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Pulmonary Vein Isolation to Reduce Future Risk of Atrial Fibrillation in Patients Undergoing Typical Flutter Ablation: Results from a Randomized Pilot Study (REDUCE AF) SANGHAMITRA MOHANTY, M.D., M.S., F.H.R.S.,∗ ANDREA NATALE, M.D., F.E.S.C., F.H.R.S., F.A.C.C.,∗ ,†,‡ PRASANT MOHANTY, M.B.B.S., M.P.H.,∗ LUIGI DI BIASE, M.D., Ph.D., F.H.R.S., F.A.H.A.,∗ ,§ CHINTAN TRIVEDI, M.D., M.P.H.,∗ PASQUALE SANTANGELI, M.D.,¶ RONG BAI, M.D., F.H.R.S.,∗ J. DAVID BURKHARDT, M.D.,∗ G. JOSEPH GALLINGHOUSE, M.D.,∗ RODNEY HORTON, M.D.,∗ JAVIER E. SANCHEZ, M.D.,∗ PATRICK M. HRANITZKY, M.D.,∗ AMIN AL-AHMAD, M.D., STEVEN HAO, M.D.,‡ RICHARD HONGO, M.D.,‡ SALWA BEHEIRY, R.N.,‡ GEMMA PELARGONIO, M.D.,# GIOVANNI FORLEO, M.D.,∗ ANTONIO ROSSILLO, M.D.,∗∗ SAKIS THEMISTOCLAKIS, M.D.,∗∗ MICHELA CASELLA, M.D.,∗∗∗ ANTONIO DELLO RUSSO, M.D.,∗∗∗ CLAUDIO TONDO, M.D.,∗∗∗ and SANJAY DIXIT, M.D.¶ From the ∗ Texas Cardiac Arrhythmia Institute, St. David’s Medical Center, Austin, Texas, USA; †Department of Internal Medicine, Dell Medical School, Austin, Texas, USA; ‡California Pacific Medical Center, San Francisco, California, USA; §Albert Einstein College of Medicine at Montefiore Hospital, New York, USA; ¶University of Pennsylvania, Pennsylvania, USA; #Catholic University, Rome, Italy; Univ Tor Vergata, Rome, Italy; ∗∗ Ospedale dell’Angelo, Mestre /Venice, Italy; and ∗∗∗ RCCS Monzino Hospital, Milan, Italy
Benefits of PVI in Patients with Atrial Flutter. Background: This study examined incidence of AF following cavotricuspid isthmus (CTI) ablation alone or CTI plus prophylactic pulmonary vein isolation (PVI) in patients presenting with isolated atrial flutter (AFL) with no history of AF. Methods and Results: We enrolled 216 patients with isolated typical atrial flutter and randomized them to CTI alone (group 1, n = 108, 61.2 ± 9.7 year, 75% male) or CTI+PVI ablation (group 2, n = 108, 62.4 ± 9.3 year, 73% male). Insertible loop recorder (ILR) was implanted in 21 and 19 patients from groups 1 and 2, respectively. Remaining patients were monitored with event recorders, ECG, 7-day Holter. Follow-up period was for 18 ± 6 months. Compared to group 1, group 2 had significantly longer procedural duration (75.9 ± 33 min vs. 161 ± 48 min [P < 0.001]) and fluoroscopy time (15.9 ± 12.3 min vs. 56.4+21 min [P < 0.001]). At the end of follow-up, 65 (60.2%) in group 1 and 77 (71.3%) in group 2 were arrhythmia free off-AAD (log-rank P = 0.044). A subgroup analysis was performed with 55 year age cut-off. In the 85%2,4 for long-term arrhythmia control. However, despite the high success rate of CTI ablation for controlling AFL, these patients remain at risk of developing atrial fibrillation (AF), the incidence of which has been reported to be as high as 50%.5-7 The mechanism responsible for the development of AF after ablation of AFL is unclear.5 Evidence suggests that both arrhythmias may share the same electrophysiologic triggers7 doi: 10.1111/jce.12688
820
Journal of Cardiovascular Electrophysiology
Vol. 26, No. 8, August 2015
and anatomic substrate.2 In addition, the 2 arrhythmias also have common predictive factors such as hypertension, heart failure, and pulmonary disease.8 The emergence of AF despite elimination of AFL has several possible consequences, the most significant being the heightened risk of stroke.9 Therefore, pursuing a strategy that decreases the future occurrence of AF in patients undergoing AFL ablation is worthwhile. It has been reproducibly shown that ࣙ90% of the triggers for paroxysmal AF originate in and around the pulmonary veins (PVs); and in these subjects, PV isolation (PVI) alone can result in ࣙ70% long-term AF control.10 Thus, the best ablation strategy to reduce the long-term occurrence of AF in patients presenting with typical AFL may be CTI ablation combined with PVI. We, therefore, conducted a prospective randomized study to assess the benefit of prophylactic PVI to reduce future risk of AF in patients with AFL undergoing CTI ablation (REDUCE AF). We hypothesized that in patients with AFL, a combination of CTI ablation and PVI should be more efficacious than CTI ablation alone in reducing long-term occurrence of AF. Methods Study Design This was an open-label, randomized, study conducted at multiple centers assessing the benefit of prophylactic PVI+CTI over CTI only in patients with typical flutter. Patients were considered eligible for the trial if they met the following inclusion criteria: (1) diagnosis of typical AFL confirmed by 12-lead ECG, (2) no documented AF on ECG at any time, and (3) undergoing radiofrequency catheter ablation for AFL. Patients with known AF episodes, prior ablation procedures, inability to take oral anticoagulants for any reason, and failure to provide informed consent were excluded from the study. Patients were screened after being referred for ablation therapy and included in the trial only if they provided signed informed consent. Prior recorded electrocardiograms were reviewed to confirm diagnosis of isolated typical AFL. Counter clockwise AFL, the most common typical AFL, is defined as negative saw-tooth flutter waves in electrocardiogram leads II, III, and aVF with a constant beat-to-beat cycle length at approximately 300 beats per minute.7 Consenting eligible subjects were randomly assigned (1:1 ratio) to receive CTI ablation alone (group 1) or combined CTI ablation +PVI (group 2). The primary study endpoint was freedom from atrial arrhythmias (AF, organized atrial tachyarrhythmias—OATs or AFL) during the 1-year follow-up period beginning after the 12-week blanking period postablation. Any episode of AF/OAT/AFL longer than 30 seconds in the absence of antiarrhythmic drugs (AAD) at follow-up was considered as recurrence. Episodes that occurred during the first 12 weeks (blanking period) after the procedure were not considered as recurrences.11 Since the trial was conducted as a pilot study and its purpose was to assess the feasibility of recruiting eligible patient, we did not estimate a sample size. Instead, we specified a 2year period for enrolling subjects. Also, since AF seems to be uncommon in patients younger than 55 years and prevalence of AF is known to steadily increase with advancing age, especially over 55 years,12-15 we performed an exploratory analysis post-hoc to assess the effect of the 2 strategies on 2 different age groups using a cut-off at 55 years.
The study was approved by Institutional Review Boards of participating centers and registered at clinicaltrials.gov (NCT01710150). Randomization Procedure A central randomization process was implemented to allocate an equal number of patients to each ablation strategy. A computer algorithm written in SAS (Cary, NC, USA) was used for performing block randomization. The SAS program generated 10 randomized block allocations for each study site. More blocks than necessary were created for any possible over-enrollment by a given investigator. Ablation Procedure Our approach to PVI for AF and CTI ablation for AFL has been previously described.7,11,16-18 General anesthesia was used for patients allocated to PVI+CTI and conscious sedation was used for patients undergoing CTI-only. Antiarrhythmic drugs (AAD) were discontinued 5 half-lives before the ablation. Brief Summary of the Ablation Procedures Periprocedural anti-coagulation management Standard peri-procedural anticoagulation protocol was followed for all patients. The international normalized ratio (INR) was monitored every week for 4 weeks preceding the procedure to ascertain therapeutic level (>2.0). No transesophageal echocardiography (TEE) was performed if the INR was therapeutic in the preceding 4 weeks and on the day of ablation. Before transseptal punctures, a heparin bolus (100-150 U/kg) was administered. During the procedure, the activated clotting time was kept above 300 seconds. At the end of the procedure, the heparin infusion was discontinued, and anticoagulation was reversed with protamine. Sheaths were pulled when the activated clotting time (ACT) was
Pulmonary Vein Isolation to Reduce Future Risk of Atrial Fibrillation in Patients Undergoing Typical Flutter Ablation: Results from a Randomized Pilot Study (REDUCE AF) SANGHAMITRA MOHANTY, M.D., M.S., F.H.R.S.,∗ ANDREA NATALE, M.D., F.E.S.C., F.H.R.S., F.A.C.C.,∗ ,†,‡ PRASANT MOHANTY, M.B.B.S., M.P.H.,∗ LUIGI DI BIASE, M.D., Ph.D., F.H.R.S., F.A.H.A.,∗ ,§ CHINTAN TRIVEDI, M.D., M.P.H.,∗ PASQUALE SANTANGELI, M.D.,¶ RONG BAI, M.D., F.H.R.S.,∗ J. DAVID BURKHARDT, M.D.,∗ G. JOSEPH GALLINGHOUSE, M.D.,∗ RODNEY HORTON, M.D.,∗ JAVIER E. SANCHEZ, M.D.,∗ PATRICK M. HRANITZKY, M.D.,∗ AMIN AL-AHMAD, M.D., STEVEN HAO, M.D.,‡ RICHARD HONGO, M.D.,‡ SALWA BEHEIRY, R.N.,‡ GEMMA PELARGONIO, M.D.,# GIOVANNI FORLEO, M.D.,∗ ANTONIO ROSSILLO, M.D.,∗∗ SAKIS THEMISTOCLAKIS, M.D.,∗∗ MICHELA CASELLA, M.D.,∗∗∗ ANTONIO DELLO RUSSO, M.D.,∗∗∗ CLAUDIO TONDO, M.D.,∗∗∗ and SANJAY DIXIT, M.D.¶ From the ∗ Texas Cardiac Arrhythmia Institute, St. David’s Medical Center, Austin, Texas, USA; †Department of Internal Medicine, Dell Medical School, Austin, Texas, USA; ‡California Pacific Medical Center, San Francisco, California, USA; §Albert Einstein College of Medicine at Montefiore Hospital, New York, USA; ¶University of Pennsylvania, Pennsylvania, USA; #Catholic University, Rome, Italy; Univ Tor Vergata, Rome, Italy; ∗∗ Ospedale dell’Angelo, Mestre /Venice, Italy; and ∗∗∗ RCCS Monzino Hospital, Milan, Italy
Benefits of PVI in Patients with Atrial Flutter. Background: This study examined incidence of AF following cavotricuspid isthmus (CTI) ablation alone or CTI plus prophylactic pulmonary vein isolation (PVI) in patients presenting with isolated atrial flutter (AFL) with no history of AF. Methods and Results: We enrolled 216 patients with isolated typical atrial flutter and randomized them to CTI alone (group 1, n = 108, 61.2 ± 9.7 year, 75% male) or CTI+PVI ablation (group 2, n = 108, 62.4 ± 9.3 year, 73% male). Insertible loop recorder (ILR) was implanted in 21 and 19 patients from groups 1 and 2, respectively. Remaining patients were monitored with event recorders, ECG, 7-day Holter. Follow-up period was for 18 ± 6 months. Compared to group 1, group 2 had significantly longer procedural duration (75.9 ± 33 min vs. 161 ± 48 min [P < 0.001]) and fluoroscopy time (15.9 ± 12.3 min vs. 56.4+21 min [P < 0.001]). At the end of follow-up, 65 (60.2%) in group 1 and 77 (71.3%) in group 2 were arrhythmia free off-AAD (log-rank P = 0.044). A subgroup analysis was performed with 55 year age cut-off. In the 85%2,4 for long-term arrhythmia control. However, despite the high success rate of CTI ablation for controlling AFL, these patients remain at risk of developing atrial fibrillation (AF), the incidence of which has been reported to be as high as 50%.5-7 The mechanism responsible for the development of AF after ablation of AFL is unclear.5 Evidence suggests that both arrhythmias may share the same electrophysiologic triggers7 doi: 10.1111/jce.12688
820
Journal of Cardiovascular Electrophysiology
Vol. 26, No. 8, August 2015
and anatomic substrate.2 In addition, the 2 arrhythmias also have common predictive factors such as hypertension, heart failure, and pulmonary disease.8 The emergence of AF despite elimination of AFL has several possible consequences, the most significant being the heightened risk of stroke.9 Therefore, pursuing a strategy that decreases the future occurrence of AF in patients undergoing AFL ablation is worthwhile. It has been reproducibly shown that ࣙ90% of the triggers for paroxysmal AF originate in and around the pulmonary veins (PVs); and in these subjects, PV isolation (PVI) alone can result in ࣙ70% long-term AF control.10 Thus, the best ablation strategy to reduce the long-term occurrence of AF in patients presenting with typical AFL may be CTI ablation combined with PVI. We, therefore, conducted a prospective randomized study to assess the benefit of prophylactic PVI to reduce future risk of AF in patients with AFL undergoing CTI ablation (REDUCE AF). We hypothesized that in patients with AFL, a combination of CTI ablation and PVI should be more efficacious than CTI ablation alone in reducing long-term occurrence of AF. Methods Study Design This was an open-label, randomized, study conducted at multiple centers assessing the benefit of prophylactic PVI+CTI over CTI only in patients with typical flutter. Patients were considered eligible for the trial if they met the following inclusion criteria: (1) diagnosis of typical AFL confirmed by 12-lead ECG, (2) no documented AF on ECG at any time, and (3) undergoing radiofrequency catheter ablation for AFL. Patients with known AF episodes, prior ablation procedures, inability to take oral anticoagulants for any reason, and failure to provide informed consent were excluded from the study. Patients were screened after being referred for ablation therapy and included in the trial only if they provided signed informed consent. Prior recorded electrocardiograms were reviewed to confirm diagnosis of isolated typical AFL. Counter clockwise AFL, the most common typical AFL, is defined as negative saw-tooth flutter waves in electrocardiogram leads II, III, and aVF with a constant beat-to-beat cycle length at approximately 300 beats per minute.7 Consenting eligible subjects were randomly assigned (1:1 ratio) to receive CTI ablation alone (group 1) or combined CTI ablation +PVI (group 2). The primary study endpoint was freedom from atrial arrhythmias (AF, organized atrial tachyarrhythmias—OATs or AFL) during the 1-year follow-up period beginning after the 12-week blanking period postablation. Any episode of AF/OAT/AFL longer than 30 seconds in the absence of antiarrhythmic drugs (AAD) at follow-up was considered as recurrence. Episodes that occurred during the first 12 weeks (blanking period) after the procedure were not considered as recurrences.11 Since the trial was conducted as a pilot study and its purpose was to assess the feasibility of recruiting eligible patient, we did not estimate a sample size. Instead, we specified a 2year period for enrolling subjects. Also, since AF seems to be uncommon in patients younger than 55 years and prevalence of AF is known to steadily increase with advancing age, especially over 55 years,12-15 we performed an exploratory analysis post-hoc to assess the effect of the 2 strategies on 2 different age groups using a cut-off at 55 years.
The study was approved by Institutional Review Boards of participating centers and registered at clinicaltrials.gov (NCT01710150). Randomization Procedure A central randomization process was implemented to allocate an equal number of patients to each ablation strategy. A computer algorithm written in SAS (Cary, NC, USA) was used for performing block randomization. The SAS program generated 10 randomized block allocations for each study site. More blocks than necessary were created for any possible over-enrollment by a given investigator. Ablation Procedure Our approach to PVI for AF and CTI ablation for AFL has been previously described.7,11,16-18 General anesthesia was used for patients allocated to PVI+CTI and conscious sedation was used for patients undergoing CTI-only. Antiarrhythmic drugs (AAD) were discontinued 5 half-lives before the ablation. Brief Summary of the Ablation Procedures Periprocedural anti-coagulation management Standard peri-procedural anticoagulation protocol was followed for all patients. The international normalized ratio (INR) was monitored every week for 4 weeks preceding the procedure to ascertain therapeutic level (>2.0). No transesophageal echocardiography (TEE) was performed if the INR was therapeutic in the preceding 4 weeks and on the day of ablation. Before transseptal punctures, a heparin bolus (100-150 U/kg) was administered. During the procedure, the activated clotting time was kept above 300 seconds. At the end of the procedure, the heparin infusion was discontinued, and anticoagulation was reversed with protamine. Sheaths were pulled when the activated clotting time (ACT) was
