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Atrioventricular nodal ablation predicts survival benefit in patients with atrial fibrillation receiving cardiac resynchronization therapy
Atrioventricular nodal ablation predicts survival benefit in patients with atrial fibrillation receiving cardiac resynchronization therapy Kan Dong, MD,‡ Win-Kuang Shen, MD, FHRS,* Brian D. Powell, MD,* Ying-Xu Dong, MD, PhD,¶ Robert F. Rea, MD,* Paul A. Friedman, MD, FHRS,* David O. Hodge, MS,† Heather J. Wiste, BA,† Tracy Webster, RN,* David L. Hayes, MD, FHRS,* Yong-Mei Cha, MD* From the *Division of Cardiovascular Diseases and †Division of Biomedical Statistics and Informatics), Mayo Clinic, Rochester, Minnesota, ‡Department of Cardiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, and ¶Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China. BACKGROUND Cardiac resynchronization therapy (CRT) benefits patients with advanced heart failure. The role of atrioventricular nodal (AVN) ablation in improving CRT outcomes, including survival benefit in CRT recipients with atrial fibrillation, is uncertain. OBJECTIVE The purpose of this study was to assess the impact of AVN ablation on clinical and survival outcomes in a large atrial fibrillation and heart failure population that met the current indication for CRT and to determine whether AVN ablation is an independent predictor of survival in CRT recipients. METHODS Of 154 patients with atrial fibrillation who received CRT-D, 45 (29%) underwent AVN ablation (⫹AVN-ABL group), whereas 109 (71%) received drug therapy for rate control during CRT (⫺AVN-ABL group). New York Heart Association (NYHA) class, electrocardiogram, and echocardiogram were assessed before and after CRT. Survival data were obtained from the national death and location database (Accurint). RESULTS CRT comparably improved left ventricular ejection fraction (8.1% ⫾ 10.7% vs 6.8% ⫾ 9.6%, P ⫽ .49) and left ventricular end-diastolic diameter (⫺2.1 ⫾ 5.9 mm vs ⫺2.1 ⫾ 6.7 mm, P ⫽ .74) in both ⫹AVN-ABL and ⫺AVN-ABL groups. Improvement in NYHA class was significantly greater in the ⫹AVN-ABL group than in ⫺AVN-ABL group (⫺0.7 ⫾ 0.8 vs ⫺0.4 ⫾ 0.8, P ⫽ .04). Survival estimates at 2 years were 96.0% (95% confidence interval
Introduction In clinical trials, cardiac resynchronization therapy (CRT) has been associated with improvement in heart failure (HF) symptoms, effort tolerance, cardiac function, and structural remodeling in patients with New York Heart Association (NYHA) functional class III or IV HF with wide QRS complex.1– 4 Atrial fibrillation (AF) occurs frequently in patients with HF; its prevalence parallels the severity of HF, from 10% in NYHA class II up to 50% in NYHA class IV.5
Address reprint requests and correspondence: Dr. Yong-Mei Cha, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail address: [email protected]. (Received June 17, 2009; accepted February 5, 2010.)
[CI] 88.6%–100%) for ⫹AVN-ABL group and 76.5% (95% CI 68.1%– 85.8%) for–AVN-ABL group (P ⫽ .008). AVN ablation was independently associated with survival benefit from death (hazard ratio [HR] 0.13, 95% CI 0.03– 0.58, P ⫽ .007) and from combined death, heart transplant, and left ventricular assist device (HR 0.19, 95% CI 0.06 – 0.62, P ⫽ .006) after CRT. CONCLUSION Among patients with atrial fibrillation and heart failure receiving CRT, AVN ablation for definitive biventricular pacing provides greater improvement in NYHA class and survival benefit. Larger-scale randomized trials are needed to assess the clinical and survival outcomes of this therapy. KEYWORDS Atrial fibrillation; Atrioventricular nodal ablation; Cardiac resynchronization therapy; Heart failure ABBREVIATIONS ABL ⫽ ablation; AF ⫽ atrial fibrillation; AVN ⫽ atrioventricular node; CI ⫽ confidence interval; CRT ⫽ cardiac resynchronization therapy; HF ⫽ heart failure; HR ⫽ hazard ratio; LV ⫽ left ventricular; LVEDD ⫽ left ventricular end-diastolic dimension; LVEF ⫽ left ventricular ejection fraction; LVESD ⫽ left ventricular endsystolic dimension; MR ⫽ mitral regurgitation; NYHA ⫽ New York Heart Association (Heart Rhythm 2010;7:1240–1245) © 2010 Heart Rhythm Society. All rights reserved.
Although the outcome of CRT in patients with AF is limited (majority of CRT trials excluded patients with AF), prospective studies and meta-analysis confer a comparable clinical benefit in patients with AF and sinus rhythm.6 –12 As a result, CRT for AF patients is considered a class IIA indication in the most recent guidelines for implantation of cardiac pacemakers and antiarrhythmic devices.13 However, an important question pertaining to this AF and HF population (approximately one third of CRT recipients) that has been inadequately addressed is the necessity of atrioventricular nodal (AVN) ablation. AVN ablation ensures a high percentage of resynchronized QRS complexes in order to deliver a high dose of therapy and attenuate cardiac output impairment due to R-R interval variability. The results from several studies
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doi:10.1016/j.hrthm.2010.02.011
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of a small number of AF patients with AVN ablation were inconsistent.9 –11 Results from the largest AVN ablation group showed that only patients who underwent AVN ablation with 100% CRT delivery responded to CRT.7 The objective of this study was to assess the impact of AVN ablation on clinical and survival outcomes in a large AF and HF population that met the current indication for CRT and to determine whether AVN ablation is an independent predictor of survival in CRT recipients.
Methods Patient population Of 502 CRT recipients at Mayo Clinic from January 1, 2002 to December 31, 2006, 172 (34%) patients received CRT with (CRT-D, n ⫽ 154 [90%]) or without (CRT-P, n ⫽ 18 [10%]) concomitant defibrillator in the setting of AF, including patients undergoing upgrade of a conventional pacemaker or defibrillator to CRT. Indications for CRT were HF symptoms despite optimal medical therapy, left ventricular ejection fraction (LVEF) ⬍35%, and QRS duration ⱖ120 ms. To minimize selection bias and unify the patient population, the study cohort included only the 154 patients who received CRT-D. Of these patients, 109 (71%) received medical therapy for ventricular rate control (⫺AVNABL group), whereas the other 45 (29%) patients underwent AVN ablation to ensure biventricular resynchronization (⫹AVN-ABL group). Clinical information, including NYHA class, HF etiology, and laboratory data pre- and post-CRT documented as part of routine clinical care, were collected. Clinical and survival outcomes were assessed in the ⫹AVN-ABL and –AVN-ABL groups. The study was approved by the Mayo Clinic Institutional Review Board, and all patients who consented to use of their records for research were included.
Twelve-lead ECG and 24-hour Holter monitoring Baseline 12-lead ECGs were obtained for each patient to assess QRS duration and resting heart rate. Twenty-four– hour ambulatory ECGs (Holter monitor) before CRT were collected in 48 of 154 patients. Minimum, maximum, and average heart rates were analyzed using the Aria Holter Monitor system (Del Mar Avionics, Irvine, CA, USA).
Echocardiography Echocardiography was performed as part of routine clinical care. Baseline and follow-up echocardiographic parameters included LVEF, left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), pulmonary arterial systolic pressure (estimated from tricuspid regurgitant velocity and estimate of right atrial pressures), and mitral regurgitation (MR) severity [grade 0 (none or trivial), 1 (mild), 2 (moderate), 3 (severe)]. MR severity was assessed by a combination of quantification by proximal isovelocity surface area method and/or continuity equation and/or visual assessment of jet.14
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Device implantation and CRT programming Commercially available devices and leads were used. Left ventricular (LV) lead placement was prioritized as lateral or posterolateral, anterior lateral, middle cardiac veins, or anterior vein, as allowed by ability to cannulate veins, pacing thresholds, or diaphragmatic stimulation. Typical CRT settings were interventricular delay 0 ms with VVIR mode and standard lower (60 bpm) and upper (120 –130 bpm) pacing rates. In patients with paroxysmal AF, paced AV delay was set at 130 ms. Device programming was subject to change, based on operator preference. Algorithms designed to promote CRT pacing, including ventricular-sensed response pacing, were routinely activated to ensure biventricular pacing.
Clinical follow-up Patients were asked to return for clinical follow-up after device implant. Data on percentage of biventricular pacing after CRT was collected during device interrogation. Survival status as of May 15, 2007 for the entire cohort, including patients who did not return for follow-up, was obtained from the Mayo Clinic registration database and an institutionally approved national death and location database (Accurint), as previously described.15
Statistical analysis Continuous variables are expressed as mean ⫾ SD or median (Q1, Q3) for variables where data were skewed. Twosample t-tests were used to assess the differences between the ⫹AVN-ABL and –AVN-ABL groups, except in the case of biventricular percentage pacing, for which a rank sum test was used. Paired t-tests were used to assess the differences in preimplant and postimplant continuous variables within the ⫹AVN-ABL and –AVN-ABL groups. Categorical variables are expressed as count (percent), and differences across groups were assessed using Chi-square test or Fisher exact test in the case of small numbers. Survival estimates for the event of death were calculated by the Kaplan-Meier method. Comparisons in survival between groups were assessed using a log rank test. Univariate Cox proportional hazards regression models were used to evaluate the association of clinical and echocardiographic parameters with survival. Multivariate models were fit to evaluate the independent association of ablation with survival after controlling for echocardiographic parameters of interest. Relative risks are expressed as hazard ratio (HR) with 95% confidence interval (CI). In all cases, two-tailed P ⬍.05 was considered significant. All analyses were performed using SAS version 9.1.3 (SAS, Inc., Cary, NC, USA).
Results Baseline demographic characteristics Of 154 patients who received CRT-D, 45 (29%) underwent AVN ablation to ensure ventricular resynchronization. The majority of patients (88%)had chronic AF. Median (Q1, Q3) duration from CRT device implant to ablation was –13 (⫺220, 1) days. Two patients who had AVN ablation 1 year after CRT implant were categorized in the –AVN-ABL
1242 Table 1
Heart Rhythm, Vol 7, No 9, September 2010 Baseline demographic characteristics of–AVN-ABL and ⫹AVN-ABL groups
Variable
No.
⫺AVN-ABL group (N ⫽ 109)
⫹AVN-ABL group (N ⫽ 45)
P value
Age at implant (years) Male Coronary artery disease Ischemic cardiomyopathy Hypertension Diabetes Renal failure Chronic obstructive pulmonary disease Creatinine (dL) NYHA class LVEF (%) LVEDD mm LVESD mm MR severity Pulmonary arterial systolic pressure (mmHg) ECG heart rate (bpm) QRS duration (ms) Holter minimum heart rate (bpm) Holter average heart rate (bpm) Holter maximum heart rate (bpm) Digoxin Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker Beta-blocker Calcium channel blocker Propafenone/flecainide Sotalol/amiodarone Pulmonary vein isolation
154 154 154 154 154 154 154 154 149 154 149 137 77 133 127 148 154 48 48 48 153 151 153 153 153 153 153
71.5 ⫾ 9.4 95 (87%) 69 (63%) 66 (61%) 12 (11%) 32 (29%) 22 (20%) 23 (21%) 1.5 ⫾ 0.4 3.0 ⫾ 0.4 22.6 ⫾ 6.4 66.2 ⫾ 8.4 58.0 ⫾ 8.5 1.6 ⫾ 0.8 51.0 ⫾ 14.1 70.4 ⫾ 13.5 174.6 ⫾ 34.6 56.8 ⫾ 11.3 69.7 ⫾ 10.1 105.0 ⫾ 18.6 68 (63%) 93 (88%) 86 (80%) 4 (4%) 0 (0%) 22 (20%) 0 (0%)
68.1 ⫾ 10.5 38 (84%) 25 (56%) 23 (51%) 5 (11%) 9 (20%) 6 (13%) 7 (16%) 1.4 ⫾ 0.4 2.9 ⫾ 0.5 25.5 ⫾ 8.1 64.0 ⫾ 8.2 54.1 ⫾ 7.9 1.4 ⫾ 0.7 42.1 ⫾ 11.5 85.6 ⫾ 15.9 161.2 ⫾ 35.0 68.5 ⫾ 11.2 83.5 ⫾ 10.6 120.3 ⫾ 13.8 29 (64%) 37 (82%) 27 (60%) 3 (7%) 1 (2%) 7 (16%) 3 (6.7%)
.048 .66 .37 .28 .99 .23 .32 .43 .05 .021 .022 .16 .06 .20 ⬍.001 ⬍.001 .030 ⬍.001 ⬍.001 .002 .86 .37 .012 .42 .29 .49 .024
Values are given as mean ⫾ SD or number (percent). AVN-ABL ⫽ atrioventricular nodal ablation; LVEDD ⫽ left ventricular end-diastolic dimension; LVEF ⫽ left ventricular ejection fraction; LVESD ⫽ left ventricular end-systolic dimension; MR ⫽ mitral regurgitation; NYHA ⫽ New York Heart Association functional class.
group. Compared to those in the –AVN-ABL group, patients in the ⫹AVN-ABL group were younger (68.1 ⫾ 10.5 years vs 71.5 ⫾ 9.4 years, P ⫽ .048), had lower NYHA class (2.9 ⫾ 0.5 vs 3.0 ⫾ 0.4, P ⫽ .021), higher LVEF (25.5% ⫾ 8.1% vs 22.6% ⫾ 6.4%, P ⫽ .022), higher resting, average, and maximum heart rate by ECG, and Holter before CRT (Table 1). Fewer patients in the ⫹AVNABL group were taking beta-blockers compared to patients in the –AVN-ABL group (P ⫽ .012). Three patients in the ⫹AVNABL group but none in the –AVN-ABL group underwent pulmonary vein isolation (P ⫽ .024). Of the 154 patients who received CRT-D, 85 (55%) had new (de novo) implant; the rest of the 69 (45%) patients had an existing pacemaker or defibrillator upgraded to a CRT-D device. Baseline characteristics were different in the presence of ischemic cardiomyopathy (51% vs 67%, P ⫽ .045), diabetes (34% vs 17%, P ⫽ .02), LVEF (22.4% ⫾ 6.9% vs 24.7% ⫾ 7.0%, P ⫽ .047), LVEDD (66.7 ⫾ 8.8 mm vs 63.9 ⫾ 7.5 mm, P ⫽ .05), and QRS duration (157 ⫾ 33 ms vs 188 ⫾ 30 ms, P ⬍.001) between de novo and upgrade groups. The other baseline demographic features were comparable. LV lead locations in the ⫹AVN-ABL and –AVN-ABL groups were comparable (lateral vein 49% vs 47%, anterior lateral vein 33% vs 33%, anterior interventricular vein 11% vs 12%, middle cardiac vein 7% vs 6%, P ⫽ .93).
Clinical outcomes after CRT Of the 154 patients, 117 (76%) returned for clinical followup. Of the 37 patients who did not return for follow-up, 15 died and 2 underwent heart transplantation; the remaining
20 were asked to complete questionnaires. Medical records of follow-up with a primary physician, including outpatient visit, hospitalization, and follow-up echocardiography, were obtained for 18 of these patients; 2 patients could not be reached. Median (Q1, Q3) duration from implant to postCRT echocardiographic follow-up was 274 (193, 427) days in the ⫹AVN-ABL group and 222 (111, 501) days in the ⫺AVN-ABL group (P ⫽ .22). Median (Q1, Q3) percentage of biventricular pacing after CRT was 99.0% (95%–100%) in the ⫹AVN-ABL group compared to 96.0% (85.5%– 99.0%) in the –AVN-ABL group (P ⫽ .05). Heart rate by ECG after CRT was similar between the two groups (73.4 ⫾ 10.8 bpm vs 75.7 ⫾ 13.2 bpm, P ⫽ .33). Changes in NYHA functional class and echocardiographic parameters observed in the two groups after CRT are shown in Figure 1. Both ⫹AVNABL and –AVN-ABL groups had significant improvements in NYHA class, LVEF, and LVEDD. Improvement in NYHA class was significantly greater in the ⫹AVN-ABL group compared to the ⫺AVN-ABL group (0.7 ⫾ 0.8 vs 0.4 ⫾ 0.8, P ⫽ .04), whereas improvement in echocardiographic parameters was not significantly different between the two groups (Figure 1). After CRT-D implantation, 9 (20%) of 45 patients in the ⫹AVN-ABL group were admitted to St. Mary’s Hospital or a local hospital for HF, similar to the 17 (16%) of 107 patients in the ⫺AVN-ABL group (P ⫽ .51). Improvement in NYHA class, LVEF, LV diastolic dimension, and severity of MR were not significantly different when comparing patients who received de novo devices to those who received upgrade devices.
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Figure 1 Changes in (A) New York Heart Association (NYHA) functional class, (B) left ventricular ejection fraction (LVEF), and (C) left ventricular end-diastolic dimension (LVEDD). Bars represent mean and SD. *P ⬍.05; **P ⬍.01 vs pre– cardiac resynchronization therapy. AVN-ABL ⫽ atrioventricular nodal ablation.
Differential survival benefit in ⴙAVN-ABL and –AVN-ABL groups There were 4 deaths in the ⫹AVN-ABL group and 30 deaths in the –AVN-ABL group over median follow-up of 2.1 years (interquartile 1.4 –3.0 years). Kaplan-Meier survival estimates are shown in Figure 2A. Survival estimates at 2 years were 96.0% (95% CI 88.6%–100%) for the ⫹AVNABL group and 76.5% (95% CI 68.1%– 85.8%) for the –AVN-ABL group (P ⫽ .008). Four patients underwent heart transplant, and one received an LV assist device due to advanced HF despite CRT and medical therapy. Two-year survival estimates for the combined events of death, heart transplant, and LV assist device were 93.7% (95% CI 85.3%–100%) for the ⫹AVN-ABL group and 73.6% (95% CI 65.0%– 83.3%) for the ⫺AVN-ABL group (P ⫽ .007; Figure 2B).
Survival predictors Univariate analysis showed that the severity of MR before CRT was associated with poor survival (HR 2.00, 95% CI 1.22-3.26, P ⫽ .006), whereas AVN ablation (HR 0.27, 95% CI 0.09 – 0.77, P ⫽ .014) was associated with improved sur-
Figure 2 Kaplan-Meier survival estimates in the ⫹AVNABL and –AVN-ABL groups after cardiac resynchronization therapy. Events of death and combined events of death, transplant, or left ventricular assist device (LVAD). AVN-ABL ⫽ atrioventricular nodal ablation.
vival (Table 2). Baseline NYHA class showed a trend toward poorer survival (HR 1.81, 95% CI 0.90 –3.62, P ⫽ .093), whereas baseline ECG heart rate (HR 0.98, 95% CI 0.95–1.00, P ⫽ .071) and percentage of biventricular pacing showed a trend toward lower mortality (HR 0.98, 95% CI 0.95–1.00, P ⫽ .094). In multivariate analysis, after adjusting for NYHA and LVEF, AVN ablation showed an independent association with survival benefit from death after CRT (HR 0.13, 95% CI 0.03– 0.58, P ⫽ .007) and survival benefit from combined events of death, heart transplant, and LV assist device implant as shown in table 3 (HR 0.19, 95% CI 0.06 – 0.62, P ⫽ .006).
Discussion Main findings Patients with AF who undergo CRT and concomitant AVN ablation may experience improved survival as well as improvement in NYHA class, LV systolic function, and reversal of LV structural remodeling. Furthermore, AVN ablation was an independent predictor of improved all-cause mortality and combined events of death, heart transplant, and LV assist device.
1244 Table 2
Heart Rhythm, Vol 7, No 9, September 2010 Univariate predictors for survival after CRT
Variable
No.
Hazard ratio
95% Confidence interval
P value
Age at implant Male gender Ischemic cardiomyopathy NYHA LVEF LVEDD LVESD MR Left atrial volume ECG heart rate Holter minimum heart rate Holter average heart rate Holter maximum heart rate Digoxin Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker Beta-blocker AVN ablation Biventricular pacing percentage
154 154 154 154 149 137 77 133 114 148 48 48 48 153 151 153 154 113
1.01 0.62 1.34 1.81 0.98 0.99 1.00 2.00 1.00 0.98 1.00 1.00 0.97 1.16 1.14 1.54 0.27 0.98
(0.97, (0.23, (0.67, (0.90, (0.93, (0.95, (0.94, (1.22, (0.99, (0.95, (0.94, (0.93, (0.92, (0.54, (0.35, (0.67, (0.09, (0.95,
.672 .331 .409 .093 .551 .624 .947 .006 .387 .071 .869 .877 .157 .700 .833 .313 .014 .094
1.04) 1.63) 2.67) 3.62) 1.04) 1.03) 1.07) 3.26) 1.01) 1.00) 1.05) 1.06) 1.01) 2.53) 3.74) 3.54) 0.77) 1.00)
AVN ⫽ atrioventricular nodal; CRT ⫽ cardiac resynchronization therapy; LVEDD ⫽ left ventricular end-diastolic dimension; LVEF ⫽ left ventricular ejection fraction; LVESD ⫽ left ventricular end-systolic dimension; MR ⫽ mitral regurgitation; NYHA ⫽ New York Heart Association functional class.
Efficacy of CRT in patients with AF HF and AF are the most common cardiovascular disorders that often coexist.16 The prevalence of AF is related to the extent of LV dysfunction and the patient’s HF status.5 In patients with preexisting LV dysfunction, AF may further aggravate HF symptoms, resulting in a vicious cycle. CRT has proved to be beneficial in improving HF symptoms, LV structural remodeling, and function in patients with drugrefractory HF and AF.6 –12 However, the role of AVN ablation in facilitating full biventricular resynchronization has been underinvestigated. Limited data regarding the concomitant use of AVN ablation in patients with AF who are receiving CRT have been reported.7,17 The focus of this study was to determine the impact of AVN ablation on CRT clinical and survival outcomes. We presented 154 patients with AF who received CRT for advanced HF in a large single center. One third of these patients underwent AVN ablation at the time of device implant, before or after CRT. Patients who underwent AVN ablation had a higher resting and maximum heart rate than Table 3
Multivariate predictors for survival after CRT
Variable Model 1: Survival to Death AVN ablation NYHA LVEF Model 2: Survival To Death/ Heart Transplant/ Left Ventricular Assist Device AVN ablation NYHA LVEF
Hazard ratio
95% Confidence interval
P value
0.13 1.76 1.02
0.03, 0.58 0.75, 4.09 0.96, 1.09
.007 .192 .553
0.19 1.89 1.00
0.06, 0.62 0.86, 4.15 0.94, 1.06
.006 .112 .859
AVN ⫽ atrioventricular nodal; CRT ⫽ cardiac resynchronization therapy; LVEF ⫽ left ventricular ejection fraction; NYHA ⫽ New York Heart Association functional class.
did those without AVN ablation. It is apparent that persuasion of these patients toward AVN ablation was made to ensure the adequacy of biventricular resynchronization. Improvement in HF symptoms, NYHA functional class, LV systolic function, and reversal of LV remodeling was observed in both ⫹AVN-ABL and –AVN-ABL groups after CRT. The results corroborate findings from previous studies that CRT is beneficial in ventricular resynchronization alone, despite the lack of atrial ventricular synchrony in these patients.6 –12 Furthermore, the ⫹AVN-ABL groups had a more significant improvement in NYHA class compared to the –AVN-ABL group. A higher percentage of biventricular pacing, adequate control of ventricular rate, and elimination of ventricular irregularity, especially during exercise, may better explain HF symptomatic control. Improvement in NYHA class and LVEF was comparable in patients who received de novo device and those who had upgrade of an existing device to CRT-D. The detrimental effect of chronic right ventricular pacing in the presence of LV dysfunction is known.18,19 In the LV-based cardiac stimulation Post AV Nodal Ablation Evaluation (PAVE) study, improved functional capacity by assessing the 6-minute walk test and ejection fraction was observed in the biventricular pacing group compared to the right ventricular pacing alone group.19
AVN-ABL is independent predictor of survival after CRT Ozcan et al20 addressed the impact of AVN ablation and permanent pacing on long-term survival in the AF population. In the absence of underlying heart disease, survival after AVN ablation was neutral, as expected, in the general population. The clinical and survival benefit of permanent AVN ablation in recipients of CRT-D with advanced cardiomyopathy is underinvestigated. Our observation may suggest that AVN ablation improves survival in this patient population. The only published results on this subject were reported by Gasparini et al,17 who showed a favorable survival benefit from AVN ablation in
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patients with AF who received CRT-D (40%) and CRT-P (60%) devices, compared to those who received drug therapy for rate control. All patients in both the ⫹AVN-ABL and –AVN-ABL groups in our study cohort received CRT-D. Our findings show improved overall survival in patients receiving CRT with AVN ablation, compared with those receiving CRT and drug therapy. In our study, patients who underwent AVN ablation demonstrated lesser severity of NYHA class function and higher LVEF compared to those without AVN ablation at baseline. This group of patients may be less sick before CRT; nevertheless, we found that AVN ablation is an independent predictor of survival post-CRT after controlling for LVEF and NYHA (previously unreported observation). AVN ablation provides complete heart rate control and rhythm regularity in AF,17 an advantage of overcoming high ventricular rate and ventricular irregularity-induced cardiomyopathy.21–23 The higher percentage of biventricular pacing may be another explanation for improved survival in patients undergoing AVN ablation.24 Because we routinely program ventricular-sensed response pacing to the “on” setting for patients with AF and some devices do not have the algorithm to separate true-paced beats from sense-paced beats, the percentage of “clean” versus “fused” biventricular pacing that may be minimally resynchronized is not known. Patients with AVN ablation may have received not only a higher percentage of biventricular pacing but also a higher quality of truly paced resynchronization. A well-designed prospective study may more accurately assess the efficacy and survival benefit of true (complete) and fused (partial) resynchronization. Nevertheless, we agree with Gasparini et al,7 who assert that achieving maximal biventricular pacing time is essential to attaining the full benefit of CRT.
Study limitations This observational study has several limitations. Some baseline characteristics between the two groups were different (e.g., patients in the ⫹AVN-ABL group had a higher resting and maximal heart rate, reflecting our clinical preference for definitive heart rate control in patients with a high ventricular rate). Among patients undergoing AVN ablation, most had intervention at the time of CRT implant. A future randomized study would be important to eliminate patient selection bias. Second, the two groups of patients in the study were not numerically balanced. The death events in the ablation group are small. To address the role of AVN ablation in long-term survival, large-scale randomized studies targeting the AF and HF population are needed.17,25
Conclusion In this large, single-center study, AVN ablation improved long-term survival in patients with AF and advanced HF requiring CRT compared to patients who received drug therapy. These data suggest that AVN ablation could be considered sooner in the treatment algorithm for patients with AF undergoing CRT. Prospective randomized studies are needed to further address the efficacy and survival rates of patients with AF who receive CRT and AVN ablation.
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References 1. Abraham W, Fisher W, Smith A, Delurgio D, Leon A. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 2. Bristow M, Saxon L, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140 –2150. 3. Cleland J, Daubert J, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539 –1549. 4. Stellbrink C, Breithardt O, Franke A, et al. Impact of cardiac resynchronization therapy using hemodynamically optimized pacing on the left ventricular remodeling in patients with congestive heart failure and ventricular conducti0n disturbances. J Am Coll Cardiol 2001;38:1957–1965. 5. Maisel W, Stevenson L. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91:2D– 8D. 6. Delnoy P, Ottervanger J, Luttikhuis H, et al. Comparison of usefulness of cardiac resynchronization therapy in patients with atrial fibrillation and heart failure versus patients with sinus rhythm and heart failure. Am J Cardiol 2007;99:1252–1257. 7. Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol 2006;48:734 –743. 8. Khadjooi K, Foley PW, Chalil S, et al. Long-term effects of cardiac resynchronisation therapy in patients with atrial fibrillation. Heart 2008;94:879 – 883. 9. Leclercq C, Victor F, Alonso C, et al. Comparative effects of permanent biventricular pacing for refractory heart failure in patients with stable sinus rhythm or chronic atrial fibrillation. Am J Cardiol 2000;85:1154 –1156. 10. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002;40:111–118. 11. Molhoek S, Bax J, Bleeker G, et al. Comparison of response to cardiac resynchronization therapy in patients with sinus rhythm versus chronic atrial fibrillation. Am J Cardiol 2004;94:1506 –1509. 12. Upadhyay G, Choudhry N, Auricchio A, Ruskin J, Singh J. Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies. J Am Coll Cardiol 2008;52:1239 –1246. 13. Epstein A, DiMarco J, Ellenbogen K, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 2008;117:e350 – e408. 14. Cha Y, Rea R, Wang M, et al. Response to cardiac resynchronization therapy predicts survival in heart failure: a single-center experience. J Cardiovasc Electrophysiol 2007;18:1015–1019. 15. Owan T, Hodge D, Herges R, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251–259. 16. Ehrlich J, Nattel S, Hohnloser S. Atrial fibrillation and congestive heart failure: specific considerations at the intersection of two common and important cardiac disease sets. J Cardiovasc Electrophysiol 2002;13:399 – 405. 17. Gasparini M, Auricchio A, Metra M, et al. Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of atrio-ventricular junction ablation in patients with permanent atrial fibrillation. Eur Heart J 2008;29:1644–1652. 18. Wilkoff B, Cook J, Epstein A, et al. Dual-chamber pacing or ventricular back-up pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002;288:3115–3123. 19. Doshi R. Optimizing resynchronization therapy: can we increase the number of true responders? J Cardiovasc Electrophysiol 2005;16(Suppl 1):548 –551. 20. Ozcan C, Jahangir A, Friedman P, 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;344:1043–1051. 21. Grogan M, Smith H, Gersh B, Wood D. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Am J Cardiol 1992;69:1570 –1573. 22. Kieny J, Sacrez A, Facello A, et al. Increase in radionuclide left ventricular ejection fraction after cardioversion of chronic atrial fibrillation in idiopathic dilated cardiomyopathy. Eur Heart J 1992;13:1290 –1295. 23. Wasmund S, Li J, Page R, Wood D. Effect of atrial fibrillation and an irregular ventricular response on sympathetic nerve activity in human subjects. Circulation 2003;107:2011–2015. 24. Spears D, Selvaraj R, Dhopeswarkar R, Nanthakumar K. Atrial tracking with a single ICD lead in the ventricular. J Cardiovasc Electrophysiol 2008;19:440 – 441. 25. 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 J 2007;4:224 –232.
Introduction In clinical trials, cardiac resynchronization therapy (CRT) has been associated with improvement in heart failure (HF) symptoms, effort tolerance, cardiac function, and structural remodeling in patients with New York Heart Association (NYHA) functional class III or IV HF with wide QRS complex.1– 4 Atrial fibrillation (AF) occurs frequently in patients with HF; its prevalence parallels the severity of HF, from 10% in NYHA class II up to 50% in NYHA class IV.5
Address reprint requests and correspondence: Dr. Yong-Mei Cha, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail address: [email protected]. (Received June 17, 2009; accepted February 5, 2010.)
[CI] 88.6%–100%) for ⫹AVN-ABL group and 76.5% (95% CI 68.1%– 85.8%) for–AVN-ABL group (P ⫽ .008). AVN ablation was independently associated with survival benefit from death (hazard ratio [HR] 0.13, 95% CI 0.03– 0.58, P ⫽ .007) and from combined death, heart transplant, and left ventricular assist device (HR 0.19, 95% CI 0.06 – 0.62, P ⫽ .006) after CRT. CONCLUSION Among patients with atrial fibrillation and heart failure receiving CRT, AVN ablation for definitive biventricular pacing provides greater improvement in NYHA class and survival benefit. Larger-scale randomized trials are needed to assess the clinical and survival outcomes of this therapy. KEYWORDS Atrial fibrillation; Atrioventricular nodal ablation; Cardiac resynchronization therapy; Heart failure ABBREVIATIONS ABL ⫽ ablation; AF ⫽ atrial fibrillation; AVN ⫽ atrioventricular node; CI ⫽ confidence interval; CRT ⫽ cardiac resynchronization therapy; HF ⫽ heart failure; HR ⫽ hazard ratio; LV ⫽ left ventricular; LVEDD ⫽ left ventricular end-diastolic dimension; LVEF ⫽ left ventricular ejection fraction; LVESD ⫽ left ventricular endsystolic dimension; MR ⫽ mitral regurgitation; NYHA ⫽ New York Heart Association (Heart Rhythm 2010;7:1240–1245) © 2010 Heart Rhythm Society. All rights reserved.
Although the outcome of CRT in patients with AF is limited (majority of CRT trials excluded patients with AF), prospective studies and meta-analysis confer a comparable clinical benefit in patients with AF and sinus rhythm.6 –12 As a result, CRT for AF patients is considered a class IIA indication in the most recent guidelines for implantation of cardiac pacemakers and antiarrhythmic devices.13 However, an important question pertaining to this AF and HF population (approximately one third of CRT recipients) that has been inadequately addressed is the necessity of atrioventricular nodal (AVN) ablation. AVN ablation ensures a high percentage of resynchronized QRS complexes in order to deliver a high dose of therapy and attenuate cardiac output impairment due to R-R interval variability. The results from several studies
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doi:10.1016/j.hrthm.2010.02.011
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of a small number of AF patients with AVN ablation were inconsistent.9 –11 Results from the largest AVN ablation group showed that only patients who underwent AVN ablation with 100% CRT delivery responded to CRT.7 The objective of this study was to assess the impact of AVN ablation on clinical and survival outcomes in a large AF and HF population that met the current indication for CRT and to determine whether AVN ablation is an independent predictor of survival in CRT recipients.
Methods Patient population Of 502 CRT recipients at Mayo Clinic from January 1, 2002 to December 31, 2006, 172 (34%) patients received CRT with (CRT-D, n ⫽ 154 [90%]) or without (CRT-P, n ⫽ 18 [10%]) concomitant defibrillator in the setting of AF, including patients undergoing upgrade of a conventional pacemaker or defibrillator to CRT. Indications for CRT were HF symptoms despite optimal medical therapy, left ventricular ejection fraction (LVEF) ⬍35%, and QRS duration ⱖ120 ms. To minimize selection bias and unify the patient population, the study cohort included only the 154 patients who received CRT-D. Of these patients, 109 (71%) received medical therapy for ventricular rate control (⫺AVNABL group), whereas the other 45 (29%) patients underwent AVN ablation to ensure biventricular resynchronization (⫹AVN-ABL group). Clinical information, including NYHA class, HF etiology, and laboratory data pre- and post-CRT documented as part of routine clinical care, were collected. Clinical and survival outcomes were assessed in the ⫹AVN-ABL and –AVN-ABL groups. The study was approved by the Mayo Clinic Institutional Review Board, and all patients who consented to use of their records for research were included.
Twelve-lead ECG and 24-hour Holter monitoring Baseline 12-lead ECGs were obtained for each patient to assess QRS duration and resting heart rate. Twenty-four– hour ambulatory ECGs (Holter monitor) before CRT were collected in 48 of 154 patients. Minimum, maximum, and average heart rates were analyzed using the Aria Holter Monitor system (Del Mar Avionics, Irvine, CA, USA).
Echocardiography Echocardiography was performed as part of routine clinical care. Baseline and follow-up echocardiographic parameters included LVEF, left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), pulmonary arterial systolic pressure (estimated from tricuspid regurgitant velocity and estimate of right atrial pressures), and mitral regurgitation (MR) severity [grade 0 (none or trivial), 1 (mild), 2 (moderate), 3 (severe)]. MR severity was assessed by a combination of quantification by proximal isovelocity surface area method and/or continuity equation and/or visual assessment of jet.14
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Device implantation and CRT programming Commercially available devices and leads were used. Left ventricular (LV) lead placement was prioritized as lateral or posterolateral, anterior lateral, middle cardiac veins, or anterior vein, as allowed by ability to cannulate veins, pacing thresholds, or diaphragmatic stimulation. Typical CRT settings were interventricular delay 0 ms with VVIR mode and standard lower (60 bpm) and upper (120 –130 bpm) pacing rates. In patients with paroxysmal AF, paced AV delay was set at 130 ms. Device programming was subject to change, based on operator preference. Algorithms designed to promote CRT pacing, including ventricular-sensed response pacing, were routinely activated to ensure biventricular pacing.
Clinical follow-up Patients were asked to return for clinical follow-up after device implant. Data on percentage of biventricular pacing after CRT was collected during device interrogation. Survival status as of May 15, 2007 for the entire cohort, including patients who did not return for follow-up, was obtained from the Mayo Clinic registration database and an institutionally approved national death and location database (Accurint), as previously described.15
Statistical analysis Continuous variables are expressed as mean ⫾ SD or median (Q1, Q3) for variables where data were skewed. Twosample t-tests were used to assess the differences between the ⫹AVN-ABL and –AVN-ABL groups, except in the case of biventricular percentage pacing, for which a rank sum test was used. Paired t-tests were used to assess the differences in preimplant and postimplant continuous variables within the ⫹AVN-ABL and –AVN-ABL groups. Categorical variables are expressed as count (percent), and differences across groups were assessed using Chi-square test or Fisher exact test in the case of small numbers. Survival estimates for the event of death were calculated by the Kaplan-Meier method. Comparisons in survival between groups were assessed using a log rank test. Univariate Cox proportional hazards regression models were used to evaluate the association of clinical and echocardiographic parameters with survival. Multivariate models were fit to evaluate the independent association of ablation with survival after controlling for echocardiographic parameters of interest. Relative risks are expressed as hazard ratio (HR) with 95% confidence interval (CI). In all cases, two-tailed P ⬍.05 was considered significant. All analyses were performed using SAS version 9.1.3 (SAS, Inc., Cary, NC, USA).
Results Baseline demographic characteristics Of 154 patients who received CRT-D, 45 (29%) underwent AVN ablation to ensure ventricular resynchronization. The majority of patients (88%)had chronic AF. Median (Q1, Q3) duration from CRT device implant to ablation was –13 (⫺220, 1) days. Two patients who had AVN ablation 1 year after CRT implant were categorized in the –AVN-ABL
1242 Table 1
Heart Rhythm, Vol 7, No 9, September 2010 Baseline demographic characteristics of–AVN-ABL and ⫹AVN-ABL groups
Variable
No.
⫺AVN-ABL group (N ⫽ 109)
⫹AVN-ABL group (N ⫽ 45)
P value
Age at implant (years) Male Coronary artery disease Ischemic cardiomyopathy Hypertension Diabetes Renal failure Chronic obstructive pulmonary disease Creatinine (dL) NYHA class LVEF (%) LVEDD mm LVESD mm MR severity Pulmonary arterial systolic pressure (mmHg) ECG heart rate (bpm) QRS duration (ms) Holter minimum heart rate (bpm) Holter average heart rate (bpm) Holter maximum heart rate (bpm) Digoxin Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker Beta-blocker Calcium channel blocker Propafenone/flecainide Sotalol/amiodarone Pulmonary vein isolation
154 154 154 154 154 154 154 154 149 154 149 137 77 133 127 148 154 48 48 48 153 151 153 153 153 153 153
71.5 ⫾ 9.4 95 (87%) 69 (63%) 66 (61%) 12 (11%) 32 (29%) 22 (20%) 23 (21%) 1.5 ⫾ 0.4 3.0 ⫾ 0.4 22.6 ⫾ 6.4 66.2 ⫾ 8.4 58.0 ⫾ 8.5 1.6 ⫾ 0.8 51.0 ⫾ 14.1 70.4 ⫾ 13.5 174.6 ⫾ 34.6 56.8 ⫾ 11.3 69.7 ⫾ 10.1 105.0 ⫾ 18.6 68 (63%) 93 (88%) 86 (80%) 4 (4%) 0 (0%) 22 (20%) 0 (0%)
68.1 ⫾ 10.5 38 (84%) 25 (56%) 23 (51%) 5 (11%) 9 (20%) 6 (13%) 7 (16%) 1.4 ⫾ 0.4 2.9 ⫾ 0.5 25.5 ⫾ 8.1 64.0 ⫾ 8.2 54.1 ⫾ 7.9 1.4 ⫾ 0.7 42.1 ⫾ 11.5 85.6 ⫾ 15.9 161.2 ⫾ 35.0 68.5 ⫾ 11.2 83.5 ⫾ 10.6 120.3 ⫾ 13.8 29 (64%) 37 (82%) 27 (60%) 3 (7%) 1 (2%) 7 (16%) 3 (6.7%)
.048 .66 .37 .28 .99 .23 .32 .43 .05 .021 .022 .16 .06 .20 ⬍.001 ⬍.001 .030 ⬍.001 ⬍.001 .002 .86 .37 .012 .42 .29 .49 .024
Values are given as mean ⫾ SD or number (percent). AVN-ABL ⫽ atrioventricular nodal ablation; LVEDD ⫽ left ventricular end-diastolic dimension; LVEF ⫽ left ventricular ejection fraction; LVESD ⫽ left ventricular end-systolic dimension; MR ⫽ mitral regurgitation; NYHA ⫽ New York Heart Association functional class.
group. Compared to those in the –AVN-ABL group, patients in the ⫹AVN-ABL group were younger (68.1 ⫾ 10.5 years vs 71.5 ⫾ 9.4 years, P ⫽ .048), had lower NYHA class (2.9 ⫾ 0.5 vs 3.0 ⫾ 0.4, P ⫽ .021), higher LVEF (25.5% ⫾ 8.1% vs 22.6% ⫾ 6.4%, P ⫽ .022), higher resting, average, and maximum heart rate by ECG, and Holter before CRT (Table 1). Fewer patients in the ⫹AVNABL group were taking beta-blockers compared to patients in the –AVN-ABL group (P ⫽ .012). Three patients in the ⫹AVNABL group but none in the –AVN-ABL group underwent pulmonary vein isolation (P ⫽ .024). Of the 154 patients who received CRT-D, 85 (55%) had new (de novo) implant; the rest of the 69 (45%) patients had an existing pacemaker or defibrillator upgraded to a CRT-D device. Baseline characteristics were different in the presence of ischemic cardiomyopathy (51% vs 67%, P ⫽ .045), diabetes (34% vs 17%, P ⫽ .02), LVEF (22.4% ⫾ 6.9% vs 24.7% ⫾ 7.0%, P ⫽ .047), LVEDD (66.7 ⫾ 8.8 mm vs 63.9 ⫾ 7.5 mm, P ⫽ .05), and QRS duration (157 ⫾ 33 ms vs 188 ⫾ 30 ms, P ⬍.001) between de novo and upgrade groups. The other baseline demographic features were comparable. LV lead locations in the ⫹AVN-ABL and –AVN-ABL groups were comparable (lateral vein 49% vs 47%, anterior lateral vein 33% vs 33%, anterior interventricular vein 11% vs 12%, middle cardiac vein 7% vs 6%, P ⫽ .93).
Clinical outcomes after CRT Of the 154 patients, 117 (76%) returned for clinical followup. Of the 37 patients who did not return for follow-up, 15 died and 2 underwent heart transplantation; the remaining
20 were asked to complete questionnaires. Medical records of follow-up with a primary physician, including outpatient visit, hospitalization, and follow-up echocardiography, were obtained for 18 of these patients; 2 patients could not be reached. Median (Q1, Q3) duration from implant to postCRT echocardiographic follow-up was 274 (193, 427) days in the ⫹AVN-ABL group and 222 (111, 501) days in the ⫺AVN-ABL group (P ⫽ .22). Median (Q1, Q3) percentage of biventricular pacing after CRT was 99.0% (95%–100%) in the ⫹AVN-ABL group compared to 96.0% (85.5%– 99.0%) in the –AVN-ABL group (P ⫽ .05). Heart rate by ECG after CRT was similar between the two groups (73.4 ⫾ 10.8 bpm vs 75.7 ⫾ 13.2 bpm, P ⫽ .33). Changes in NYHA functional class and echocardiographic parameters observed in the two groups after CRT are shown in Figure 1. Both ⫹AVNABL and –AVN-ABL groups had significant improvements in NYHA class, LVEF, and LVEDD. Improvement in NYHA class was significantly greater in the ⫹AVN-ABL group compared to the ⫺AVN-ABL group (0.7 ⫾ 0.8 vs 0.4 ⫾ 0.8, P ⫽ .04), whereas improvement in echocardiographic parameters was not significantly different between the two groups (Figure 1). After CRT-D implantation, 9 (20%) of 45 patients in the ⫹AVN-ABL group were admitted to St. Mary’s Hospital or a local hospital for HF, similar to the 17 (16%) of 107 patients in the ⫺AVN-ABL group (P ⫽ .51). Improvement in NYHA class, LVEF, LV diastolic dimension, and severity of MR were not significantly different when comparing patients who received de novo devices to those who received upgrade devices.
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Figure 1 Changes in (A) New York Heart Association (NYHA) functional class, (B) left ventricular ejection fraction (LVEF), and (C) left ventricular end-diastolic dimension (LVEDD). Bars represent mean and SD. *P ⬍.05; **P ⬍.01 vs pre– cardiac resynchronization therapy. AVN-ABL ⫽ atrioventricular nodal ablation.
Differential survival benefit in ⴙAVN-ABL and –AVN-ABL groups There were 4 deaths in the ⫹AVN-ABL group and 30 deaths in the –AVN-ABL group over median follow-up of 2.1 years (interquartile 1.4 –3.0 years). Kaplan-Meier survival estimates are shown in Figure 2A. Survival estimates at 2 years were 96.0% (95% CI 88.6%–100%) for the ⫹AVNABL group and 76.5% (95% CI 68.1%– 85.8%) for the –AVN-ABL group (P ⫽ .008). Four patients underwent heart transplant, and one received an LV assist device due to advanced HF despite CRT and medical therapy. Two-year survival estimates for the combined events of death, heart transplant, and LV assist device were 93.7% (95% CI 85.3%–100%) for the ⫹AVN-ABL group and 73.6% (95% CI 65.0%– 83.3%) for the ⫺AVN-ABL group (P ⫽ .007; Figure 2B).
Survival predictors Univariate analysis showed that the severity of MR before CRT was associated with poor survival (HR 2.00, 95% CI 1.22-3.26, P ⫽ .006), whereas AVN ablation (HR 0.27, 95% CI 0.09 – 0.77, P ⫽ .014) was associated with improved sur-
Figure 2 Kaplan-Meier survival estimates in the ⫹AVNABL and –AVN-ABL groups after cardiac resynchronization therapy. Events of death and combined events of death, transplant, or left ventricular assist device (LVAD). AVN-ABL ⫽ atrioventricular nodal ablation.
vival (Table 2). Baseline NYHA class showed a trend toward poorer survival (HR 1.81, 95% CI 0.90 –3.62, P ⫽ .093), whereas baseline ECG heart rate (HR 0.98, 95% CI 0.95–1.00, P ⫽ .071) and percentage of biventricular pacing showed a trend toward lower mortality (HR 0.98, 95% CI 0.95–1.00, P ⫽ .094). In multivariate analysis, after adjusting for NYHA and LVEF, AVN ablation showed an independent association with survival benefit from death after CRT (HR 0.13, 95% CI 0.03– 0.58, P ⫽ .007) and survival benefit from combined events of death, heart transplant, and LV assist device implant as shown in table 3 (HR 0.19, 95% CI 0.06 – 0.62, P ⫽ .006).
Discussion Main findings Patients with AF who undergo CRT and concomitant AVN ablation may experience improved survival as well as improvement in NYHA class, LV systolic function, and reversal of LV structural remodeling. Furthermore, AVN ablation was an independent predictor of improved all-cause mortality and combined events of death, heart transplant, and LV assist device.
1244 Table 2
Heart Rhythm, Vol 7, No 9, September 2010 Univariate predictors for survival after CRT
Variable
No.
Hazard ratio
95% Confidence interval
P value
Age at implant Male gender Ischemic cardiomyopathy NYHA LVEF LVEDD LVESD MR Left atrial volume ECG heart rate Holter minimum heart rate Holter average heart rate Holter maximum heart rate Digoxin Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker Beta-blocker AVN ablation Biventricular pacing percentage
154 154 154 154 149 137 77 133 114 148 48 48 48 153 151 153 154 113
1.01 0.62 1.34 1.81 0.98 0.99 1.00 2.00 1.00 0.98 1.00 1.00 0.97 1.16 1.14 1.54 0.27 0.98
(0.97, (0.23, (0.67, (0.90, (0.93, (0.95, (0.94, (1.22, (0.99, (0.95, (0.94, (0.93, (0.92, (0.54, (0.35, (0.67, (0.09, (0.95,
.672 .331 .409 .093 .551 .624 .947 .006 .387 .071 .869 .877 .157 .700 .833 .313 .014 .094
1.04) 1.63) 2.67) 3.62) 1.04) 1.03) 1.07) 3.26) 1.01) 1.00) 1.05) 1.06) 1.01) 2.53) 3.74) 3.54) 0.77) 1.00)
AVN ⫽ atrioventricular nodal; CRT ⫽ cardiac resynchronization therapy; LVEDD ⫽ left ventricular end-diastolic dimension; LVEF ⫽ left ventricular ejection fraction; LVESD ⫽ left ventricular end-systolic dimension; MR ⫽ mitral regurgitation; NYHA ⫽ New York Heart Association functional class.
Efficacy of CRT in patients with AF HF and AF are the most common cardiovascular disorders that often coexist.16 The prevalence of AF is related to the extent of LV dysfunction and the patient’s HF status.5 In patients with preexisting LV dysfunction, AF may further aggravate HF symptoms, resulting in a vicious cycle. CRT has proved to be beneficial in improving HF symptoms, LV structural remodeling, and function in patients with drugrefractory HF and AF.6 –12 However, the role of AVN ablation in facilitating full biventricular resynchronization has been underinvestigated. Limited data regarding the concomitant use of AVN ablation in patients with AF who are receiving CRT have been reported.7,17 The focus of this study was to determine the impact of AVN ablation on CRT clinical and survival outcomes. We presented 154 patients with AF who received CRT for advanced HF in a large single center. One third of these patients underwent AVN ablation at the time of device implant, before or after CRT. Patients who underwent AVN ablation had a higher resting and maximum heart rate than Table 3
Multivariate predictors for survival after CRT
Variable Model 1: Survival to Death AVN ablation NYHA LVEF Model 2: Survival To Death/ Heart Transplant/ Left Ventricular Assist Device AVN ablation NYHA LVEF
Hazard ratio
95% Confidence interval
P value
0.13 1.76 1.02
0.03, 0.58 0.75, 4.09 0.96, 1.09
.007 .192 .553
0.19 1.89 1.00
0.06, 0.62 0.86, 4.15 0.94, 1.06
.006 .112 .859
AVN ⫽ atrioventricular nodal; CRT ⫽ cardiac resynchronization therapy; LVEF ⫽ left ventricular ejection fraction; NYHA ⫽ New York Heart Association functional class.
did those without AVN ablation. It is apparent that persuasion of these patients toward AVN ablation was made to ensure the adequacy of biventricular resynchronization. Improvement in HF symptoms, NYHA functional class, LV systolic function, and reversal of LV remodeling was observed in both ⫹AVN-ABL and –AVN-ABL groups after CRT. The results corroborate findings from previous studies that CRT is beneficial in ventricular resynchronization alone, despite the lack of atrial ventricular synchrony in these patients.6 –12 Furthermore, the ⫹AVN-ABL groups had a more significant improvement in NYHA class compared to the –AVN-ABL group. A higher percentage of biventricular pacing, adequate control of ventricular rate, and elimination of ventricular irregularity, especially during exercise, may better explain HF symptomatic control. Improvement in NYHA class and LVEF was comparable in patients who received de novo device and those who had upgrade of an existing device to CRT-D. The detrimental effect of chronic right ventricular pacing in the presence of LV dysfunction is known.18,19 In the LV-based cardiac stimulation Post AV Nodal Ablation Evaluation (PAVE) study, improved functional capacity by assessing the 6-minute walk test and ejection fraction was observed in the biventricular pacing group compared to the right ventricular pacing alone group.19
AVN-ABL is independent predictor of survival after CRT Ozcan et al20 addressed the impact of AVN ablation and permanent pacing on long-term survival in the AF population. In the absence of underlying heart disease, survival after AVN ablation was neutral, as expected, in the general population. The clinical and survival benefit of permanent AVN ablation in recipients of CRT-D with advanced cardiomyopathy is underinvestigated. Our observation may suggest that AVN ablation improves survival in this patient population. The only published results on this subject were reported by Gasparini et al,17 who showed a favorable survival benefit from AVN ablation in
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patients with AF who received CRT-D (40%) and CRT-P (60%) devices, compared to those who received drug therapy for rate control. All patients in both the ⫹AVN-ABL and –AVN-ABL groups in our study cohort received CRT-D. Our findings show improved overall survival in patients receiving CRT with AVN ablation, compared with those receiving CRT and drug therapy. In our study, patients who underwent AVN ablation demonstrated lesser severity of NYHA class function and higher LVEF compared to those without AVN ablation at baseline. This group of patients may be less sick before CRT; nevertheless, we found that AVN ablation is an independent predictor of survival post-CRT after controlling for LVEF and NYHA (previously unreported observation). AVN ablation provides complete heart rate control and rhythm regularity in AF,17 an advantage of overcoming high ventricular rate and ventricular irregularity-induced cardiomyopathy.21–23 The higher percentage of biventricular pacing may be another explanation for improved survival in patients undergoing AVN ablation.24 Because we routinely program ventricular-sensed response pacing to the “on” setting for patients with AF and some devices do not have the algorithm to separate true-paced beats from sense-paced beats, the percentage of “clean” versus “fused” biventricular pacing that may be minimally resynchronized is not known. Patients with AVN ablation may have received not only a higher percentage of biventricular pacing but also a higher quality of truly paced resynchronization. A well-designed prospective study may more accurately assess the efficacy and survival benefit of true (complete) and fused (partial) resynchronization. Nevertheless, we agree with Gasparini et al,7 who assert that achieving maximal biventricular pacing time is essential to attaining the full benefit of CRT.
Study limitations This observational study has several limitations. Some baseline characteristics between the two groups were different (e.g., patients in the ⫹AVN-ABL group had a higher resting and maximal heart rate, reflecting our clinical preference for definitive heart rate control in patients with a high ventricular rate). Among patients undergoing AVN ablation, most had intervention at the time of CRT implant. A future randomized study would be important to eliminate patient selection bias. Second, the two groups of patients in the study were not numerically balanced. The death events in the ablation group are small. To address the role of AVN ablation in long-term survival, large-scale randomized studies targeting the AF and HF population are needed.17,25
Conclusion In this large, single-center study, AVN ablation improved long-term survival in patients with AF and advanced HF requiring CRT compared to patients who received drug therapy. These data suggest that AVN ablation could be considered sooner in the treatment algorithm for patients with AF undergoing CRT. Prospective randomized studies are needed to further address the efficacy and survival rates of patients with AF who receive CRT and AVN ablation.
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References 1. Abraham W, Fisher W, Smith A, Delurgio D, Leon A. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 2. Bristow M, Saxon L, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140 –2150. 3. Cleland J, Daubert J, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539 –1549. 4. Stellbrink C, Breithardt O, Franke A, et al. Impact of cardiac resynchronization therapy using hemodynamically optimized pacing on the left ventricular remodeling in patients with congestive heart failure and ventricular conducti0n disturbances. J Am Coll Cardiol 2001;38:1957–1965. 5. Maisel W, Stevenson L. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91:2D– 8D. 6. Delnoy P, Ottervanger J, Luttikhuis H, et al. Comparison of usefulness of cardiac resynchronization therapy in patients with atrial fibrillation and heart failure versus patients with sinus rhythm and heart failure. Am J Cardiol 2007;99:1252–1257. 7. Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol 2006;48:734 –743. 8. Khadjooi K, Foley PW, Chalil S, et al. Long-term effects of cardiac resynchronisation therapy in patients with atrial fibrillation. Heart 2008;94:879 – 883. 9. Leclercq C, Victor F, Alonso C, et al. Comparative effects of permanent biventricular pacing for refractory heart failure in patients with stable sinus rhythm or chronic atrial fibrillation. Am J Cardiol 2000;85:1154 –1156. 10. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002;40:111–118. 11. Molhoek S, Bax J, Bleeker G, et al. Comparison of response to cardiac resynchronization therapy in patients with sinus rhythm versus chronic atrial fibrillation. Am J Cardiol 2004;94:1506 –1509. 12. Upadhyay G, Choudhry N, Auricchio A, Ruskin J, Singh J. Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies. J Am Coll Cardiol 2008;52:1239 –1246. 13. Epstein A, DiMarco J, Ellenbogen K, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 2008;117:e350 – e408. 14. Cha Y, Rea R, Wang M, et al. Response to cardiac resynchronization therapy predicts survival in heart failure: a single-center experience. J Cardiovasc Electrophysiol 2007;18:1015–1019. 15. Owan T, Hodge D, Herges R, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251–259. 16. Ehrlich J, Nattel S, Hohnloser S. Atrial fibrillation and congestive heart failure: specific considerations at the intersection of two common and important cardiac disease sets. J Cardiovasc Electrophysiol 2002;13:399 – 405. 17. Gasparini M, Auricchio A, Metra M, et al. Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of atrio-ventricular junction ablation in patients with permanent atrial fibrillation. Eur Heart J 2008;29:1644–1652. 18. Wilkoff B, Cook J, Epstein A, et al. Dual-chamber pacing or ventricular back-up pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002;288:3115–3123. 19. Doshi R. Optimizing resynchronization therapy: can we increase the number of true responders? J Cardiovasc Electrophysiol 2005;16(Suppl 1):548 –551. 20. Ozcan C, Jahangir A, Friedman P, 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;344:1043–1051. 21. Grogan M, Smith H, Gersh B, Wood D. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Am J Cardiol 1992;69:1570 –1573. 22. Kieny J, Sacrez A, Facello A, et al. Increase in radionuclide left ventricular ejection fraction after cardioversion of chronic atrial fibrillation in idiopathic dilated cardiomyopathy. Eur Heart J 1992;13:1290 –1295. 23. Wasmund S, Li J, Page R, Wood D. Effect of atrial fibrillation and an irregular ventricular response on sympathetic nerve activity in human subjects. Circulation 2003;107:2011–2015. 24. Spears D, Selvaraj R, Dhopeswarkar R, Nanthakumar K. Atrial tracking with a single ICD lead in the ventricular. J Cardiovasc Electrophysiol 2008;19:440 – 441. 25. 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 J 2007;4:224 –232.