Outcomes and complications of catheter ablation for atrial fibrillation in females

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1 Outcomes and complications of catheter ablation for atrial fibrillation in females Dimpi Patel, DO,* Prasant Mohanty, MBBS, MPH,* Luigi Di Biase, MD,* Javier E. Sanchez, MD,* Mazen H. Shaheen, MD, J. David Burkhardt, MD,* Mohammed Bassouni, MD, Jennifer Cummings, MD, Yan Wang, MD,* William R. Lewis, MD,** Alberto Diaz, MD,** Rodney P. Horton, MD,* Salwa Beheiry, RN, Richard Hongo, MD, G. Joseph Gallinghouse, MD,* Jason D. Zagrodzky, MD,* Shane M. Bailey, MD,* Amin Al-Ahmad, MD, Paul Wang, MD, Robert A. Schweikert, MD, FHRS, Andrea Natale, MD, FHRS* From the *St. David s Medical Center, Texas Cardiac Arrhythmia Institute, Austin, Texas, Department of Cardiology University of Foggia, Foggia, Italy, Department of Biomedical Engineering, University of Texas, Austin, Texas, University of Cincinnati, Cincinnati, Ohio, University of Cairo, Egypt, Akron General Hospital, Akron, Ohio, **Metro Health, Cleveland, Ohio, California Pacific Medical Center, San Francisco, California, and Stanford University, Palo Alto, California. BACKGROUND Most atrial fibrillation (AF) ablation studies have consisted predominantly of males; accordingly, there is a paucity of information on the safety and efficacy of catheter ablation in a large cohort of female AF patients. OBJECTIVE The purpose of this study was to evaluate catheter ablation for AF in female patients. METHODS From January 2005 to May 2008, 3265 females underwent pulmonary vein antrum isolation. Success rates, patient profiles, and complications were collected. RESULTS Approximately 16% of our population was female (P.001). Females were older (59 13 vs years; P.01) and had a lower prevalence of paroxysmal atrial fibrillation (PAF; 46% vs. 55%; P.001). Females failed more antiarrhythmics (4 1 vs. 2 3; P.04) and were referred later for catheter ablation ( vs years; P.02) than males. More females failed ablation (31.5% vs. 22.5%; P.001) and had nonantral sites of firing than males (P.001). Female patients had 11 (2.1%) hematomas versus 27 (0.9%) in males. CONCLUSIONS Five times as many males underwent catheter ablation than females. Females failed more ablations possibly because of a higher prevalence of nonantral firing, non-paf, and longer history of AF. Females had more bleeding complications than males. KEYWORDS Atrial fibrillation; Catheter ablation; Pulmonary vein isolation; Female; gender; Hematoma; Referral patterns; Nonantral firing ABBREVIATIONS AF atrial fibrillation; BMI body mass index; EF ejection fraction; LA left atrium; LSPAF longstanding persistent atrial fibrillation; PAF paroxysmal atrial fibrillation; PV pulmonary vein; PVAI pulmonary vein antrum isolation (Heart Rhythm 2010;7: ) 2010 Heart Rhythm Society. All rights reserved. Preliminary data were presented at the American College of Cardiology, which was held in Orlando, Florida, in March 29-31, J. David Burkhardt is a speaker for St. Jude Medical and Biosense Webster and Chief Medical Officer for Stereotaxis. Robert A. Schweikert is a consultant for Biosense Webster and a speaker for Medtronic, St. Jude Medical, Boston Scientific, Biosense Webster, and Reliant Pharmaceuticals. Andrea Natale is a speaker for St. Jude Medical, Boston Scientific, Medtronic, and Biosense Webster and a member of the Advisory Board for Stereotaxis and Biosense Webster. She also received a research grant from St. Jude Medical. Rodney Horton is on the Speakers Bureau for Hansen Medical, St. Jude Medical, Medtronic, Boston Scientific, and Biosense Webster. Javier E. Sanchez receives speaker fees from Boston Scientific, St. Jude Medical, and Biosense Webster. G. Joseph Gallinghouse is a consultant for St. Jude Medical and Hansen Medical. All other authors have no conflicts of interest. Address reprint requests and correspondence: Andrea Natale, M.D., Executive Medical Director of the Texas Cardiac Arrhythmia Institute, 1015 East 32d Street, Suite 506, Austin, Texas address: dr.natale@gmail.com. (Received July 24, 2009; accepted October 19, 2009.) Over the past decade, catheter ablation for the management of atrial fibrillation (AF) has evolved from a provisional therapy to one that many electrophysiologists routinely use. 1 The majority of AF ablation studies had predominantly consisted of males; accordingly, there is a paucity of information on the safety and efficacy of catheter ablation in a large cohort of female AF patients. While male gender is an independent risk factor for AF, so is increasing age. Since women tend to have longer life spans than men, the absolute number of men and women with AF is similar. 2 Moreover, in women, AF is often more symptomatic and is associated with greater cardiovascular mortality, a higher risk of thromboembolic stroke, and a poorer quality of life than in men. 3 Considering these issues, it becomes relevant to assess the safety and efficacy of pulmonary vein antrum isolation (PVAI) in women /$ -see front matter 2010 Heart Rhythm Society. All rights reserved. doi: /j.hrthm

2 168 Heart Rhythm, Vol 7, No 2, February 2010 The objective of this study was to (1) evaluate catheter ablation procedural success and complication rates between males and females patients and (2) to further investigate whether certain clinical characteristics predicted procedural failure in an all-female cohort. Methods Patient population We screened 3265 consecutive patients with highly symptomatic and drug-refractory AF who underwent ablation at Sutter Pacific Medical Center, San Francisco, California; Metro Health Case Western Reserve, Cleveland, Ohio; Stanford University, Palo Alto, California; Akron General Hospital, Akron, Ohio; and Texas Cardiac Arrhythmia Institute at St. David s Medical Center, Austin, Texas from January 2005 to May All female patients were selected from each center s AF ablation registry. Male patients served as a control population. This multicenter study was retrospective; however, the databases at each center were prospectively collected. This study has Institutional Review Board approval. Definitions AF was classified according to the 2007 expert consensus statement of the Heart Rhythm Society/Heart Rhythm Association/European Cardiac Arrhythmia Society on catheter and surgical ablation of AF. 4 AF was classified as paroxysmal AF (PAF), persistent AF, and long-standing persistent AF (LSPAF). The nonparoxysmal AF group was made up of all persistent AF and LSPAF cases. Survival status was found by using the National Death Registry and the Social Security Death Index. Procedural failure is defined as any episode of AF/atrial tachycardia without antiarrhythmic drugs that lasted longer than 1 minute after the first 8 weeks. Episodes occurring during the first 8 weeks (blanking period) after the procedure were not considered to be recurrences. Success rates were reported in terms of primary ablation at the participating centers. Extra pulmonary vein (PV) firing sites were defined as any sites of firing outside of the PV antrum before or after the administration of high-dose isoproterenol. Non-PV triggers were documented by the presence of firing leading to short bursts of tachycardia or AF after the completion of the basic procedure. Firing was mostly disclosed by administration of high-dose isoproterenol. Complications included stroke, PV stenosis/occlusion, atrioesophageal fistula, pericardial effusion, hematoma, and pseudoaneurysm. Ablation protocol Before ablation Antiarrhythmic drugs were discontinued four to five halflives before ablation. Patients on amiodarone discontinued the medication 5 6 months before ablation. Patients with persistent AF or LSPAF had a transesophageal echocardiography or were treated with warfarin for approximately 5 6 weeks before the procedure. Warfarin was stopped 2 3 days before the procedure and bridged with 0.5 mg/kg of low molecular weight heparin. In one center, patients who had procedures after June 2005 did not discontinue warfarin before the procedure, and the international normalized ratio was maintained between 2.0 and 3.0. Ablation procedure All patients underwent the ablation procedure using the same ablation strategy. We used a circular mapping catheter (Lasso, Biosense Webster, Diamond Bar, CA) and a 3.5-mm open-irrigation-tip catheter (ThermoCool, Biosense Webster) for ablation. Intracardiac echocardiography was used to image the anatomy of the PVs. In additional, an electroanatomical mapping system was used to confirm the distribution of scar. During ablation with the open-irrigation catheter, radiofrequency energy was delivered at 40 W for a maximum of 20 seconds at each site. At sites where the ablation tip was parallel to the wall of the left atrium (LA), the energy was increased to 45 W. Power was limited to 35 W on the posterior wall and for a maximum of 20 seconds per application. Energy delivery was discontinued when the esophageal temperature probe reached 39 C. If the temperature in the esophagus increased rapidly, the power was lowered to 30 W. The esophageal course was monitored with intracardiac echocardiography and with fluoroscopy through the esophageal probe. The height of the esophageal temperature probe was adjusted in relation to the position of the ablation catheter for a more accurate temperature monitoring. In patients with paroxysmal AF, the antrum of the PVs including the entire posterior wall between the PVs was isolated. In addition, the tissue anterior to the right PVs along the left septum was ablated. The endpoint was defined as elimination of all the PV potentials along the antra or inside the veins (entry block). Occasionally, exit block was also shown for some veins after isolation (dissociated firing). The superior vena cava along the ostium was also ablated if PV-like potentials were found around this region and when high-output pacing did not capture the phrenic nerve. 5 After ablation, all patients were administered highdose isoproterenol challenge (20 30 g/min) to ensure electrical disconnection or to locate extra non-pv firing sites that were not previously present. All sites that showing firing were ablated. 6,7 In patients with nonparoxysmal AF, the PV antrum and the superior vena cava were isolated. Ablation in the posterior wall was extended down to the coronary sinus, and the left side of the septum was ablated as well. In addition, the left and the right atrium (including the coronary sinus) were mapped to identify areas with fractionation. These areas were targeted until complete elimination of fractionated atrial electrograms. Fractionated electrograms were defined as atrial electrograms with fractionation and were composed of two deflections or more and/or had continuous activity of the baseline or atrial electrograms with a continuous cycle length 120 ms as described by Nademanee et al. 8 After

3 Patel et al PV Antrum Isolation in Females 169 ablation, high-dose isoproterenol challenge (20 30 g/min) was performed in all patients to ensure electrical disconnection or to locate extra non-pv firing sites that were not previously present. Non-PV firing sites were ablated with conventional activation mapping. Anticoagulation A heparin bolus ( U/kg) was given before transseptal punctures. The infusion rate was adjusted to keep the activated clotting time between 350 and 450 seconds. After PVAI, heparin was discontinued and IV protamine mg was given. Sheaths were pulled when the activated clotting time was 280 seconds. At the end of all procedures, patients were given oral 325 mg of aspirin before leaving the electrophysiology laboratory. Oral anticoagulation with warfarin was resumed on the same night of the procedure. A half dose of subcutaneous low molecular weight heparin was administered twice a day until the patient s international normalized ratio was therapeutic. Since 2005, one center has kept its patients on warfarin during the procedure. The other intuitions have kept their patients on warfarin during the procedure starting from June to September Follow-up All patients were discharged on oral anticoagulation therapy (warfarin). Follow-up was scheduled at 3, 6, 9, and 12 months after the procedure and every 6 months thereafter. If patients were unable to be seen, their status was assessed by a nurse practitioner via the telephone and monitoring tests were obtained by the referring physician. During the first 5 months after the ablation, cardiac event monitoring was used to assess AF recurrence. Patients were asked to transmit their rhythm status 3 times a day and when they experienced symptoms consistent with AF. In addition, 48-hour Holter monitoring was performed at 3, 6, 9, and 12 months and every 6 months thereafter. In June 2007, 48-hour Holter was replaced by 7-day Holter monitoring. Statistical analysis Continuous data were described as mean standard deviation and as counts and percent if categorical. Student s t-test, one-way analysis of variance, 2 -test, and Fisher s exact test were used to compare differences across AF types. Multivariate Cox regression was used for identifying significant predictors of AF recurrence while controlling for clinically relevant covariates. All potential confounders were entered into the model based on known or expected clinical relevance, regardless of their statistical significance. The controlling variables used in the model were age, preprocedure left ventricular ejection fraction (EF), LA size, hypertension, diabetes, coronary artery disease, non-pv trigger, and type of AF. For the purpose of analysis, age was dichotomized into 55 and 50 years, and left ventricular EF and LA size were categorized into 50 and 40 mm, respectively. Tests were run to examine the presence of any significant interactions and to identify possible multicollinearity of the covariates. The hazard ratio (HR) and 95% confidence interval (CI) of AF recurrence were computed. Recurrence-free survival over time was calculated by Kaplan-Meier method. All tests were two-sided, and P.05 was considered statistically significant. Analysis was performed using SAS 9.2 (SAS Institute Inc., Cary, NC). Results Patient characteristics Females made up 15.8% of the population (P.001). The number of females who underwent catheter ablation during the observation period steadily increased from 105 in 2005 to 148 in 2008 (Figure 1). Females were older and had a higher incidence of prior stroke and LSPAF and a lower incidence of diabetes type II and coronary artery disease than males. Female had more non-pv sites of firing than males (261 [50.4%] vs. 449 [16.3%]; P.001]. Females had failed more antiarrhythmic agents and were referred later for catheter ablation than males (Table 1). Ablation success and complication rates After months of follow-up, females had lower success rates than males (68.5% vs. 77.5% P.001). Kaplan-Meier survival estimates for freedom from AF/atrial tachycardia after ablation are shown in Figure 2. Cox regression demonstrated that in female patients, higher body mass index (BMI), non-paf, and non-pv triggers predicted procedural failure. Females with non-paf or non-pv triggers were twice as likely to fail catheter ablation (Table 2). Females had more hematomas (2.1% vs. 0.9%; P.026) and pseudoaneurysms (0.6% vs. 0.1%; P.031) than males (Table 3). Adjusted Cox regression showed that type of AF (non-paf), BMI ( 30), and diabetes type II predicted complications in an all-female cohort (Table 4). Five (0.96%) females died over the course of the study period. None of the patients died due to complications associated with catheter ablation. Discussion Main findings To the best of our knowledge, this is the largest multicenter study to date that has reported the safety and efficacy of catheter ablation for AF in female patients. The main findings of this study were that (1) significantly fewer females than males had undergone catheter ablation in our experi- Figure 1 The yearly prevalence of females who underwent catheter ablation over the course of this study.

4 170 Heart Rhythm, Vol 7, No 2, February 2010 Table 1 Patient characteristics (n 3265) Female Male P No. of subjects, n (%) 518 (15.8) 2747 (84.2).001 a Age, years a BMI, kg/m Comorbidities, n (%): Diabetes type II 57 (11) 414 (15).016 a Hypertension 286 (55.2) 1100 (40).001 a Coronary artery disease 36 (7) 312 (11.3).003 a Stroke 20 (3.8) 45 (1.6).001 a Type of AF, n (%): Paroxysmal 237 (46) 1506 (55).001 a Persistent atrial 140 (28) 692 (25).379 Long-standing persistent 141 (27) 549 (20).001 a Echo parameters: Preprocedure EF, % a Preprocedure LA, cm a No. of failed antiarrhythmic drugs a Time from diagnosis to catheter ablation referral, years a Follow-up period, in months ence; (2) females who had undergone catheter ablation tended to be older, had a higher prevalence of non-paf, had failed more antiarrhythmic agents, and were referred later than males; (3) females failed ablation more often; (4) higher BMI, extra non-pv triggers, and type of AF predicted procedural failure in our female cohort; (5) females who had undergone catheter ablation had significantly more non-pv firing sites than males; and (6) female patients had significantly higher bleeding complications. Referral patterns in women undergoing catheter ablation of AF Over 5 times more males than females have undergone AF ablation in this retrospective multicenter study. Previous studies have also reported gender disparities in the use of innovative or costly cardiovascular technologies. Women have been under-referred for implantable cardioverter-defibrillator implantation, coronary artery bypass graft surgery, and cardiovascular diagnostic testing In our study, females were referred for catheter ablation after having failed more antiarrhythmic agents and after a longer period of time from diagnosis of AF to catheter ablation than males. Dagres et al 14 also reported that women were referred for atrioventricular node reentrant tachycardia ablation later than males, after a longer duration of symptoms, and after having failed more antiarrhythmic drugs. Forleo et al 15 reported that in a multicenter study, in which 71 females underwent catheter ablation, the mean time of AF before ablation was 60 months in females versus 47 months in males, and while females had a slightly higher number of failed antiarrhythmic agents, it was not statistically significant. We reported a longer interval from diagnosis of AF to ablation and a larger number of failed antiarrhythmic agents than Forleo et al; however, these differences in findings Table 2 AF Multivariate Cox regression analysis for recurrence of Figure 2 Kaplan-Meier survival curve showing freedom from AF over the follow-up period of the study. Predictors of failure HR Lower 95% CI Upper 95% CI P Age Diabetes type II Hypertension BMI a Coronary artery disease EF 50% LA size 40 mm AF type (non-paf) a Non-PV triggers a Note: Non-PV triggers are triggers located outside of the PV antrum.

5 Patel et al PV Antrum Isolation in Females 171 could possibly be due to differences in health care practices. 15 Prior studies have also reported that once women are diagnosed with AF, they are often treated less aggressively than male patients. The reason why fewer female patients are referred for catheter ablation of AF and after a longer time interval than male patients is not completely apparent. It is possible that females tend to complain less and therefore are less likely to be considered for an invasive procedure. Other explanations may include that female patients are more reluctant to undergo an invasive procedure, physician gender bias referral, and child care issues. Clinical profile of female patients undergoing catheter ablation for AF Forleo et al 15 also reported that female patients undergoing AF catheter ablation were older and had a higher prevalence of diabetes, hypertension, and coronary artery disease and dilated cardiomyopathy than males. In our study, females patients were older and had a higher prevalence of stroke and hypertension than the male patients. Predictors for procedural failure Forleo et al reported that males and females had similar AF catheter ablation recurrence rates. However, their study only included 77 females. This discrepancy in success rates in our study can be attributed to the larger number nonparoxysmal cases in our female population. In this respect, LSPAF and persistent AF are more difficult to treat irrespective of gender. Moreover, female patients were substantially more likely to have extra non-pv antral triggers, which can be more challenging to treat effectively. As previously shown, age did not predict failure On the other hand, LSPAF and extra non-pv antrum triggers predicted failure in our study. Table 3 Incidence of complications secondary to ablation in females and males Females (n 518) Males (n 2747) P Complications, n (%): 26 (5) 66 (2.4).001 a Hematoma 11 (2.1) 27 (0.9).026 a Moderate to severe 6 (1.2) 12 (0.4).053 PV stenosis Stroke 4 (0.8) 17 (0.6).762 Pericardial effusion 2 (0.4) 8 (0.29).665 Pseudoaneurysm 3 (0.6) 2 (0.1).031 a Table 4 Adjusted multivariate Cox proportional hazards regression showing predictors of complications in females Predictors of complications in females PVAI complications in women In our study, females patients tended to have more cases of hematoma and pseudoaneurysm. When multivariate analysis was performed, higher BMI was found to be a predictor for bleeding complications. However, obesity was not limited to female patients alone. Additionally, there was no statistical difference in BMI between the male and female populations. Another possible cause of the larger number of hematomas in female patients can be attributed to anatomical variations in the relationship of the femoral vein to the artery. In females, the femoral artery and circumflex branches run very close and often overlap the femoral vein, increasing the risk of inadvertent arterial puncture. 19,20 Limitations (1) Our study is retrospective in nature and is thereby subject to all the limitations inherent to this study design. However, all data was prospectively collected. (2) Transient recurrence of AF may be undetected if it occurred during a period in which patients were not monitored. Conclusion Over 5 times more males than females had undergone AF ablation in our catheter ablation experience. Overall, females had lower procedural success rates and higher risk of bleeding complications than their male counterparts. 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