . Stable CF during radiofrequency application increases the likelihood of 12-month success . ( THERMOCOOL ® SMARTTOUCH ® Catheter for Treatment of Symptomatic Paroxysmal Atrial Fibrillation ; NCT01385202 ) INTRODUCTION Catheter ablation of paroxysmal AF using the Cryoballoon ( CRYO ) has yielded similar success rates to conventional wide encirclement using radiofrequency catheter ablation ( RFCA ) , but r and omized data are lacking . Pilot data suggested a high success rate with a combined approach ( COMBINED ) using wide encirclement with RFCA followed by 2 CRYO applications to each vein . We compared these 3 strategies in a r and omized controlled trial . METHODS AND RESULTS Patients undergoing first time paroxysmal AF ablation were r and omized to RFCA , CRYO , or COMBINED . Patients were followed up at 3 , 6 , and 12 months with 7 days of ambulatory ECG monitoring . Success was defined as freedom from arrhythmia without antiarrhythmic drugs after a single procedure . A total of 237 patients were r and omized . Success at 1 year was achieved in 47 % in the RFCA group , 67 % in the CRYO group , and 76 % in the COMBINED group ( P < 0.001 for RFCA vs. CRYO , P<0.001 for RFCA vs. COMBINED , and P = 0.220 for CRYO vs. COMBINED ) . Procedure time was 211 ( IQR 174 - 256 ) minutes for RFCA compared to 167 ( 136 - 202 ) minutes for CRYO and 278 ( 243 - 327 ) minutes for COMBINED ( P < 0.001 for RFCA vs. COMBINED , RFCA vs. CRYO , and CRYO vs. COMBINED groups ) . CONCLUSIONS Pulmonary vein isolation for paroxysmal AF is faster with CRYO and results in a higher single procedure success rate than conventional point by point RFCA . The COMBINED approach was not superior to CRYO alone INTRODUCTION The additional benefit of contact force ( CF ) technology during pulmonary vein isolation ( PVI ) for paroxysmal atrial fibrillation ( AF ) to improve mid-term clinical outcome is unclear . METHODS AND RESULTS Eligible patients with symptomatic paroxysmal AF were enrolled in this prospect i ve trial , comparing circular antral catheter ablation ( guided by Carto 3 System , Biosense Webster ) using either a new open-irrigated CF catheter ( SmartTouch Thermocool , Biosense Webster ) ( CF group ) or a non-CF open-irrigated catheter ( EZ Steer Thermocool , Biosense Webster ) ( control group ) . Overall , 30 patients were enrolled in each group , with a st and ardized 12-month follow-up , free of antiarrhythmic therapy . Demographic , cardiovascular and anatomic characteristics were similar in both groups . Though complete PVI was eventually achieved in all cases in both groups , success using an exclusive anatomic approach was 80.0 % in CF group versus 36.7 % in control group ( P < 0.0001 ) . CF use was associated with significant reductions in fluoroscopy exposure ( P < 0.01 ) and radiofrequency time ( P = 0.01 ) . The incidence rates of AF recurrence were 10.5 % ( 95 % CI , 1.38 - 22.4 ) in the CF group , and 35.9 % ( 95 % CI , 12.4 - 59.4 ) in the control group ( log rank test , P = 0.04 ) . After adjustment on potential confounders , the use of CF catheter was found to be associated with a lower AF recurrence ( OR 0.18 , 95 % CI 0.04 - 0.94 , P = 0.04 ) . CONCLUSION Our findings suggest a potential benefit of real-time CF sensing technology , in reducing AF recurrence during the first year after PVI This article discusses the history and development of  r and omized clinical trial methodology  , the reasons for its status and authority as a method of therapeutic evaluation , and the continuing role of clinical judgement in design ing , interpreting , and applying the findings of trials BACKGROUND Results from r and omized trials design ed to compare cryoenergy with radiofrequency for pulmonary vein ( PV ) isolation are lacking . OBJECTIVE To compare the efficacy of a simplified strategy for PV cryoablation ( group C ) vs PV isolation with open-irrigated radiofrequency catheters ( group R ) . METHODS Fifty patients with paroxysmal atrial fibrillation ( AF ) and 4 independent PVs received a Reveal XT implantable cardiac monitor and were r and omized to group C or group R. In group C , PV ablation was done with a single A rct ic Front balloon ( 23 or 28 mm ) per patient and two 300-second applications per PV . No further applications were delivered to close residual conduction gaps . In group R , bidirectional PV conduction block was pursued with Lasso and Navistar ThermoCool catheters and the CARTO system . The primary end point was the proportion of patients remaining free from AF recurrences ≥2 minutes without taking antiarrhythmic drugs 12 months after ablation . RESULTS The primary end point was met by 12 ( 48 % ) patients in group C and 25 ( 68 % ) patients in group R ( odds ratio 0.43 ; P = .05 ) . This difference disappeared after adjustment for acute procedural outcome . In patients for whom all 4 PVs were blocked at the end of the procedure , there was no difference between group C and group R in the primary end point ( 67 % vs 68 % ; P = .94 ) . CONCLUSIONS The efficacy of the simplified strategy for PV cryoablation tested in this study is inferior to PV isolation using open-irrigated radiofrequency catheters with electrophysiological and electroanatomical guidance . Complete PV conduction block is critical to the success of AF ablation BACKGROUND Experimental data suggest that use of cryoablation in pulmonary vein isolation ( PVI ) is associated with less cell damage and less thrombus formation compared to radiofrequency ( RF ) energy . OBJECTIVE The purpose of this study was to test the hypothesis that cryoablation significantly reduces markers of cell damage , platelet activation , and inflammation in patients undergoing PVI for treatment of atrial fibrillation ( AF ) . METHODS Sixty patients with symptomatic drug-resistant AF ( age 56 ± 9 years , 48 males , 38 with paroxysmal AF ) were r and omly assigned to undergo PVI using either an open irrigated-tip RF catheter or a cryoballoon . Markers of cell damage ( high-sensitive troponin T [ hs-TnT ] , microparticles ) , platelet activation ( platelet reactivity by aggregometry , expression of platelet surface proteins P-selectin and activated glycoprotein [ GP ] IIb/IIIa ) , and inflammatory response ( high-sensitive C-reactive protein [ hs-CRP ] ) were determined before and up to 48 hours after the procedure . RESULTS PVI result ed in a significant rise in hs-TnT , microparticles , markers of platelet activation , and hs-CRP over time , with distinct temporal patterns for each parameter . However , after Bonferroni correction for repeated measurements , no significant differences were noted in these parameters between patients treated with cryoablation or RF energy . Procedural time was significantly shorter in patients treated with cryoballoon ( 177 ± 30 minutes vs 200 ± 46 minutes , P = .03 ) , with no differences in fluoroscopic time , periprocedural complications , or success rate . CONCLUSION Cryoablation and RF energy result in a comparable rise of markers of cell damage , platelet activation and inflammatory response . The data do not support the concept of an improved safety profile for cryoablation in PVI CONTEXT Antiarrhythmic drugs are commonly used for prevention of recurrent atrial fibrillation ( AF ) despite inconsistent efficacy and frequent adverse effects . Catheter ablation has been proposed as an alternative treatment for paroxysmal AF . OBJECTIVE To determine the efficacy of catheter ablation compared with antiarrhythmic drug therapy ( ADT ) in treating symptomatic paroxysmal AF . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve , multicenter , r and omized ( 2:1 ) , unblinded , Bayesian- design ed study conducted at 19 hospitals of 167 patients who did not respond to at least 1 antiarrhythmic drug and who experienced at least 3 AF episodes within 6 months before r and omization . Enrollment occurred between October 25 , 2004 , and October 11 , 2007 , with the last follow-up on January 19 , 2009 . INTERVENTION Catheter ablation ( n = 106 ) or ADT ( n = 61 ) , with assessment for effectiveness in a comparable 9-month follow-up period . MAIN OUTCOME MEASURES Time to protocol -defined treatment failure . The proportion of patients who experienced major treatment-related adverse events within 30 days of catheter ablation or ADT was also reported . RESULTS At the end of the 9-month effectiveness evaluation period , 66 % of patients in the catheter ablation group remained free from protocol -defined treatment failure compared with 16 % of patients treated with ADT . The hazard ratio of catheter ablation to ADT was 0.30 ( 95 % confidence interval , 0.19 - 0.47 ; P < .001 ) . Major 30-day treatment-related adverse events occurred in 5 of 57 patients ( 8.8 % ) treated with ADT and 5 of 103 patients ( 4.9 % ) treated with catheter ablation .  Mean quality of life scores improved significantly in patients treated by catheter ablation compared with ADT at 3 months ; improvement was maintained during the course of the study . CONCLUSION Among patients with paroxysmal AF who had not responded to at least 1 antiarrhythmic drug , the use of catheter ablation compared with ADT result ed in a longer time to treatment failure during the 9-month follow-up period . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00116428 BACKGROUND Current guidelines recommend pulmonary-vein isolation by means of catheter ablation as treatment for drug-refractory paroxysmal atrial fibrillation .  Radiofrequency ablation is the most common method , and cryoballoon ablation is the second most frequently used technology . METHODS We conducted a multicenter , r and omized trial to determine whether cryoballoon ablation was noninferior to radiofrequency ablation in symptomatic patients with drug-refractory paroxysmal atrial fibrillation . The primary efficacy end point in a time-to-event analysis was the first documented clinical failure ( recurrence of atrial fibrillation , occurrence of atrial flutter or atrial tachycardia , use of antiarrhythmic drugs , or repeat ablation ) following a 90-day period after the index ablation . The noninferiority margin was prespecified as a hazard ratio of 1.43 . The primary safety end point was a composite of death , cerebrovascular events , or serious treatment-related adverse events . RESULTS A total of 762 patients underwent r and omization ( 378 assigned to cryoballoon ablation and 384 assigned to radiofrequency ablation ) . The mean duration of follow-up was 1.5 years . The primary efficacy end point occurred in 138 patients in the cryoballoon group and in 143 in the radiofrequency group ( 1-year Kaplan-Meier event rate estimates , 34.6 % and 35.9 % , respectively ; hazard ratio , 0.96 ; 95 % confidence interval [ CI ] , 0.76 to 1.22 ; P<0.001 for noninferiority ) . The primary safety end point occurred in 40 patients in the cryoballoon group and in 51 patients in the radiofrequency group ( 1-year Kaplan-Meier event rate estimates , 10.2 % and 12.8 % , respectively ; hazard ratio , 0.78 ; 95 % CI , 0.52 to 1.18 ; P=0.24 ) . CONCLUSIONS In this r and omized trial , cryoballoon ablation was noninferior to radiofrequency ablation with respect to efficacy for the treatment of patients with drug-refractory paroxysmal atrial fibrillation , and there was no significant difference between the two methods with regard to overall safety . ( Funded by Medtronic ; FIRE AND ICE Clinical Trials.gov number , NCT01490814 . )
target: Conclusion Our systemic review and meta- analysis revealed further evidence that cryoballoon ablation is an equally effective alternative procedure to the st and ard radiofrequency treatment with a slightly , non-significant higher freedom from AF 1 year after the ablation and a shorter procedure time
background: Objective The aim of this study was to evaluate the clinical efficacy and safety outcomes of the treatment with cryoballoon ( CB ) compared to the treatment with traditional irrigated radiofrequency ablation ( RF ) for pulmonary vein isolation ( PVI ) in patients with paroxysmal atrial fibrillation ( pAF ) and refractory to antiarrhythmic drug therapy ( AAD ) .