Abstract

Aims To determine long-term effects of atrioventricular junction ablation and pacing (AVJAP) on cardiac function and quality of life.

Methods and results Prospective follow-up was performed on consenting patients recruited in two participating centres representing majority of the Australian intervention randomized control of rate in atrial fibrillation trial (AIRCRAFT) cohort after 4–7 years. All patients underwent history, physical examination, 24 h ambulatory ECG monitoring, and transthoracic echocardiogram. Quality of life questionnaires in original AIRCRAFT trial were re-administered including CAST, assessment quality of life, and sickness impact profile. Of the 63 eligible patients, 14 refused participation, and 1 patient was lost to follow-up. The remaining 48 patients (25 males, current mean age 74 ± 7.5 years), 23 randomized to AVJAP and 25 to pharmacologic therapy (MED) were re-evaluated. In the MED group, LVEF was 62 ± 11% at baseline, 63 ± 10% at 6 months, 64 ± 9% at 12 months, and 59 ± 12% at 5 years (P < 0.01). In the AVJAP group LVEF was 54 ± 19% at baseline, 55 ± 13% at 6 months, 53 ± 15% at 12 months, and 51 ± 17% at 5 years (P = 0.02). NYHA functional class was not statistically different between MED and AVJAP patients (1.4 vs. 1.5, P = 0.48). Death occurred in 10 MED and 5 AVJAP patients. Survival analysis incorporating all 63 patients showed no statistical difference between the 2 treatment groups (P = 0.26). The CAST quality of life questionnaire revealed that patients in the AVJAP group had fewer symptoms of irregular heart beat (P < 0.001), chest pain (P = 0.02), and difficulty breathing (P = 0.02). Psychosocial scores and overall life satisfaction were similar (P > 0.05).

Conclusion In this long-term follow-up of the AIRCRAFT cohort, similar decline in LVEF and NYHA class was observed in both treatment groups. AVJAP patients have better quality of life with fewer symptoms. Based on improved quality of life, ablate and pace strategy for permanent atrial fibrillation should be considered for highly symptomatic patients refractory to pharmacologic therapy.

Introduction

The AFFIRM trial1 demonstrated that ventricular rate control is an acceptable therapeutic strategy for symptomatic patients with atrial fibrillation (AF). In most cases, control of ventricular rate is achieved with pharmacologic therapy (MED), with atrioventricular junction ablation and pacing (AVJAP) reserved for patients in whom medications are insufficient or associated with side effects (Class IIa indication).2 AVJAP may however be an attractive option for some elderly patients who are non-compliant to medications. There are very few long-term follow-up studies on patients undergoing AVJAP.

The Australian intervention randomized control of rate in atrial fibrillation trial (AIRCRAFT)3 was a multicentre, prospective, randomized trial comparing AVJAP to pharmacologic treatment in patients with permanent AF. At 12 months follow-up, there were no significant difference in left ventricular ejection fraction (LVEF) or exercise duration on treadmill testing between the groups but the AVJAP patients had better ventricular rate control, fewer symptoms and improvement in quality of life. Most studies have limited follow-up period similar to AIRCRAFT. The potentially deleterious effects of ventricular dyssynchrony from right ventricular (RV) apical pacing might manifest in the longer term beyond the rather limited follow-up of previously reported studies.

The purpose of this study is to describe the long-term effects of AVJAP on cardiac function and quality of life in AIRCRAFT cohort.

Methods

In this study, long-term follow-up was performed on AIRCRAFT patients in the 2 largest participating centres (Royal Perth Hospital and Hollywood Private Hospital. Nedlands, Western Australia) representing 63 of 81 patients (78%) of the study cohort, 4–7 years after initial randomization. For logistical reasons, it was not possible to follow-up patients in other centres.

Study protocol

The study protocol was approved by the Ethics Committee of the Royal Perth Hospital in February 2005. Follow-up of all eligible patients commenced in June and continued until October 2005.

The study inclusion criteria were: AIRCRAFT patients recruited in either Royal Perth or Hollywood Private Hospitals.6 Inclusion trial in AIRCRAFT was

  • age > 40 years;

  • symptomatic permanent AF with uncontrolled ventricular rate defined as resting heart rate (HR) >80 and exercise HR > 150 after a screening period of 3 months;

  • ability to give informed consent, and to perform a treadmill test.

The exclusion criteria were

  • unwillingness or inability to cooperate or to give informed consent.

The primary end-point was cardiac function measured by echocardiography. The secondary end-points were ventricular rate control (evaluated by 24 h Holter) and quality of life.

Patient evaluation method

All recruited patients in the two of five centres were invited to participate in this study. An invitation letter was sent initially to the patient and if there was no response, a telephone follow-up was made by the research nurse. All patients who re-consented for the study underwent detailed history and physical examination (including assessment of NYHA class), a 12-lead ECG, a 24 h ambulatory ECG monitoring, echocardiography estimation of LV function (ejection fraction and chamber size).

Quality of life assessment

In the AIRCRAFT trial, the questionnaires administered comprised of the assessment quality of life questionnaire (AQoL),4 the CAST quality of life questionnaire,5 and the sickness impact profile (SIP).6 These questionnaires were re-administered to consented patients during the follow-up assessment.

Survival analysis

All eligible patients were included in the survival data. In cases where the patients were uncontactable, hospital/state-wide medical database were searched for hospitalization records or death and the final cause of death ascertained from the Western Australian Registry of births, deaths, and marriages. Survival analysis included the patients who refused study participation.

Statistical analysis

Independent statistical analysis was undertaken with the assistance of the bio-statistical consulting service of the University of Western Australia (demographic, cardiac function and ventricular rate and quality of life data). Data were analysed using the SSPS software package. The intent-to-treat principal was used for all analyses. Continuous variables were compared using the t-test and categorical variables were compared using Pearson χ2 test. The quality of life questionnaires were scored according to rules of the original authors. The quality of life data were analysed using the Mann–Whitney U-test (two-sided) for non-parametric independent samples; because a large number of statistical tests were performed, only P-values less than 0.01 were considered significant similar in the AIRCRAFT trial6. For all data other than the quality of life data, a P-value less than 0.05 was considered significant.

Results

Out of a total of 63 eligible patients (28 AVJAP and 35 MED patient), 14 patients refused participation, while 1 patient was unable to be contacted because he had moved overseas, 8 patients (53%) were over 80 years of age. Cited reasons for not participating in this follow-up study included eight (53%) for physical frailty, two (13%) patients with dementia, two (13%) had terminal malignancy, two (13%) disinterested although they were well. The remaining 48 patients (25 males, current mean age 74 ± 7.5 years) with 23 randomized to AVJAP and 25 randomized to MED were re-evaluated.

The patient characteristics of both groups were well matched for age, gender ratio and there was no statistical difference in structural heart disease such as ischemic heart disease, valvular heart disease, or dilated cardiomyopathy (Table 1), while the incidence of hypertension (87 vs. 39%, P = 0.005) and diabetes (40 vs. 6%, P = 0.016) were both higher in the MED group.

Table 1

Patient characteristics

 MEDn = 15 AVJAPn = 18 P Remaining populationn = 33 
Age, years 73. ± 6.8 75 ± 8.0 0.446* 74 ± 7.5 
Male gender 72% 80% 0.604 76% 
Ischemic heart disease 47% 39% 0.653 42% 
Dilated cardiomyopathy 7% 11% 0.658 9% 
Valvular heart disease 0% 11% 0.183 6% 
Hypertension 87% 39% 0.005 61% 
Diabetes 40% 6% 0.016 21% 
 MEDn = 15 AVJAPn = 18 P Remaining populationn = 33 
Age, years 73. ± 6.8 75 ± 8.0 0.446* 74 ± 7.5 
Male gender 72% 80% 0.604 76% 
Ischemic heart disease 47% 39% 0.653 42% 
Dilated cardiomyopathy 7% 11% 0.658 9% 
Valvular heart disease 0% 11% 0.183 6% 
Hypertension 87% 39% 0.005 61% 
Diabetes 40% 6% 0.016 21% 

P-values obtained using Pearson χ2 test.

* denotesP-value obtained with two-samplet-test.

Pharmacologic treatment

Figure 1A and B outlines the pharmacological treatment used in the MED and AVJAP patients. Most patients in the MED group were on concomitant therapy for ventricular rate control. Pharmacologic therapy was withdrawn in two MED patients due to bradycardia-related symptoms. In AVJAP patients, hypertension and ischemic heart disease and cardiac failure were the most common reasons for continuation of MEDs which block AV conduction. Concomitant therapy (>1 MEDs) occurred in 10 (67%) MED patients primarily to control ventricular rate.

Figure 1

Pharmacologic therapy in MED and AVJAP patients.

Figure 1

Pharmacologic therapy in MED and AVJAP patients.

Cardiac function and performance

Biplane quantification of LV volume and ejection fraction measurements using Simpson's method were not routinely performed during the initial recruitment of patients due to suboptimal images with the older echocardiographic machines. The Teicholz formula was used to calculate LVEF in the initial AIRCRAFT trial. To maintain consistency of echocardiographic data and allow comparisons between baseline parameters, 6 and 12 months, we elected to use the Teicholz method in this current follow-up study. Visual verification of LV systolic function was performed by two experienced echocardiologists.

LVEF data were available at baseline, 6 months, 12 months, and 5 years in 10 MED and 12 AVJAP patients. In the AIRCRAFT trial, LVEF was not available for 5 MED and 6 AVJAP patients due to suboptimal imaging quality and concerns of data inaccuracy. Similar decline in mean LVEF was observed in MED and AVJAP patients at baseline compared to 5 years (Figure 2A and B). In the MED group, LVEF was 62 ± 11% at baseline, 63 ± 10% at 6 months, 64 ± 9% at 12 months, and 59 ± 12% at 5 years (P < 0.01). In the AVJAP group, LVEF was 54 ± 19% at baseline, 55 ± 13% at 6 months, 53 ± 15% at 12 months, and 51 ± 17% at 5 years (P = 0.02).

Figure 2

Changes in left ventricular ejection fraction (LVEF) in MED and AVJAP patients.

Figure 2

Changes in left ventricular ejection fraction (LVEF) in MED and AVJAP patients.

The degree of mitral regurgitation (MR) is graded by the reporting cardiologist (nil = 0, mild = 1, moderate = 2, and severe = 3). The mean score was higher but not statistically different in the AVJAP group (1.3 vs. 1.2, P = 0.09).

NYHA functional class was not statistically different between MED and AVJAP patients (1.4 vs. 1.5, P = 0.48).

Holter monitor

Patients in the AVJAP group had a higher minimum HR (60 vs. 45 bpm, P = 0.001) (Table 2). The peak HR during activities of daily life was 108 ± 12 bpm (AVJAP) vs. 132 ± 29 bpm (MED), P < 0.01. The mean HR was 79 ± 6 bpm (AVJAP) vs. 72 ± 11 bpm (MED), P > 0.05. Differences in the minimum and maximum HR may reflect device programming, with the pacing rate and degree of rate response determined by the treating physician according to the perceived patient needs and activity levels.

Table 2

Holter results

 Baseline 6 months 12 months 4–6 years 
 MED n = 50 AVJAP n = 49 MED n = 49 AVJAP n = 36 MED n = 47 AVJAP n = 34 MED n = 15 AVJAP n = 18 
Holter         
Minimum HR (bpm) 41 ± 12 41 ± 17 42 ± 12 70 ± 7* 39 ± 9 70 ± 9* 44 ± 13 60 ± 9* 
Mean HR (bpm) 77 ± 17 79 ± 20 76 ± 17 77 ± 6 71 ± 11 76 ± 7* 72 ± 11 79 ± 6 
Maximum HR (bpm) 153 ± 37 152 ± 41 150 ± 39 116 ± 19* 152 ± 37 117 ± 16* 132 ± 29 108 ± 12* 
 Baseline 6 months 12 months 4–6 years 
 MED n = 50 AVJAP n = 49 MED n = 49 AVJAP n = 36 MED n = 47 AVJAP n = 34 MED n = 15 AVJAP n = 18 
Holter         
Minimum HR (bpm) 41 ± 12 41 ± 17 42 ± 12 70 ± 7* 39 ± 9 70 ± 9* 44 ± 13 60 ± 9* 
Mean HR (bpm) 77 ± 17 79 ± 20 76 ± 17 77 ± 6 71 ± 11 76 ± 7* 72 ± 11 79 ± 6 
Maximum HR (bpm) 153 ± 37 152 ± 41 150 ± 39 116 ± 19* 152 ± 37 117 ± 16* 132 ± 29 108 ± 12* 

Values are mean ± SD. n, number of patients.

*P < 0.05.

Quality of life

The CAST quality of life questionnaire revealed that patients in the AVJAP group had fewer symptoms of irregular heart beat (P < 0.001), chest pain (P = 0.02), and difficulty breathing (P = 0.02). Psychosocial scores and overall life satisfaction were similar (P > 0.05). The overall SIP scores were not statistically different between the groups (P = 0.16) but physical scores were lower in AVJAP patients (P = 0.04) implying better physical function. AQoL questionnaires were not significantly different.

Adverse events, deaths, and survival

Two patients in the AVJAP group had their pacemaker upgraded to a biventricular device due to development of symptomatic heart failure. One patient in the MED group underwent a pacemaker implantation due to AF with prolonged pause of 5 s. One patient in the AVJAP arm had documented failure to capture related to partial lead fracture during the follow-up Holter monitor and underwent an emergency insertion of new pacemaker lead.

Clinical follow-up was performed in the 33 remaining patients (15 MED and 18 AVJAP). Of the 10 deaths in the MED group, one patient died of myocardial infarction/cardiac arrest, one pulmonary oedema/advanced cardiomyopathy, one massive subdural haemorrhage, two terminal malignancy, one septicaemia, and four were classified as ‘multi-organ failure’ in the setting of severe heart failure (two patients have chronic renal failure, one precipitated by sepsis–pneumonia, one ischaemic bowel). In AVJAP patients, one patient died of ventricular fibrillation (VF) arrest, one death was related to ischaemic foot and progressive sepsis, and three patients had terminal malignancy. There were a total of 15 deaths after mean 5.4 ± 0.9 years involving 10 MED and 5 AVJAP patients. Kaplan–Meier survival curve incorporating all participating and non-participating patients revealed no significant difference in survival between MED and AVJAP patients (P = 0.26) (Figure 3).

Figure 3

Kaplan-Meier survival analysis.

Figure 3

Kaplan-Meier survival analysis.

Discussion

This study provides rare long-term follow-up of a randomized study comparing AVJAP with pharmacological rate control in permanent AF. Ablation of the AV junction is often performed for permanent AF in patients with refractory symptoms. Despite earlier reports suggesting beneficial effects on cardiac function following AVJAP, several studies with longer follow-up have shown decline in LV function. In this long-term follow-up of the AIRCRAFT cohort, a similar decline in LVEF and NYHA class was seen in the AVJAP group, however, a similar decline was also observed in the MED group and Kaplan–Meier survival was not statistically different. In the longer term, AVJAP patients have better quality of life with fewer symptoms. Concerns of detrimental effects of RV apical pacing were not observed in this very small cohort.

The patient demographics were equally matched in the AIRCRAFT trial. Statistical difference in hypertension in this follow-up study could be explained by the fact that two patients in the AVJAP group who previously had hypertensive was now relatively hypotensive from progressive cardiomyopathy—both required upgrading to biventricular pacemakers. In addition, two MED patients were now hypertensive and this may reflect essential hypertension or may be related to MEDs such as use of prednisolone in a patient with severe chronic obstructive airways disease.

Trends in pharmacologic prescribing

It is generally known that digoxin is probably not as effective compared to beta-blockers or calcium channel blockers for ventricular rate control, especially during exercise when vagal tone is low and sympathetic tone high.7–9 Despite this, a significant proportion of MED patients were treated with digoxin alone and this concurs with observation from previous surveys suggesting the widespread use of digoxin to control ventricular rate.10 Ventricular rate controlling medications were not prescribed in two MED patients due to symptomatic bradycardia.

In AVJAP patients, the indication for digoxin was for heart failure and is prescribed at the discretion of the treating physician. Although digoxin use has not been associated with mortality benefit, the DIG trial demonstrated reduced rate of hospitalization.11 In the case of patients with heart failure, beta-blockers used were carvedilol or metoprolol. Calcium channel blockers were used in AVJAP patients for control of hypertension. Concomitant therapy (>1 medications) was prescribed in MED patients primarily for rate control while in AVJAP patients, the indication was for heart failure.

Changes in cardiac function

Although a decline in LVEF was observed in AVJAP patients, similar decline was observed in the MED group, which reflects perhaps not only deleterious effects of RV pacing but also natural evolution of AF and of underlying disease.

Severe MR is an important but uncommon cause of clinical deterioration after AV junction ablation.12 In a study of 256 patients, 5% (14 patients) developed haemodynamically significant compromising MR. Our study did not demonstrate significant differences in development of MR between AVJAP and MED patients.

In patients with symptomatic AF, an ablate and pace strategy is associated with symptom improvement in comparison to pharmacologic ventricular rate control as well as improvement in cardiac function.13–17 Improvements in cardiac function may be related to reversal of tachycardia-related cardiomyopathy or haemodynamic effects of a regular ventricular rhythm.17,18

Acute and long-term benefits of AVJAP by eliminating rhythm irregularity17 was observed in a study of 50 patients comprising of 21 AVJAP and 29 medically managed patients. Acute haemodynamic data before and 15 min after ablation (during RV pacing) demonstrated increased cardiac output (4.7 ± 0.8 vs. 5.2 ± 0.9 L/min; P = 0.05), decreased pulmonary capillary wedge pressure (16 ± 5 vs. 13 ± 4 mmHg; P = 0.001), and decreased LV end-diastolic pressure (14 ± 4 vs. 11 ± 3 mmHg; P < 0.05). Increased LVEF was observed in AVJAP patients (44 ± 6% vs. 49 ± 5%; P = 0.02) at 12 months.

In the ablate and pace trial,15 NYHA functional class improved from 2.1 at baseline to 1.8 at 3 months, and 1.9 at 12 months of follow-up (P = 0.0001). The mean LVEF improved from 0.50 ± 0.20 at baseline to 0.54 ± 0.20 at 3 months (P = 0.03) but at 12 months 0.52 ± 0.20 (not statistically significant). Patients with reduced systolic function at baseline had the greatest improvement of LVEF from 0.31 ± 0.20 at baseline to 0.41 ± 0.20 at 3 months and 0.41 ± 0.30 at 12 months (P = 0.0001).

Manolis et al.19 also reported significant improvement of LVEF following AVJAP in a study of 30 patients with drug refractory atrial tachycarrhythmias and heart failure. In contrast, the randomized study of 66 AF patients with clinical heart failure by Brignole et al.16 did not demonstrate significant differences in NYHA functional class, or objective measures of cardiac function. The AIRCRAFT trial,3 the most recent randomized study, also did not show differences in cardiac function measured by ejection fraction during a 12 months follow-up.

There have been concerns of the possible detrimental impact of RV apical pacing in recent years. Szili-Torok et al.20 reported significant decline in LVEF 3 months after AVJAP. Negative impact of AVJAP on LV remodelling was observed in a long-term follow-up of 7 ± 2 years by Vernooy et al.21 In this study, LV dimensions, LV mass, left atrial diameter, and MR all increased while LVEF decreased.

Another recent study by Tops et al.22 has also questioned longer-term effects of AVJAP on cardiac function. In 55 patients with drug-refractory AF undergoing AVJAP, 27 patients (49%) had developed LV dyssynchrony after a mean of 3.8 ± 1.7 years. In these patients, worsening of NYHA functional class (from 1.8 ± 0.6 to 2.2 ± 0.7, P < 0.05), with a decrease in LVEF (from 48 ± 7% to 43 ± 7%, P < 0.05) and an increase in LV end-diastolic volume (from 116 ± 39 to 130 ± 52 ml, P < 0.05) was observed. In patients without LV dyssynchrony, heart failure symptoms, LV function, or LV volumes remained stable.

Upgrading to biventricular pacing has been reported to improve LV performance and functional state. Biventricular pacing have also been superior to RV pacing in patients with impaired LVEF and permanent AF.23,24 The PAVE trial demonstrated significant improvement in 6-min walk test, 6 months post-ablation in the biventricular pacing group compared to RV pacing,25 particularly in those with ejection fraction ≤45% or with NYHA Class II/III symptoms. Furthermore, emerging data on longer-term follow-up of 4 years of CRT following ablation of AV junction demonstrated significant increase in ejection fraction.25 Beneficial effects on LV parameters/ejection fraction, functional class and symptoms by upgrading to biventricular pacing has been shown in previous studies.26,27 In a small study of 13 patients, undergoing AV junction ablation, RV apex pacing was associated with reduced LV compliance and increase in MR while shifting the pacing site to RVOT reduces the degree of MR.28

Other investigators have studied selective site pacing in non-RV apical locations which may be preferable in cases where it is not possible to pace the left ventricle.29 Bifocal RV pacing has also been suggested as an alternative to biventricular pacing.30

Adverse events, death, and survival

Although there was a difference in mortality rate between the 2 patient groups (10 MED patients and 5 AVJAP), the study was not sufficiently powered to examine this as an endpoint. Arrhythmic cause of death was present in one MED patient (in the setting of acute myocardial infarction) and one patient in the AVJAP group (VF arrest). Although there have been concerns about sudden death following AVJAP31 possibly due to bradycardia-dependent QT prolongation leading to VF, recent publications have disputed this association with AVJAP.31,32 Life-threatening ventricular arrhythmias may occur after AVJAP33,34 but usually occur early. Kaplan–Meier survival suggested no statistical difference in survival between the groups.

Long term effects of AVJAP on survival has been reported in a non-randomized study35 for patients with LVEF < 40%. Survival was significantly lower in patients without improvement in LVEF (29% of patients = 16 of 56 patients) compared to similar control group taken from age and gender-matched normal subjects drawn from the Minnesota population. The subset of patients with improvement in LVEF had similar survival to control group.

In a series of 350 patients from the Mayo Clinic,32 AVJAP was not associated with increase mortality in the absence of underlying heart disease during a mean follow-up of 3 years. In the absence of prior myocardial infarction, a history of HF, and requirement for cardiac drug therapy after ablation expected survival was the same as in the general population and in patients who received pharmacologic therapy for rate control.

Quality of life

Analysis of the CAST quality of life questionnaires showed improvement in quality of life with significantly lower symptoms of irregular heart beat, chest pain, and breathlessness in AVJAP patients while overall life satisfaction and psychosocial scores were similar. The AQoL and SIP questionnaires are not disease specific and provide a global impression of health-related quality of life but the better SIP physical scores would also support improved quality of life among AVJAP patients.

Published studies have also shown consistently improved quality of life for patients undergoing AVJAP. Ueng et al. demonstrated improvement in quality of life at 12 months after ablation, with significantly lower scores in general quality of life (−20%; P < 0.001), improvement of overall symptoms (−24%; P < 0.001), and overall activity scale (−23%; P = 0.004). In the ablate and pace trial, quality of life measured at 3 and 12 months after catheter ablation showed significant improvement in quality of life scores for all 8 subscales of the health status questionnaire, overall rating of the quality of life index, the health and function subscales, and arrhythmia-related symptoms were markedly reduced as measured by the Symptom Checklist: Frequency and Severity scale.15

Study limitations

The main limitation of this study is the small cohort group due largely to the proportion of patients who refused follow-up. A vast majority of patients 8 (53%) were over 80 years of age, 2 (13%) had significant cognitive impairment, and 2 (13%) declined, due to terminal malignancy, highlighting the difficulties in following up elderly patient cohorts. Majority of patients 8 (53%) cited physical frailty as the reason precluding participation in this study. Mindful of this, the exercise test component of the initial protocol was omitted. Despite our endeavours, we were unable to persuade the remaining patients to participate in this study. At the time of initial recruitment of AIRCRAFT trial, Teicholz formula was used to assess EF. The imaging quality on the older echocardiographic machines was suboptimal to allow accurate assessment of LV volume and Simpson's biplane method to calculate ejection fraction. To maintain consistency of measurements and allow direct comparisons of ejection fractions, LVEF was estimated using the Teicholz formula. Cardiac function was visually verified and graded by two experienced echocardiologists. In addition, not all echo data was available in all patients at baseline during the AIRCRAFT trial due to suboptimal transthoracic imaging.

Conclusions

In this long-term follow-up of the AIRCRAFT cohort, similar decline in LVEF and NYHA class was observed in both treatment groups. AVJAP patients have better quality of life with fewer symptoms. Based on improved quality of life, ablate and pace strategy for permanent AF should be considered for highly symptomatic patients refractory to pharmacologic therapy.

Conflict of interest: none declared.

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Supplementary data