Long-term Preservation of Left Ventricular Function and Heart Failure Incidence with Ablate and Pace Therapy Utilizing Biventricular Pacing

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1 The Journal of Innovations in Cardiac Rhythm Management, 3 (2012), HEART FAILURE RESEARCH ARTICLE Long-term Preservation of Left Ventricular Function and Heart Failure Incidence with Ablate and Pace Therapy Utilizing Biventricular Pacing 1,2 RAHUL N. DOSHI, MD, 1 NIKHIL GUPTA, BSc, 1 NATASHA DOSHI, 1 DANIEL LANDA, MD, 1 PAUL WEINSTEIN, MD, 1 DAVID WEINBERG, MD, 1 FRANK BONAVITA, MD and 1 CHRISTINA CASILLAS 1 Fullerton Cardiovascular Medical Group, Fullerton, CA 2 University of California Irvine, Irvine, CA ABSTRACT. Ablate and pace therapy has been utilized to improve symptoms in patients with symptomatic atrial fibrillation (AF) but requires dedicated ventricular pacing. Biventricular (BiV) pacing may eliminate the potential negative consequences of dedicated right ventricular (RV) pacing. We reviewed 245 patients who were considered at risk for congestive heart failure (CHF) with preserved left ventricular ejection fraction (LVEF) and underwent ablate and pace therapy with a BiV pacemaker. A total of 225 patients had follow-up greater than 1 year, and 175 patients had echocardiogram data prior to the procedure. Follow-up echocardiograms were obtained. Patients were assessed whether they were predominantly in sinus rhythm (SR) or AF. Patients were screened for CHF admissions during the follow-up period. All 245 patients had successful implantation without significant complications. The mean follow-up was months. LVEF remained preserved over the follow-up period (53 12% pre-ablation and 58 11% post ablation). Patients in SR showed a significant improvement in LVEF, whereas the mild improvement in patients in AF did not reach statistical significance. The 1-year survival rate of the total population at 1, 3, and 5 years is 97.4%, 87.6%, and 78.0%, respectively. The CHF hospitalization-free rates at 1, 3, and 5 years are 100%, 96.8%, and 92.7%, respectively. Ablate and pace therapy with BiV pacing results in long-term preservation in LVEF with a low incidence of heart failure in patients with preserved left ventricular function at risk for heart failure. A large-scale randomized clinical trial is warranted to determine if this approach should be widely utilized. KEYWORDS. ablate and pace, atrial fibrillation, biventricular pacing, heart failure. ISSN (print) ISSN (online) 2012 Innovations in Cardiac Rhythm Management Introduction Ablate and pace therapy have been demonstrated to effectively improve symptoms of atrial fibrillation (AF) and improve exercise tolerance. 1 Biventricular (BiV) pacing has been utilized to prevent the negative effects The authors report no conflicts of interest for the published content. Manuscript received August 11, 2012, final version accepted September 4, Address correspondence to: Rahul N. Doshi, MD, Fullerton Cardiovascular Medical Group, 2240 N. Harbor Blvd Suite 200, Fullerton, CA rdoshi@fullertonheart.com of committed pacing in this population. 2 4 The Left Ventricular-Based Cardiac Stimulation Post AV Nodal Ablation Evaluation (PAVE) study demonstrated that BiV pacing results in the preservation of left ventricular (LV) function in patients undergoing atrioventricular nodal (AVN) ablation when compared with right ventricular (RV) pacing at 6 months. 2 Similarly, the Ablate and Pace in Atrial Fibrillation (APAF) trial demonstrated in a population of 186 patients with symptomatic persistent AF that BiV pacing shows preservation of left ventricular ejection fraction (LVEF) over a longer follow-up with a mean duration of 20 The Journal of Innovations in Cardiac Rhythm Management, October

2 R N Doshi, N Gupta, N Doshi, et al. months. 3 However, roughly half the patients had severe LV dysfunction (mean LVEF 37%) requiring defibrillator therapy. 3 The Pacing to Avoid Cardiac Enlargement (PACE) study demonstrated that patients with preserved LV function and sinus rhythm (SR) had improved LV function with a BiV pacemaker compared with RV apical pacing at 1 year. 4 Thus, preservation of LVEF is seen in patients with SR or persistent AF who have dedicated ventricular pacing over 1 year and perhaps longer. Conversely, Zhang and colleagues 5 described patients with new RV apical pacing for complete heart block and preserved LV function having a high risk of congestive heart failure (CHF), especially elderly patients, those with coronary disease or myocardial infarction, AF, or a wide paced QRS complex. It is still controversial whether dedicated RV pacing in the ablate and pace population leads to deleterious effects and whether this population should instead receive a BiV pacemaker. Whether there is long-term (.1 year) preservation of LVEF in the normal LVEF population with AF and prior AVN ablation has not yet been demonstrated. It has been our practice to employ BiV pacing when performing ablate and pace therapy in our patients who are elderly and otherwise have demonstrated or are considered at risk for CHF, regardless of baseline LV function. We reviewed our patient population of ablate and pace therapy with BiV pacing and preserved LVEF to determine the long-term effects on LV function and incidence of heart failure admissions. Methods We performed a retrospective chart review of 245 patients who underwent ablate and pace therapy with BiV pacemaker implantation at our institution between July 2005 and December 2011 and had maintained follow-up in our pacemaker clinic. Patients had either paroxysmal or persistent AF and symptomatic palpitations, dyspnea, or precipitation of heart failure with Table 1: Baseline implant demographics (N5245) N (%) Age (years) 77 9 Male 154 (63) Prior CHF 64 ((26) HTN 101 (41) CAD 45 (18) Valve disease 39 (16) COPD 24 (10) DM 25 (10) Predominant rhythm Atrial fibrillation 128 (52) Sinus rhythm 117 (48) AAD drug use Amiodarone 61 (25) Other AAD 21 (8) Warfarin 156 (64) AAD: CAD: coronary artery disease; CHF: congestive heart failure; COPD: chronic obstructive pulmonary disease; DM: diabetes mellitus; HTN: Table 2: Implant results (N5245) N (%) Time implant (min) Time fluoroscopy (min) Complications Pneumothorax 0 (0) Hematoma 3 (1.2) Cardiac tamponade 0 (0) Lead dislodgement 3 (1.2) Infection 0 (0) Phrenic nerve stimulation 14 (5.7) (requiring revision) 0 (0) rapid AF. All patients had relatively preserved LV function (LVEF.45%) at the time of implantation and were considered high risk for developing heart failure (prior heart failure, hypertensive heart disease, coronary artery disease, valvular heart disease, diabetes mellitus, or age >75). 5 Patients were not excluded if they had prior catheter ablation for AF. Medical records were examined for heart failure symptoms/admissions and mortality. Patients were also contacted to determine whether they had been hospitalized for heart failure at another institution. Subjects were then screened for both continued follow-up and the presence of echocardiographic data prior to implantation. A total of 20 patients were lost to follow-up, leaving 225 patients for analysis. A total of 175 patients had echocardiographic data available prior to the procedure. A repeat echocardiogram was then obtained to complete the follow-up. Echocardiograms performed during the follow-up period were not included for analysis. Patients were also separated into predominantly SR (programmed in a DDDR mode) and persistent/permanent AF (programmed in a VVIR mode). Table 3: Patient demographics.1 year follow-up (N5175) N (%) Mean follow-up (months) 37 18* Age (years) 77 9* Male 109 (62)* Prior CHF 43 (25)* HTN 86 (49)* CAD 39 (22)* Valve disease 31 (18)* COPD 21 (12)* DM 20 (11)* Predominant rhythm Sinus rhythm 85 (49)* Atrial fibrillation 90 (51)* AAD drug use Amiodarone 46 (26)* Other AAD 15 (8.6)* Warfarin 126 (72)* AAD: CAD: coronary artery disease; CHF: congestive heart failure; COPD: chronic obstructive pulmonary disease; DM: diabetes mellitus; HTN: *P5NS compared to total implant group. 977 The Journal of Innovations in Cardiac Rhythm Management, October 2012

3 Preservation LVEF and CHF with Ablate and Pace and BiV Pacing Table 4: Predominant sinus rhythm versus atrial fibrillation SR group N585 (%) AF group N590 (%) Mean follow-up (months) Age (years) Male 57 (67) 52 (58) CHF 23 (27) 20 (22) HTN 40 (47) 46 (51) CAD 22 (26) 17 (19) Valve disease 15 (18) 16 (18) COPD 7 (8.2) 14 (16) DM 11 (15) 9 (10) AAD medications Amiodarone 29 (39) 17 (19)* Other AAD 11 (15) 4 (4.4) Warfarin 46 (61) 79 (88)* AAD: AF: atrial fibrillation; CAD: coronary artery disease; CHF: congestive heart failure; COPD: chronic obstructive pulmonary disease; DM: diabetes mellitus; HTN: SR: sinus rhythm. *p,0.05. All data were analyzed utilizing Microsoft Excel (Microsoft, Seattle, WA). Statistical comparisons were made using the Student s t-test (two tails, equal variance). Kaplan Meier survival and event-free estimates were generated on Microsoft Excel (Microsoft, Seattle, WA). Results The baseline patient characteristics of the 245 patients who underwent implantation with a BiV pacer with AVN ablation are shown in Table 1. The patients were elderly (mean age 77 9 years), and the majority were male (63%). The populations were fairly balanced between those in AF Figure 1: Left ventricular ejection fraction pre- and post atrioventricular nodal ablation, mean follow-up months, N5175. The Journal of Innovations in Cardiac Rhythm Management, October

4 R N Doshi, N Gupta, N Doshi, et al. Figure 2: Left ventricular ejection fraction pre- and post atrioventricular nodal ablation, sinus rhythm group (N585) versus atrial fibrillation group (N590). and predominantly SR (52% and 48%, respectively). Twenty-six percent of patients had prior heart failure. The most common comorbidity was hypertension (41%). The acute implant results are given in Table 2. All 245 patients were successfully implanted with a mean time of implantation of min. There were three lead dislodgements requiring lead revision during the same hospital stay (two atrial lead dislodgements, one LV lead dislodgement). The most frequent complication was phrenic nerve stimulation (5.7%), although no patients required lead revision and simply managed by programming changes. The patient demographics of the 175 patients with follow-up and echocardiographic data greater than 1 year are shown in Table 3. The mean follow-up was months. There were no significant differences from the original implant group (Table 1). A comparison between the group predominantly in SR (programmed in a DDDR mode) and the group in persistent/longstanding AF is shown in Table 4. There were no significant differences between the two groups in follow-up duration, age, sex, or comorbid disease. There was a significant difference in both the use of warfarin and the use of amiodarone between the groups in SR and AF (61% and 88%, respectively). Note that the antiarrhythmic drug use reflects usage at the time of implant. The echocardiographic LVEF pre- and post-ablation is shown in Figure 1. The mean LVEF prior to AVN ablation and implantation was 53 12%, and was 58 11% at the end of the follow-up period of months (p5not significant). A comparison of the pre- and post-ablation between the group in SR and AF is depicted in Figure 2. The group predominantly in SR had a mean LVEF prior to implantation of 51 12% and improved to 57 12% (p ). The AF group had a baseline mean LVEF of 56 12% and at follow-up an LVEF of 58 9, but this was not statistically significant (p50.14). Kaplan Meier survival estimates for the total population are graphically depicted in Figure 3. The 1-year survival rates at 1, 3, and 5 years are 97.4%, 87.6%, and 78.0%, respectively. The number of patients at the end of the follow-up period is quite low, with only 34 patients with 60 months of follow-up. In contrast to the significant mortality in this population, the CHF hospitalization-free estimates are shown in Figure 4. There were no CHF admissions during the first 12 months of follow-up, with a total of five admissions over the 60- month period. The event-free rates at 1, 3, and 5 years are 100%, 96.8%, and 92.7%, respectively. Discussion Our data support the use of BiV pacing when performing AVN ablation for symptomatic AF to preserve LV 979 The Journal of Innovations in Cardiac Rhythm Management, October 2012

5 Preservation LVEF and CHF with Ablate and Pace and BiV Pacing Figure 3: Kaplan Meier survival curve total population. function in patients with normal systolic function at baseline who are at risk of developing CHF 4 over a long (37 18 months) duration. Preservation of LV function is seen in patients predominantly in SR or in persistent AF. The acute implant results (Table 2) demonstrate that the procedure can be done safely and with a high initial success rate in an elderly population (mean age 77 years old) without major complications. Although our overall procedure times are short and complication rates low, the data are incomplete and do not demonstrate whether addition of an LV transvenous lead results in increased complications. There was one acute LV lead revision, and the most frequent complication of phrenic nerve stimulation did not require any surgical intervention. This likely represents the increased ability to reprogram pacing vectors in BiV pacemakers even when compared with BiV defibrillators, especially considering the ability to program unipolar pacing. Ablate and pace therapy has been demonstrated previously to cause improvements in both LVEF and exercise tolerance. 1 However, the data from the Ablate and Pace Trial was over a 1-year period. A meta-analysis from the same group demonstrated improved ejection fraction, symptoms, and exercise tolerance at 1 year with a similar mortality to medical therapy. 6 However, this may represent populations with significant improvement in ejection fraction related to tachycardia-mediated cardiomyopathy, and is reflective of short study duration. Previous studies have demonstrated a decrease in LVEF with RV-only pacing and AVN ablation. 7,8 The RV-only group in the PAVE study demonstrated a decrease in overall LVEF at 6 months, but the benefits were seen in patients with a lower baseline ejection fraction. 2 The results are similar in the APAF trial, again with a low baseline LVEF. 3 It is likely that the magnitude of the benefit is greater in the lower LVEF population, while the destabilizing effect of RV-only pacing takes a longer time period to manifest itself. It also seems likely that changes in echocardiographic parameters may be detectable earlier than hospitalizations for heart failure or mortality. The PACE study was able to demonstrate a lower LVEF with RV-only pacing than BiV pacing in patients with preserved LVEF and need for ventricular pacing at 1 year. 4 The high incidence (26%) of newly onset heart failure seen by Zhang et al 5 in patients with acquired AV block was seen over a follow-up period of 7.8 years. While our study cannot make any comparisons with an RV-pacing group, the data are supportive that the preservation of LVEF is maintained over a longer follow-up period. The patient group predominantly in SR showed a statistically significant improvement in LVEF at the end of the follow-up period, while the group in persistent AF showed only a modest improvement that did not reach statistical significance. The group in SR had a lower LVEF at baseline, with virtually identical LVEF in both groups at the end of the follow-up period. We would hypothesize The Journal of Innovations in Cardiac Rhythm Management, October

6 R N Doshi, N Gupta, N Doshi, et al. Study limitations This is a retrospective cohort study, and thus subject to potential bias. There was no control arm, thus not allowing any comparisons with conventional therapy. The data for mortality and CHF admissions were taken from chart review and patient interview, and thus could be incomplete and underestimate the true incidence. Figure 4: Kaplan Meier curve congestive heart failure admissions total population. that this reflects the acute destabilizing effects of paroxysmal AF in the SR population that underwent AVN ablation. Whether or not patients in SR have a greater potential benefit than patients in persistent AF cannot be determined given the potential for selection bias in this retrospective analysis. Based on these studies and others, one would expect a high incidence of heart failure with ablate and pace therapy and conventional RV-only pacing. Tan and colleagues 9 examined 121 patients undergoing ablate and pace therapy with RV-only pacing over a mean follow-up of years. They found a CHF hospitalization rate of 20% and mortality of 26% over the study period despite good control of symptoms. The data presented here compare favorably with a low CHF hospitalization rate over the study period of 7.3% over 5 years. However, the mortality rates are comparable (22% at 5 years), suggesting a different mode of death other than heart failure resulting in hospitalization. In our data set, we did see a high (42%) incidence of severe chronic obstructive pulmonary disease among patients who died during the study period, but we did not characterize modes of death nor was the study powered to make any conclusions. Despite the findings of prior studies of AVN ablation and RV-only pacing, it is still controversial whether or not patients have a clinically significant negative effect in this population. Chen and colleagues 10 have examined their database of patients with echocardiographic data greater than 1 year, and in 152 patients they found no significant decrease in LVEF. However, they did find on multivariate analysis that preserved LVEF was a predictor of decline in function, and the average follow-up period is shorter (20 months) than our study. Bradley and Shen 11 from the same group have reported in a meta-analysis of several trials of ablate and pace therapy, and conclude from their analysis that utilization of BiV pacing may improve results of patients undergoing this procedure, but underscore the lack of controlled randomized data. These reports and our study underscore the importance of a large-scale prospective randomized clinical trial to be performed to determine whether or not this therapy should be utilized in all patients. Conclusions Ablate and pace therapy with BiV pacing or cardiac resynchronization therapy in an elderly population at risk for CHF with symptomatic AF and preserved LV function results in long-term preservation of LV function and low incidence of heart failure hospitalization. A randomized prospective evaluation is warranted to demonstrate conclusively the superiority of this approach when compared with RV pacing or medical therapy long term. References 1. Kay GN, Ellenbogen KA, Giudici M, et al. APT Investigators. J Interv Card Electrophysiol 1998; 2: Doshi RN, Daoud EG, Fellows C, Turk K, Duran A, Hamdan M, Pires LA for the PAVE Study Group. left ventricular-based cardiac stimulation Post AV Nodal Ablation Evaluation (The PAVE Study). J Cardiovasc Electrophysiol 2005; 16: Brignole M, Botto G, Mont L, et al. Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial. Eur Heart J 2011; 32: Yu CM, Chan JYS, Zhang Q, et al. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med 2009; 361: Zhang XH, Chen H, Siu CW, et al. Apical pacing in patients with acquired high-grade atrioventricular block and normal left ventricular function. J Cardiovasc Electrophysiol, Feb 2008; 19: Wood MA, Mahoney-Brown C, Kay GN, and Ellenbogen KA. clinical outcomes after ablation and pacing therapy for atrial fibrillation: a meta-analysis. Circulation 2000; 101: Ozcan C, Jahangir A, Friedman PA, et al. Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation. N Engl J Med 2001; 344: Twidale N, Manda V, Nave K, Seal A. Predictors of outcome after radiofrequency catheter ablation of the atrioventricular node for atrial fibrillation and congestive heart failure. Am Heart J 1998; 136: Tan ES, Rienstra M, Wiesfeld A, Schoonderwoerd BA, Hobbel H, Van Gelder IC. Long-term outcome of the atrioventricular node ablation and pacemaker implantation for symptomatic refractory atrial fibrillation. Europace 2008; 10: Chen L, Hodge D, Jahangir A, et al. Preserved Left ventricular ejection fraction following atrioventricular junction and pacing for atrial fibrillation. J Cardiovasc Electrophysiol 2008; 19: Bradley D, Shen W. Atrioventricular junction ablation combined with either right ventricular pacing or cardiac resynchronization therapy for atrial fibrillation: the need for large-scale randomized trials. Heart Rhythm 2007; 4: The Journal of Innovations in Cardiac Rhythm Management, October 2012