CLINICAL RESEARCH
Europace (2014) 16, 1772–1778 doi:10.1093/europace/euu171
Pacing and resynchronization therapy
Predictors of hospitalization for heart failure and of all-cause mortality after atrioventricular nodal ablation and right ventricular pacing for atrial fibrillation Anna Bjo¨rkenheim 1,2*, Axel Brandes 3, Tommy Andersson 1,2, Anders Magnuson 4, Nils Edvardsson 5, Birger Wandt 6, Henriette Sloth Pedersen 3, and Dritan Poc¸i 1,2 1 ¨ rebro University Hospital, O ¨ rebro, Sweden; 2Department of Medicine, O ¨ rebro University, O ¨ rebro, Sweden; 3Department of Cardiology, Odense Department of Cardiology, O ¨ rebro University Hospital, O ¨ rebro, Sweden; 5Sahlgrenska Academy, Sahlgrenska University University Hospital, Odense, Denmark; 4Clinical Epidemiology and Biostatistics Unit, O ¨ rebro University, O ¨ rebro, Sweden Hospital, Go¨teborg, Sweden; and 6School of Health and Medical Sciences, O
Received 27 April 2014; accepted after revision 4 June 2014; online publish-ahead-of-print 16 July 2014
Atrioventricular junction ablation (AVJA) is a highly effective treatment in patients with therapy refractory atrial fibrillation (AF) but renders the patient pacemaker dependent. We aimed to analyse the long-term incidence of hospitalization for heart failure (HF) and all-cause mortality in patients who underwent AVJA because of AF and to determine predictors for HF and mortality. ..................................................................................................................................................................................... Methods We retrospectively enrolled 162 consecutive patients, mean age 67 + 9 years, 48% women, who underwent AVJA because of symptomatic AF refractory to pharmacological treatment (n ¼ 117) or unsuccessful repeated pulmonary and results vein isolation (n ¼ 45). Hospitalization for HF occurred in 32 (20%) patients and 35 (22%) patients died, representing a cumulative incidence for hospitalization for HF and mortality over the first 2 years after AVJA of 9.1 and 5.2%, respectively. Hospitalization for HF occurred to the same extent in patients who failed pharmacological treatment as in patients with repeated pulmonary vein isolation (PVI), although the mortality was slightly higher in the former group. QRS prolongation ≥120 ms and left atrial diameter were independent predictors of hospitalization for HF, while hypertension and previous HF were independent predictors of death. ..................................................................................................................................................................................... Conclusion The long-term hospitalization rate for HF and all-cause mortality was low, which implies that long-term ventricular pacing was not harmful in this patient population, including patients with unsuccessful repeated PVI.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Atrial fibrillation † Atrioventricular junction ablation † Heart failure † Hospitalization † Mortality
Introduction Atrial fibrillation (AF) affects 1–2% of the general population and its prevalence is estimated to double over the next 50 years.1 Radiofrequency catheter ablation of the atrioventricular node, so-called atrioventricular junction ablation (AVJA), is a highly effective treatment when pharmacological rate control and/or rhythm control have failed to control the ventricular rate.1 Atrioventricular junction ablation has been shown to reduce symptoms and healthcare utilization2
and to increase the quality of life.3,4 Patients, however, become permanently pacemaker dependent after the AVJA and pacing from the right ventricular (RV) apex may cause left ventricular dyssynchrony and remodelling and often results in prolonged QRS durations.5,6 While long-term RV pacing has been associated with a deterioration of heart failure (HF)7,8 and even new HF in some patients,2,8,9 cardiac resynchronization therapy (CRT) may be superior to RV pacing in patients undergoing AVJA, especially in patients with a reduced left ventricular ejection fraction (LVEF).10
* Corresponding author. Tel: +46 19 6025405; fax: +46 19 6022407. E-mail address: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
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Aims
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What’s new? † The cumulative incidence of hospitalization for heart failure (HF) and all-cause mortality after atrioventricular junction ablation was low. † The outcome was similar in both patients who failed pharmacological treatment and patients with repeated pulmonary vein isolation. † QRS prolongation and left atrial diameter were independent predictors of hospitalization for HF. † Hypertension and previous HF were independent predictors of all-cause mortality. † Even though HF was the most common cause of death, most patients died of other causes than HF.
at the time of the procedure and one year after the AVJA. Transthoracic echocardiography and hospitalizations for HF during the follow-up were recorded at the end of the study period. At AVJA, AF was classified as either paroxysmal or nonparoxysmal, the latter including both persistent and permanent AF. Normal QRS duration was defined as ,120 ms. The Central Ethical Review Board in Stockholm, Sweden, and the Regional Scientific Ethical Committees for Southern Denmark made an assessment of the study protocol and considered it to be part of the ongoing quality assurance programmes of the clinics. The study complies with the Declaration of Helsinki.
Outcome measures The primary outcome measure during the follow-up was the first hospitalization for HF during follow-up or all-cause mortality.
The aims of this retrospective, two-centre study were to estimate the incidence of hospitalization for HF and all-cause mortality after AVJA, and to identify predictors of these events.
Materials and methods Consecutive patients with AF who underwent AVJA between January ¨ rebro University Hospital, Sweden, 2001 and December 2011 at O and Odense University Hospital, Denmark, were included. Indications for AVJA were (i) inadequate symptom control by pharmacological treatment as part of a rate control strategy or (ii) unsuccessful repeated pulmonary vein isolation (PVI) in a rhythm control strategy. Patients with CRT before the AVJA were excluded from further analysis.
Device implantation and atrioventricular junction ablation Pacemakers were implanted in most patients at least 1 month before the AVJA while, in the beginning of the study period, pacemaker implantation was performed on the same day as the AVJA. Patients with paroxysmal AF received dual-chamber pacemakers, and those with non-paroxysmal AF single-chamber pacemakers. The rate response function was switched on in all patients. The AVJA was performed under conscious sedation and accomplished with radiofrequency ablation. The ablation endpoint was a complete AV block persisting for at least 30 min. After the ablation procedure, the pacemaker was programmed to a basic rate of 75 or 80 beats per minute (b.p.m.) for at least 2 weeks.
Data collection Data were collected retrospectively from hospital medical records including patients’ medical history, medications, laboratory tests, 12-lead electrocardiograms (ECGs), New York Heart Association (NYHA) functional class, and transthoracic echocardiography at AVJA and during follow-up. The duration of follow-up was calculated from the time of AVJA to 31 December 2012, alternatively to death, where time and cause of death were noted. Medication was assessed
Categorical variables are presented as percentages. Continuous variables are presented as mean + standard deviation (SD) or median and interquartile range (IQR), when appropriate. The McNemar test was done to evaluate differences in the use of medication before and 1 year after AVJA and the paired t-test to evaluate echocardiographic parameters. To compare patients with pharmacological failure and PVI unpaired t-test or Mann–Whitney U test, when appropriate, was used for continuously measured baseline characteristics. x2, x2 test for trend or Fisher’s exact test, when appropriate, was used to test differences for categorical measured baseline characteristics. The time to the first hospitalization for HF was estimated using the Kaplan–Meier method and presented as cumulative incidence. All patients were followed from the AVJA to the first occurrence of hospitalization for HF and censored for mortality or end of follow-up on 31 December 2012, whichever came first. Univariate associations between potential prognostic factors, presented in Table 4, and hospitalization for HF were assessed by Cox regression. The proportional hazard assumption was evaluated and tested with Schoenfeld residuals and, in the case of non-proportionality, timedependent factors were modelled, and hazard ratios at 0–24 months of follow-up are presented here. The same strategy of statistical analysis was used for all-cause mortality. Multiple Cox regression models were used to further evaluate the potential prognostic factors for both hospitalization for HF and mortality. Variables were the same as above, except for LVEF ,35% and CHADS2 and CHA2DS2-VASc scores. Measures of association are hazard ratios (HRs) with 95% confidence intervals. A P-value of ,0.05 was considered statistically significant. All statistical analyses were done using SPSS version 21 or STATA release 11.
Results Baseline characteristics In all, 162 patients (48% women) with a mean age of 67 + 9 years at the time of the AVJA were included in the study because of symptomatic AF refractory to pharmacological treatment (n ¼ 117) or unsuccessful repeated PVI (n ¼ 45). The PVI patients had a greater
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Patient population
Statistical analysis
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proportion of paroxysmal AF (P ¼ 0.03), less coronary artery disease (P ¼ 0.03) and less treatment with diuretics (P ¼ 0.047) but were to a greater extent treated with warfarin (P ¼ 0.01) than the other subgroup (Table 1).
At the AVJA, 73 (45%) patients were treated with angiotensinconverting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) and 95 (59%) patients with loop diuretics or aldosterone antagonists. Seventy-seven percent of all patients were on warfarin,
Table 1 Baseline characteristics All, n 5 162, (%)
Pharmacological failure, n 5 117, (72%)
PVI, n 5 45 (28%)
Pa
............................................................................................................................................................................... Women/men
77/85
57/60
20/25
0.63
Age, years (mean + SD) Paroxysmal AF
67 + 9 97
68 + 10 64
65 + 7 33
0.09 0.03
Non paroxysmal AF
65
53
12
0.03
Duration of AF, months (median, IQR) Follow-up period, months (median, IQR)
68 (IQR 25–120) 58 (IQR 32–102)
60 (IQR 25–120) 66 (IQR 37–103)
72 (IQR 36–116) 45 (IQR 24–61)
0.94 0.01
HF
33 (20%)
27 (23%)
6 (13%)
0.17
Hypertension Diabetes
67 (41%) 26 (16%)
48 (41%) 21 (18%)
19 (42%) 5 (11%)
0.89 0.29
Concomitant cardiovascular disease
23 (14%)
21 (18%)
2 (4%)
0.03
9 (6%) 23 (14%)
8 (7%) 20 (17%)
1 (2%) 3 (7%)
0.45 0.09
Stroke
11 (7%)
7 (6%)
4 (9%)
0.50
TIA CHADS2 scores
3 (2%)
3 (3%)
0 (0%)
0.56
0– 1
111 (69%)
76 (65%)
35 (78%)
0.12
51 (32%)
41 (35%)
10 (22%)
0.12
0– 1
58 (36%)
40 (34%)
18 (40%)
0.49
≥2
104 (64%)
77 (66%)
27 (60%)
0.49
≥2 CHA2DS2-VASc scores
ECG QRS duration ,120 ms
137 (85%)
95 (81%)
41 (91%)
0.15
QRS duration ≥120 ms Echocardiogram
25 (15%)
21 (18%)
4 (9%)
0.15
LVEF, % (mean + SD)
56 + 10
55 + 10
57 + 10
0.20
LVEDD, mm (mean + SD) Left atrial diameter, mm (mean + SD)
50 + 7 46 + 6
50 + 7 46 + 6
50 + 6 44 + 7
0.86 0.08
90 (56%)
63 (54%)
27 (60%)
II
39 (24%)
26 (22%)
13 (29%)
III IV
32 (20%) 1 (1%)
27 (23%) 1 (1%)
5 (11%) 0 (0%)
b-Blockers ACE inhibitors/ARB
115 (71%) 73 (45%)
80 (68%) 52 (44%)
35 (78%) 21 (47%)
0.24 0.80
Aldosterone antagonists
17 (11%)
11 (9%)
6 (13%)
0.57
Digoxin Diuretics
83 (51%) 78 (48%)
64 (55%) 62 (53%)
19 (42%) 16 (36%)
0.16 0.047
Warfarin
124 (77%)
83 (71%)
41 (91%)
0.01
ASA
61 (38%)
45 (39%)
16 (36%)
0.73
Symptoms NYHA functional class I
0.20
Medications
Baseline characteristics summarized with percentage, mean + SD or median (min – max), whenever appropriate. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ASA, aspirin; CABG, coronary artery bypass graft; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PVI, pulmonary vein isolation; TIA, transient ischaemic attack. a Unpaired t-test or Mann–Whitney U test when appropriate was used for continuously measured baseline characteristics and x2, x2 test for trend or Fisher’s exact test when appropriate was used to test differences for categorical measured baseline characteristics.
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Coronary artery disease Previous CABG Valvular heart disease
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Table 2 Medications
Table 3 Echocardiographic parameters Pa
Before AVJA
One year after AVJA
(n ¼ 162)
(n ¼ 162)
115 (71%)
79 (49%)
,0.001
Calcium-channel blockers Digoxin
67 (41%) 83 (51%)
7 (4.3%) 7 (4.3%)
,0.001 ,0.001
Class I antiarrhythmics
36 (22%)
0 (0%)
,0.001
Class III antiarrhythmics ACE inhibitors/ARB
71 (44%) 73 (45%)
3 (1.9%) 81 (50%)
,0.001 0.08
Aldosterone antagonists
17 (11%)
28 (17%)
0.01
Diuretics ASA
78 (48%) 61 (38%)
90 (56%) 53 (33%)
0.02 0.13
Warfarin
124 (77%)
127 (78%)
0.65
(n ¼ 117) 80 (68%)
(n ¼ 117) 54 (46%)
,0.001
Calcium-channel blockers
46 (39%)
7 (6%)
,0.001
Digoxin Class I antiarrhythmics
64 (55%) 28 (24%)
6 (5%) 0 (0%)
,0.001 ,0.001
Class III antiarrhythmics
51 (44%)
1 (1%)
,0.001
ACE inhibitors/ARB Aldosterone antagonists
52 (44%) 11 (9%)
59 (50%) 20 (17%)
0.09 0.01
Before AVJA
................................................................................ All, n (%) b-Blockers
Pharmacological failure b-Blockers
72 (62%)
0.03
45 (39%) 83 (71%)
38 (33%) 88 (75%)
0.14 0.33
(n ¼ 45) 35 (78%) 21 (47%)
(n ¼ 45) 25 (56%) 0 (0%)
0.02 ,0.001
All LVEF (%) LVEDD (mm) Left atrial diameter (mm) Pharmacological failure
(n ¼ 142) 56 + 10
(n ¼ 142) 53 + 11
51 + 7
51 + 9
0.73
46 + 7 (n ¼ 100)
46 + 7 (n ¼ 100)
0.95
,0.001
LVEF (%)
55 + 10
53 + 11
0.01
LVEDD (mm) Left atrial diameter (mm)
50 + 7 47 + 7
50 + 8 46 + 7
0.89 0.41
(n ¼ 42)
(n ¼ 42)
LVEF (%) LVEDD (mm)
57 + 10 53 + 6
54 + 11 56 + 9
0.02 0.14
Left atrial diameter (mm)
43 + 7
46 + 8
0.21
PVI
Echocardiographic parameters summarized as mean + SD. LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction. a The time of echocardiography after AVJA varied among patients. b The change from before to 1 year after AVJA was statistically evaluated with the paired t-test.
One patient had known ventricular tachycardia during hospitalization for AVJA but had prior treatment with ICD. At the end of the follow-up period, 25 of 80 patients with dual-chamber pacemakers had been reprogrammed to VVI mode.
Digoxin
19 (44%)
1 (2.2%)
,0.001
Echocardiographic findings
Class I antiarrhythmics Class III antiarrhythmics
8 (18%) 20 (44%)
0 (0%) 2 (4.4%)
,0.001 ,0.001
ACE inhibitors/ARB
21 (47%)
22 (49%)
1.00
Aldosterone antagonists Diuretics
6 (13%) 16 (36%)
8 (18%) 18 (40%)
0.63 0.69
ASA
16 (36%)
15 (33%)
1.00
Warfarin
41 (91%)
39 (87%)
0.50
Transthoracic echocardiography was performed in all patients before the AVJA and in 142 (88%) patients at least 1 year after the AVJA. The PVI patients had slightly better LVEF and slightly smaller left atrial diameter but the differences were not significant. Left ventricular ejection fraction decreased slightly after the AVJA from 56 + 10 to 53 + 11% (P ¼ ,0.001), while the left ventricular end-diastolic diameter (LVEDD) and the left atrial diameter did not change. The results in each subgroup are shown in Table 3.
Medications summarized as a number of patients and percentages. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ASA, aspirin. a The change from before to 1 year after AVJA was statistically evaluated with the McNemar test.
while five (3%) patients had no anticoagulation treatment at all. Table 2 shows medications before and 1 year after the AVJA in the two subgroups.
Implanted devices, pacing modes and complications At the decision to perform an AVJA, 69 patients already had a pacemaker and two had implantable cardioverter-defibrillators (ICDs). The most common pacemaker indication was sinus node dysfunction. Three patients were upgraded to CRT during follow-up, at 4 months, 5 years, and 9 years after the ablation procedure, respectively.
Hospitalization for heart failure During the follow-up period of 58 (IQR 32– 102) months, 23 of the 117 (20%) patients with failed pharmacological treatment and 9 of the 45 (20%) patients in the PVI group had at least one adjudicated hospitalization for HF. Sixteen (50%) of all patients with HF hospitalization had known HF before the AVJA, three (33%) in the PVI group and 13 (57%) in the group with failed pharmacological treatment. Hospitalization for HF occurred at a median time of 53 (IQR 20– 102) months after the AVJA. The 1-year cumulative incidence for hospitalization for HF was 5.1% (95% CI 2.6 –9.9) and the 2-year cumulative incidence was 9.1% (95% CI 5.5 –14.9) (Figure 1). The unadjusted Cox proportional hazard regression analysis revealed QRS duration, coronary artery disease, LVEF ,35%, left atrial diameter and previous HF to be statistically significant risk factors for HF hospitalization, Table 4. QRS duration showed a statistically significant association both as a categorical and as a continuous variable, which supports a linear association between QRS
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62 (53%)
ASA Warfarin b-Blockers Calcium-channel blockers
Pb
................................................................................
Diuretics
PVI
One year or more after AVJAa
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with repeated PVI, while the mortality was slightly higher in the former group. Prolonged QRS duration and left atrial diameter were the only independent predictors of hospitalization for HF, and hypertension and previous HF were independent predictors of all-cause mortality.
1.0 95% CI
Hospitalization of HF
0.8
0.6
Atrioventricular junction ablation and heart failure
0.4
0.2
0.0 0
36
48
Number of subjects at risk All patients 159 148 127 108
89
12
24
60 72 84 96 Months of follow-up 75
57
52
44
108 120 132 144
28
19
6
0
Figure 1 Cumulative incidence of hospitalization for HF estimated by the Kaplan– Meier method.
All-cause mortality Thirty-five (22%) patients, 19 men and 16 women, died at a median time of 47 (IQR 24–65) months after AVJA. Among those who died, eight patients had a previous PVI (18%) and 27 (23%) pharmacological failure. Eighteen patients were known to have paroxysmal AF at the AVJA and four patients had wide QRS complexes. The 1-year cumulative incidence for mortality was 1.9% (95% CI 0.6 – 5.7%) and the 2-year cumulative incidence was 5.2% (95% CI 2.7– 10.2) (Figure 2). Causes of death were known in all patients (Table 5). The most common causes of death were HF, cancer and other causes. Eight statistically significant factors of all-cause mortality were identified in the unadjusted Cox proportional hazard regression analysis: age, non-paroxysmal AF, CHADS2 score ≥2, CHA2DS2-VASc score ≥2, hypertension, diabetes, left atrial diameter and previous HF (Table 4). Multiple Cox regression revealed hypertension [HR 2.26 (95% CI 1.08–4.75), P ¼ 0.03] and previous HF [HR 2.63 (95% CI 1.01–6.82), P ¼ 0.047] as independent predictors of all-cause mortality.
All-cause mortality after atrioventricular junction ablation Patients undergoing AVJA have a high prevalence of comorbidities, which themselves may carry an increased risk of mortality. Oczan et al.14 showed that long-term survival after AVJA was comparable with that in patients with pharmacological therapy for AF and, when adjusted for underlying heart disease, survival was similar to the expected survival in the general population. All-cause mortality occurred in 22% in the current study, which is similar to the 26% in the study of Tan et al., which had a slightly shorter follow-up period.2 The all-cause mortality was slightly lower in patients with failed PVI than in patients with failed pharmacological treatment, 18 vs. 23%. We identified several risk factors for mortality in the univariate analysis, of which age, HF and diabetes are consistent with other studies.14,15
Discussion
Atrioventricular junction ablation after failed pulmonary vein isolation
Main findings
This is, to the best of our knowledge, the first study to investigate the outcome of AVJA in patients with recurrence of AF after PVI. These patients had a significantly lower proportion of non-paroxysmal AF and less coronary artery disease. Interestingly, the PVI group had a
The rates of long-term hospitalization for HF and all-cause mortality after AVJA were low. Hospitalization for HF occurred to the same extent in patients who failed pharmacological treatment as in patients
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duration and HF. In fact, the relative risk of HF hospitalization increased 30% with every 10 ms increase in duration. The adjusted Cox regression revealed a QRS duration of ≥120 ms as a statistically significant predictor of hospitalization for HF; when adjustment was made for all potential prognostic factors, the association was HR 2.77 (95% CI 1.18–6.54), P ¼ 0.02. Left atrial diameter was also a statistically significant predictor in the adjusted Cox regression with HR 1.11 (95% CI 1.03–1.19), P ¼ 0.007, and previous HF had a borderline significance of HR 2.81 (95% CI 1.00–7.89), P ¼ 0.05.
Atrioventricular junction ablation results in reduced symptoms and improved quality of life3 but also has disadvantages. Long-term RV pacing is associated with an increased risk of new-onset HF11 and a deterioration of pre-existing HF.7 The dual-chamber and VVI implantable defibrillator trial was the first clinical trial that showed the detrimental effect of RV pacing. In this prospective multicentre randomized trial, the primary endpoint was a composite of time to death or first hospitalization for HF. Patients with DDDR-70 pacing demonstrated a poorer outcome when compared with the VVI back-up group pacing at 40 b.p.m.12 Several studies have shown that left ventricular function after AVJA improves in patients with known impairment at baseline but decreases in patients with normal ventricular function at AVJA.5,13 In our study, 32 (20%) patients were hospitalized for HF, which is in line with the data of Tan et al.2 Half of these patients had known HF before the AVJA, indicating new-onset HF in the remaining patients. This could be related to long-term RV pacing, underlying diseases or a combination of both. Predictors for hospitalization such as previous hospitalization for HF and coronary artery disease are consistent with other studies.2 In the present study we identified a minor, but statistically significant, decrease in LVEF after the AVJA. Our observation that the prolongation of QRS duration was a strong predictor of hospitalization for HF suggests that patients with prolonged QRS duration planned for AVJA could benefit from CRT compared with RV pacing.
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Table 4 Potential risk factors for hospitalization for HF and all-cause mortality evaluated with Cox regression Unadjusted (n 5 162) HR (95% CI)
Adjusteda (n 5 157) HR (95% CI)
P
P
............................................................................................................................................................................... Hospitalization for HF Age (years)
1.00 (1.00– 1.08)
0.07
Age ≤65 Age 66–75
1.00 1.17 (0.47– 2.87)
0.74
1.00 1.44 (0.49–4.24)
0.51
Age ≥76
2.60 (1.04– 6.51)
0.04
1.40 (0.46–4.31)
0.56
Gender, men Non-paroxysmal AF
1.54 (0.71– 3.34) 1.38 (0.65– 2.94)
0.28 0.41
1.37 (0.60–3.14) 1.34 (0.54–3.35)
0.46 0.54
QRS duration ≥120 ms [1]
3.30 (1.55– 7.05)
0.002
2.77 (1.18–6.54)
0.02
QRS duration (ms) [1] CHADS2 ≥2
1.03 (1.01– 1.04) 1.60 (0.73– 3.48)
,0.001 0.24
CHA2DS2-VASc≥2
1.50 (0.67– 3.33)
0.32
Hypertension Diabetes
0.93 (0.43– 2.01) 0.72 (0.22– 2.39)
0.85 0.59
1.79 (0.70–4.54) 0.56 (0.14–2.18)
0.22 0.40
0.006
2.27 (0.82–6.27)
0.11
3.04 (1.37– 6.72)
LVEF,35% [1] Left atrial diameter [5]
5.92 (2.37– 14.79) 1.13 (1.07– 1.19)
,0.001 ,0.001
1.11 (1.03–1.19)
0.007
Previous HF
6.20 (2.93– 13.11)
,0.001
2.81 (1.00–7.89)
0.05
Previous pacemaker Centre, Odense
1.61 (0.77– 3.39) 0.64 (0.29– 1.41)
0.21 0.27
1.54 (0.66–3.62) 1.09 (0.38–3.11)
0.32 0.87
Age (years) Age ≤65
1.06 (1.02– 1.09) 1.00
0.004
Age 66–75
2.03 (0.93– 4.44)
0.07
2.00 (0.85–4.70)
0.11
Age ≥76 Gender, men
3.38 (1.42– 8.04) 0.91 (0.47– 1.78)
0.006 0.79
2.30 (0.80–6.63) 1.18 (0.56–2.48)
0.12 0.30
Non-paroxysmal AF
2.18 (1.11– 4.28)
0.02
2.00 (0.91–4.40)
0.08
QRS duration ≥120 ms [1] QRS duration (ms) [1]
0.57 (0.20– 1.60) 0.99 (0.98– 1.00)
0.28 0.30
0.56 (0.19–1.68)
0.30
All-cause mortality 1.00
CHADS2 ≥2
2.99 (1.53– 5.86)
0.001
CHA2DS2-VASc≥2 Hypertension
3.47 (1.51– 8.00) 2.08 (1.07– 4.06)
0.003 0.03
2.26 (1.08–4.75)
0.03
Diabetes
2.29 (1.07– 4.89)
0.03
1.86 (0.77–4.46)
0.17
Coronary artery disease LVEF ,35% [1]
1.27 (0.53– 3.07) 1.53 (0.37– 6.41)
0.59 0.56
0.74 (0.27–2.03)
0.56
Left atrial diameter
1.07 (1.01– 1.13)
0.02
1.05 (0.99–1.12)
0.11
Previous HF Previous pacemaker
2.27 (1.09– 4.74) 1.30 (0.66– 2.54)
0.03 0.45
2.63 (1.01–6.82) 1.43 (0.66–3.11)
0.047 0.37
Centre, Odense
0.68 (0.33– 1.42)
0.30
1.84 (0.72–4.69)
0.20
1.42 (0.29– 7.05)
0.67
0– 24 monthsb
CI, confidence interval; HR, hazard ratio. [] defines number of missing values. a Adjusted for all variables except LVEF ,35%, CHADS2 and CHA2DS2-VASc b Evaluated as a time-dependent factor 0–24 months.
higher percentage of patients treated with warfarin, probably in part dictated by the PVI procedures, but had the same proportion of hospitalization for HF as the group with failed pharmacological treatment. The latter group had nearly twice as many patients with known HF before the AVJA, indicating a higher incidence of new-onset HF in the PVI group, although the difference was nonsignificant. The mortality was slightly higher in the group with failed
pharmacological treatment compared with the PVI group, indicating a subgroup of sicker patients.
Medications The present study showed a statistically significant reduction of treatment with b-blockers, calcium-channel blockers, digoxin and antiarrhythmics 1 year after the AVJA. A low proportion of patients were
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Conclusions 1.0
Long-term RV pacing was not harmful in the majority of AF patients after AVJA. Hypertension and previous HF were identified as independent predictors of all-cause mortality, and prolonged QRS duration and left atrial diameter as predictors of hospitalization for HF during long-term follow-up. When selecting a patient for AVJA, it is important to take the QRS duration into account and to consider treatment with CRT. Atrioventricular junction ablation remains a valid treatment option for otherwise therapy refractory AF, including patients with unsuccessful repeated PVI.
95% CI
All-cause mortality
0.8
0.6
0.4
0.2
0.0 0
36
48
Number of subjects at risk All patients 159 155 134 117
99
12
24
60 72 84 96 Months of follow-up 83
63
57
50
108 120 132 144
34
23
8
0
Figure 2 Cumulative incidence of all-cause mortality estimated
Conflict of interest: none declared.
Funding ¨ rebro Heart Foundation and the ReA.B. received funding from the O ¨ search Committee of Orebro University Hospital.
by the Kaplan – Meier method.
References
Table 5 Causes of death No. of patients (%)
Arrhythmias (sudden cardiac death) HF
3 (9) 6 (17)
Myocardial infarction
5 (14)
Stroke Cancer
2 (6) 6 (17)
Infections
4 (11)
Respiratory failure Other
2 (6) 7 (20)
................................................................................
on warfarin treatment both before and after the AVJA, especially in the subgroup with pharmacological failure, which is surprising. This fact is possibly due to the unusually high proportion of paroxysmal AF.
Limitations The study was retrospective in design. The study parameters are based on hospital medical records, echocardiography was not performed in all patients after AVJA and the time of the echocardiography varied among patients. Nearly half of all patients had previous pacemaker treatment for other reasons than the AVJA. The study included two centres and, while the criteria for AVJA were the same, the selection still turned out somewhat differently. This did not, however, result in any relevant statistical differences. During the first years of the enrolment period, AVJA was also offered to younger patients, and even patients with paroxysmal AF, in whom PVI had become a first-line treatment later in the enrolment period.
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Cause of death
1. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010;12:1360 –420. 2. Tan ES, Rienstra M, Wiesfeld AC, Schoonderwoerd BA, Hobbel HH, Van Gelder IC. Long-term outcome of the atrioventricular node ablation and pacemaker implantation for symptomatic refractory atrial fibrillation. Europace 2008;10:412 –8. 3. Wood MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clinical outcomes after ablation and pacing therapy for atrial fibrillation: a meta-analysis. Circulation 2000;101: 1138 –44. 4. Fitzpatrick AP, Kourouyan HD, Siu A, Lee RJ, Lesh MD, Epstein LM et al. Quality of life and outcomes after radiofrequency His-bundle catheter ablation and permanent pacemaker implantation: impact of treatment in paroxysmal and established atrial fibrillation. Am Heart J 1996;131:499–507. 5. Vernooy K, Dijkman B, Cheriex EC, Prinzen FW, Crijns HJ. Ventricular remodeling during long-term right ventricular pacing following His bundle ablation. Am J Cardiol 2006;97:1223 –7. 6. Brignole M, Botto G, Mont L, Iacopino S, De Marchi G, Oddone D et al. Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial. Eur Heart J 2011;32:2420 –9. 7. Tops LF, Schalij MJ, Holman ER, van Erven L, van der Wall EE, Bax JJ. Right ventricular pacing can induce ventricular dyssynchrony in patients with atrial fibrillation after atrioventricular node ablation. J Am Coll Cardiol 2006;48:1642 – 8. 8. Poci D, Backman L, Karlsson T, Edvardsson N. New or aggravated heart failure during long-term right ventricular pacing after AV junctional catheter ablation. Pacing Clin Electrophysiol 2009;32:209 –16. 9. Nielsen JC, Andersen HR, Thomsen PE, Thuesen L, Mortensen PT, Vesterlund T et al. Heart failure and echocardiographic changes during long-term follow-up of patients with sick sinus syndrome randomized to single-chamber atrial or ventricular pacing. Circulation 1998;97:987 –95. 10. Stavrakis S, Garabelli P, Reynolds DW. Cardiac resynchronization therapy after atrioventricular junction ablation for symptomatic atrial fibrillation: a meta-analysis. Europace 2012;14:1490 –7. 11. Zhang XH, Chen H, Siu CW, Yiu KH, Chan WS, Lee KL et al. New-onset heart failure after permanent right ventricular apical pacing in patients with acquired high-grade atrioventricular block and normal left ventricular function. J Cardiovasc Electrophysiol 2008;19:136 –41. 12. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H et al. Dualchamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the dual chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002;288:3115 –23. 13. Szili-Torok T, Bountioukos M, Muskens AJ, Theuns DA, Poldermans D, Roelandt JR et al. The presence of contractile reserve has no predictive value for the evolution of left ventricular function following atrio-ventricular node ablation in patients with permanent atrial fibrillation. Eur J Echocardiogr 2005;6:344 – 50. 14. Ozcan C, Jahangir A, Friedman PA, Patel PJ, Munger TM, Rea RF 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 –51. 15. Iuliano S, Fisher SG, Karasik PE, Fletcher RD, Singh SN. QRS duration and mortality in patients with congestive heart failure. Am Heart J 2002;143:1085 –91.
Europace (2014) 16, 1772–1778 doi:10.1093/europace/euu171
Pacing and resynchronization therapy
Predictors of hospitalization for heart failure and of all-cause mortality after atrioventricular nodal ablation and right ventricular pacing for atrial fibrillation Anna Bjo¨rkenheim 1,2*, Axel Brandes 3, Tommy Andersson 1,2, Anders Magnuson 4, Nils Edvardsson 5, Birger Wandt 6, Henriette Sloth Pedersen 3, and Dritan Poc¸i 1,2 1 ¨ rebro University Hospital, O ¨ rebro, Sweden; 2Department of Medicine, O ¨ rebro University, O ¨ rebro, Sweden; 3Department of Cardiology, Odense Department of Cardiology, O ¨ rebro University Hospital, O ¨ rebro, Sweden; 5Sahlgrenska Academy, Sahlgrenska University University Hospital, Odense, Denmark; 4Clinical Epidemiology and Biostatistics Unit, O ¨ rebro University, O ¨ rebro, Sweden Hospital, Go¨teborg, Sweden; and 6School of Health and Medical Sciences, O
Received 27 April 2014; accepted after revision 4 June 2014; online publish-ahead-of-print 16 July 2014
Atrioventricular junction ablation (AVJA) is a highly effective treatment in patients with therapy refractory atrial fibrillation (AF) but renders the patient pacemaker dependent. We aimed to analyse the long-term incidence of hospitalization for heart failure (HF) and all-cause mortality in patients who underwent AVJA because of AF and to determine predictors for HF and mortality. ..................................................................................................................................................................................... Methods We retrospectively enrolled 162 consecutive patients, mean age 67 + 9 years, 48% women, who underwent AVJA because of symptomatic AF refractory to pharmacological treatment (n ¼ 117) or unsuccessful repeated pulmonary and results vein isolation (n ¼ 45). Hospitalization for HF occurred in 32 (20%) patients and 35 (22%) patients died, representing a cumulative incidence for hospitalization for HF and mortality over the first 2 years after AVJA of 9.1 and 5.2%, respectively. Hospitalization for HF occurred to the same extent in patients who failed pharmacological treatment as in patients with repeated pulmonary vein isolation (PVI), although the mortality was slightly higher in the former group. QRS prolongation ≥120 ms and left atrial diameter were independent predictors of hospitalization for HF, while hypertension and previous HF were independent predictors of death. ..................................................................................................................................................................................... Conclusion The long-term hospitalization rate for HF and all-cause mortality was low, which implies that long-term ventricular pacing was not harmful in this patient population, including patients with unsuccessful repeated PVI.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Atrial fibrillation † Atrioventricular junction ablation † Heart failure † Hospitalization † Mortality
Introduction Atrial fibrillation (AF) affects 1–2% of the general population and its prevalence is estimated to double over the next 50 years.1 Radiofrequency catheter ablation of the atrioventricular node, so-called atrioventricular junction ablation (AVJA), is a highly effective treatment when pharmacological rate control and/or rhythm control have failed to control the ventricular rate.1 Atrioventricular junction ablation has been shown to reduce symptoms and healthcare utilization2
and to increase the quality of life.3,4 Patients, however, become permanently pacemaker dependent after the AVJA and pacing from the right ventricular (RV) apex may cause left ventricular dyssynchrony and remodelling and often results in prolonged QRS durations.5,6 While long-term RV pacing has been associated with a deterioration of heart failure (HF)7,8 and even new HF in some patients,2,8,9 cardiac resynchronization therapy (CRT) may be superior to RV pacing in patients undergoing AVJA, especially in patients with a reduced left ventricular ejection fraction (LVEF).10
* Corresponding author. Tel: +46 19 6025405; fax: +46 19 6022407. E-mail address: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
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Aims
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Predictors of hospitalization for HF and of all-cause mortality
What’s new? † The cumulative incidence of hospitalization for heart failure (HF) and all-cause mortality after atrioventricular junction ablation was low. † The outcome was similar in both patients who failed pharmacological treatment and patients with repeated pulmonary vein isolation. † QRS prolongation and left atrial diameter were independent predictors of hospitalization for HF. † Hypertension and previous HF were independent predictors of all-cause mortality. † Even though HF was the most common cause of death, most patients died of other causes than HF.
at the time of the procedure and one year after the AVJA. Transthoracic echocardiography and hospitalizations for HF during the follow-up were recorded at the end of the study period. At AVJA, AF was classified as either paroxysmal or nonparoxysmal, the latter including both persistent and permanent AF. Normal QRS duration was defined as ,120 ms. The Central Ethical Review Board in Stockholm, Sweden, and the Regional Scientific Ethical Committees for Southern Denmark made an assessment of the study protocol and considered it to be part of the ongoing quality assurance programmes of the clinics. The study complies with the Declaration of Helsinki.
Outcome measures The primary outcome measure during the follow-up was the first hospitalization for HF during follow-up or all-cause mortality.
The aims of this retrospective, two-centre study were to estimate the incidence of hospitalization for HF and all-cause mortality after AVJA, and to identify predictors of these events.
Materials and methods Consecutive patients with AF who underwent AVJA between January ¨ rebro University Hospital, Sweden, 2001 and December 2011 at O and Odense University Hospital, Denmark, were included. Indications for AVJA were (i) inadequate symptom control by pharmacological treatment as part of a rate control strategy or (ii) unsuccessful repeated pulmonary vein isolation (PVI) in a rhythm control strategy. Patients with CRT before the AVJA were excluded from further analysis.
Device implantation and atrioventricular junction ablation Pacemakers were implanted in most patients at least 1 month before the AVJA while, in the beginning of the study period, pacemaker implantation was performed on the same day as the AVJA. Patients with paroxysmal AF received dual-chamber pacemakers, and those with non-paroxysmal AF single-chamber pacemakers. The rate response function was switched on in all patients. The AVJA was performed under conscious sedation and accomplished with radiofrequency ablation. The ablation endpoint was a complete AV block persisting for at least 30 min. After the ablation procedure, the pacemaker was programmed to a basic rate of 75 or 80 beats per minute (b.p.m.) for at least 2 weeks.
Data collection Data were collected retrospectively from hospital medical records including patients’ medical history, medications, laboratory tests, 12-lead electrocardiograms (ECGs), New York Heart Association (NYHA) functional class, and transthoracic echocardiography at AVJA and during follow-up. The duration of follow-up was calculated from the time of AVJA to 31 December 2012, alternatively to death, where time and cause of death were noted. Medication was assessed
Categorical variables are presented as percentages. Continuous variables are presented as mean + standard deviation (SD) or median and interquartile range (IQR), when appropriate. The McNemar test was done to evaluate differences in the use of medication before and 1 year after AVJA and the paired t-test to evaluate echocardiographic parameters. To compare patients with pharmacological failure and PVI unpaired t-test or Mann–Whitney U test, when appropriate, was used for continuously measured baseline characteristics. x2, x2 test for trend or Fisher’s exact test, when appropriate, was used to test differences for categorical measured baseline characteristics. The time to the first hospitalization for HF was estimated using the Kaplan–Meier method and presented as cumulative incidence. All patients were followed from the AVJA to the first occurrence of hospitalization for HF and censored for mortality or end of follow-up on 31 December 2012, whichever came first. Univariate associations between potential prognostic factors, presented in Table 4, and hospitalization for HF were assessed by Cox regression. The proportional hazard assumption was evaluated and tested with Schoenfeld residuals and, in the case of non-proportionality, timedependent factors were modelled, and hazard ratios at 0–24 months of follow-up are presented here. The same strategy of statistical analysis was used for all-cause mortality. Multiple Cox regression models were used to further evaluate the potential prognostic factors for both hospitalization for HF and mortality. Variables were the same as above, except for LVEF ,35% and CHADS2 and CHA2DS2-VASc scores. Measures of association are hazard ratios (HRs) with 95% confidence intervals. A P-value of ,0.05 was considered statistically significant. All statistical analyses were done using SPSS version 21 or STATA release 11.
Results Baseline characteristics In all, 162 patients (48% women) with a mean age of 67 + 9 years at the time of the AVJA were included in the study because of symptomatic AF refractory to pharmacological treatment (n ¼ 117) or unsuccessful repeated PVI (n ¼ 45). The PVI patients had a greater
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Patient population
Statistical analysis
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A. Bjo¨rkenheim et al.
proportion of paroxysmal AF (P ¼ 0.03), less coronary artery disease (P ¼ 0.03) and less treatment with diuretics (P ¼ 0.047) but were to a greater extent treated with warfarin (P ¼ 0.01) than the other subgroup (Table 1).
At the AVJA, 73 (45%) patients were treated with angiotensinconverting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) and 95 (59%) patients with loop diuretics or aldosterone antagonists. Seventy-seven percent of all patients were on warfarin,
Table 1 Baseline characteristics All, n 5 162, (%)
Pharmacological failure, n 5 117, (72%)
PVI, n 5 45 (28%)
Pa
............................................................................................................................................................................... Women/men
77/85
57/60
20/25
0.63
Age, years (mean + SD) Paroxysmal AF
67 + 9 97
68 + 10 64
65 + 7 33
0.09 0.03
Non paroxysmal AF
65
53
12
0.03
Duration of AF, months (median, IQR) Follow-up period, months (median, IQR)
68 (IQR 25–120) 58 (IQR 32–102)
60 (IQR 25–120) 66 (IQR 37–103)
72 (IQR 36–116) 45 (IQR 24–61)
0.94 0.01
HF
33 (20%)
27 (23%)
6 (13%)
0.17
Hypertension Diabetes
67 (41%) 26 (16%)
48 (41%) 21 (18%)
19 (42%) 5 (11%)
0.89 0.29
Concomitant cardiovascular disease
23 (14%)
21 (18%)
2 (4%)
0.03
9 (6%) 23 (14%)
8 (7%) 20 (17%)
1 (2%) 3 (7%)
0.45 0.09
Stroke
11 (7%)
7 (6%)
4 (9%)
0.50
TIA CHADS2 scores
3 (2%)
3 (3%)
0 (0%)
0.56
0– 1
111 (69%)
76 (65%)
35 (78%)
0.12
51 (32%)
41 (35%)
10 (22%)
0.12
0– 1
58 (36%)
40 (34%)
18 (40%)
0.49
≥2
104 (64%)
77 (66%)
27 (60%)
0.49
≥2 CHA2DS2-VASc scores
ECG QRS duration ,120 ms
137 (85%)
95 (81%)
41 (91%)
0.15
QRS duration ≥120 ms Echocardiogram
25 (15%)
21 (18%)
4 (9%)
0.15
LVEF, % (mean + SD)
56 + 10
55 + 10
57 + 10
0.20
LVEDD, mm (mean + SD) Left atrial diameter, mm (mean + SD)
50 + 7 46 + 6
50 + 7 46 + 6
50 + 6 44 + 7
0.86 0.08
90 (56%)
63 (54%)
27 (60%)
II
39 (24%)
26 (22%)
13 (29%)
III IV
32 (20%) 1 (1%)
27 (23%) 1 (1%)
5 (11%) 0 (0%)
b-Blockers ACE inhibitors/ARB
115 (71%) 73 (45%)
80 (68%) 52 (44%)
35 (78%) 21 (47%)
0.24 0.80
Aldosterone antagonists
17 (11%)
11 (9%)
6 (13%)
0.57
Digoxin Diuretics
83 (51%) 78 (48%)
64 (55%) 62 (53%)
19 (42%) 16 (36%)
0.16 0.047
Warfarin
124 (77%)
83 (71%)
41 (91%)
0.01
ASA
61 (38%)
45 (39%)
16 (36%)
0.73
Symptoms NYHA functional class I
0.20
Medications
Baseline characteristics summarized with percentage, mean + SD or median (min – max), whenever appropriate. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ASA, aspirin; CABG, coronary artery bypass graft; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PVI, pulmonary vein isolation; TIA, transient ischaemic attack. a Unpaired t-test or Mann–Whitney U test when appropriate was used for continuously measured baseline characteristics and x2, x2 test for trend or Fisher’s exact test when appropriate was used to test differences for categorical measured baseline characteristics.
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Coronary artery disease Previous CABG Valvular heart disease
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Predictors of hospitalization for HF and of all-cause mortality
Table 2 Medications
Table 3 Echocardiographic parameters Pa
Before AVJA
One year after AVJA
(n ¼ 162)
(n ¼ 162)
115 (71%)
79 (49%)
,0.001
Calcium-channel blockers Digoxin
67 (41%) 83 (51%)
7 (4.3%) 7 (4.3%)
,0.001 ,0.001
Class I antiarrhythmics
36 (22%)
0 (0%)
,0.001
Class III antiarrhythmics ACE inhibitors/ARB
71 (44%) 73 (45%)
3 (1.9%) 81 (50%)
,0.001 0.08
Aldosterone antagonists
17 (11%)
28 (17%)
0.01
Diuretics ASA
78 (48%) 61 (38%)
90 (56%) 53 (33%)
0.02 0.13
Warfarin
124 (77%)
127 (78%)
0.65
(n ¼ 117) 80 (68%)
(n ¼ 117) 54 (46%)
,0.001
Calcium-channel blockers
46 (39%)
7 (6%)
,0.001
Digoxin Class I antiarrhythmics
64 (55%) 28 (24%)
6 (5%) 0 (0%)
,0.001 ,0.001
Class III antiarrhythmics
51 (44%)
1 (1%)
,0.001
ACE inhibitors/ARB Aldosterone antagonists
52 (44%) 11 (9%)
59 (50%) 20 (17%)
0.09 0.01
Before AVJA
................................................................................ All, n (%) b-Blockers
Pharmacological failure b-Blockers
72 (62%)
0.03
45 (39%) 83 (71%)
38 (33%) 88 (75%)
0.14 0.33
(n ¼ 45) 35 (78%) 21 (47%)
(n ¼ 45) 25 (56%) 0 (0%)
0.02 ,0.001
All LVEF (%) LVEDD (mm) Left atrial diameter (mm) Pharmacological failure
(n ¼ 142) 56 + 10
(n ¼ 142) 53 + 11
51 + 7
51 + 9
0.73
46 + 7 (n ¼ 100)
46 + 7 (n ¼ 100)
0.95
,0.001
LVEF (%)
55 + 10
53 + 11
0.01
LVEDD (mm) Left atrial diameter (mm)
50 + 7 47 + 7
50 + 8 46 + 7
0.89 0.41
(n ¼ 42)
(n ¼ 42)
LVEF (%) LVEDD (mm)
57 + 10 53 + 6
54 + 11 56 + 9
0.02 0.14
Left atrial diameter (mm)
43 + 7
46 + 8
0.21
PVI
Echocardiographic parameters summarized as mean + SD. LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction. a The time of echocardiography after AVJA varied among patients. b The change from before to 1 year after AVJA was statistically evaluated with the paired t-test.
One patient had known ventricular tachycardia during hospitalization for AVJA but had prior treatment with ICD. At the end of the follow-up period, 25 of 80 patients with dual-chamber pacemakers had been reprogrammed to VVI mode.
Digoxin
19 (44%)
1 (2.2%)
,0.001
Echocardiographic findings
Class I antiarrhythmics Class III antiarrhythmics
8 (18%) 20 (44%)
0 (0%) 2 (4.4%)
,0.001 ,0.001
ACE inhibitors/ARB
21 (47%)
22 (49%)
1.00
Aldosterone antagonists Diuretics
6 (13%) 16 (36%)
8 (18%) 18 (40%)
0.63 0.69
ASA
16 (36%)
15 (33%)
1.00
Warfarin
41 (91%)
39 (87%)
0.50
Transthoracic echocardiography was performed in all patients before the AVJA and in 142 (88%) patients at least 1 year after the AVJA. The PVI patients had slightly better LVEF and slightly smaller left atrial diameter but the differences were not significant. Left ventricular ejection fraction decreased slightly after the AVJA from 56 + 10 to 53 + 11% (P ¼ ,0.001), while the left ventricular end-diastolic diameter (LVEDD) and the left atrial diameter did not change. The results in each subgroup are shown in Table 3.
Medications summarized as a number of patients and percentages. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ASA, aspirin. a The change from before to 1 year after AVJA was statistically evaluated with the McNemar test.
while five (3%) patients had no anticoagulation treatment at all. Table 2 shows medications before and 1 year after the AVJA in the two subgroups.
Implanted devices, pacing modes and complications At the decision to perform an AVJA, 69 patients already had a pacemaker and two had implantable cardioverter-defibrillators (ICDs). The most common pacemaker indication was sinus node dysfunction. Three patients were upgraded to CRT during follow-up, at 4 months, 5 years, and 9 years after the ablation procedure, respectively.
Hospitalization for heart failure During the follow-up period of 58 (IQR 32– 102) months, 23 of the 117 (20%) patients with failed pharmacological treatment and 9 of the 45 (20%) patients in the PVI group had at least one adjudicated hospitalization for HF. Sixteen (50%) of all patients with HF hospitalization had known HF before the AVJA, three (33%) in the PVI group and 13 (57%) in the group with failed pharmacological treatment. Hospitalization for HF occurred at a median time of 53 (IQR 20– 102) months after the AVJA. The 1-year cumulative incidence for hospitalization for HF was 5.1% (95% CI 2.6 –9.9) and the 2-year cumulative incidence was 9.1% (95% CI 5.5 –14.9) (Figure 1). The unadjusted Cox proportional hazard regression analysis revealed QRS duration, coronary artery disease, LVEF ,35%, left atrial diameter and previous HF to be statistically significant risk factors for HF hospitalization, Table 4. QRS duration showed a statistically significant association both as a categorical and as a continuous variable, which supports a linear association between QRS
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62 (53%)
ASA Warfarin b-Blockers Calcium-channel blockers
Pb
................................................................................
Diuretics
PVI
One year or more after AVJAa
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A. Bjo¨rkenheim et al.
with repeated PVI, while the mortality was slightly higher in the former group. Prolonged QRS duration and left atrial diameter were the only independent predictors of hospitalization for HF, and hypertension and previous HF were independent predictors of all-cause mortality.
1.0 95% CI
Hospitalization of HF
0.8
0.6
Atrioventricular junction ablation and heart failure
0.4
0.2
0.0 0
36
48
Number of subjects at risk All patients 159 148 127 108
89
12
24
60 72 84 96 Months of follow-up 75
57
52
44
108 120 132 144
28
19
6
0
Figure 1 Cumulative incidence of hospitalization for HF estimated by the Kaplan– Meier method.
All-cause mortality Thirty-five (22%) patients, 19 men and 16 women, died at a median time of 47 (IQR 24–65) months after AVJA. Among those who died, eight patients had a previous PVI (18%) and 27 (23%) pharmacological failure. Eighteen patients were known to have paroxysmal AF at the AVJA and four patients had wide QRS complexes. The 1-year cumulative incidence for mortality was 1.9% (95% CI 0.6 – 5.7%) and the 2-year cumulative incidence was 5.2% (95% CI 2.7– 10.2) (Figure 2). Causes of death were known in all patients (Table 5). The most common causes of death were HF, cancer and other causes. Eight statistically significant factors of all-cause mortality were identified in the unadjusted Cox proportional hazard regression analysis: age, non-paroxysmal AF, CHADS2 score ≥2, CHA2DS2-VASc score ≥2, hypertension, diabetes, left atrial diameter and previous HF (Table 4). Multiple Cox regression revealed hypertension [HR 2.26 (95% CI 1.08–4.75), P ¼ 0.03] and previous HF [HR 2.63 (95% CI 1.01–6.82), P ¼ 0.047] as independent predictors of all-cause mortality.
All-cause mortality after atrioventricular junction ablation Patients undergoing AVJA have a high prevalence of comorbidities, which themselves may carry an increased risk of mortality. Oczan et al.14 showed that long-term survival after AVJA was comparable with that in patients with pharmacological therapy for AF and, when adjusted for underlying heart disease, survival was similar to the expected survival in the general population. All-cause mortality occurred in 22% in the current study, which is similar to the 26% in the study of Tan et al., which had a slightly shorter follow-up period.2 The all-cause mortality was slightly lower in patients with failed PVI than in patients with failed pharmacological treatment, 18 vs. 23%. We identified several risk factors for mortality in the univariate analysis, of which age, HF and diabetes are consistent with other studies.14,15
Discussion
Atrioventricular junction ablation after failed pulmonary vein isolation
Main findings
This is, to the best of our knowledge, the first study to investigate the outcome of AVJA in patients with recurrence of AF after PVI. These patients had a significantly lower proportion of non-paroxysmal AF and less coronary artery disease. Interestingly, the PVI group had a
The rates of long-term hospitalization for HF and all-cause mortality after AVJA were low. Hospitalization for HF occurred to the same extent in patients who failed pharmacological treatment as in patients
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duration and HF. In fact, the relative risk of HF hospitalization increased 30% with every 10 ms increase in duration. The adjusted Cox regression revealed a QRS duration of ≥120 ms as a statistically significant predictor of hospitalization for HF; when adjustment was made for all potential prognostic factors, the association was HR 2.77 (95% CI 1.18–6.54), P ¼ 0.02. Left atrial diameter was also a statistically significant predictor in the adjusted Cox regression with HR 1.11 (95% CI 1.03–1.19), P ¼ 0.007, and previous HF had a borderline significance of HR 2.81 (95% CI 1.00–7.89), P ¼ 0.05.
Atrioventricular junction ablation results in reduced symptoms and improved quality of life3 but also has disadvantages. Long-term RV pacing is associated with an increased risk of new-onset HF11 and a deterioration of pre-existing HF.7 The dual-chamber and VVI implantable defibrillator trial was the first clinical trial that showed the detrimental effect of RV pacing. In this prospective multicentre randomized trial, the primary endpoint was a composite of time to death or first hospitalization for HF. Patients with DDDR-70 pacing demonstrated a poorer outcome when compared with the VVI back-up group pacing at 40 b.p.m.12 Several studies have shown that left ventricular function after AVJA improves in patients with known impairment at baseline but decreases in patients with normal ventricular function at AVJA.5,13 In our study, 32 (20%) patients were hospitalized for HF, which is in line with the data of Tan et al.2 Half of these patients had known HF before the AVJA, indicating new-onset HF in the remaining patients. This could be related to long-term RV pacing, underlying diseases or a combination of both. Predictors for hospitalization such as previous hospitalization for HF and coronary artery disease are consistent with other studies.2 In the present study we identified a minor, but statistically significant, decrease in LVEF after the AVJA. Our observation that the prolongation of QRS duration was a strong predictor of hospitalization for HF suggests that patients with prolonged QRS duration planned for AVJA could benefit from CRT compared with RV pacing.
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Predictors of hospitalization for HF and of all-cause mortality
Table 4 Potential risk factors for hospitalization for HF and all-cause mortality evaluated with Cox regression Unadjusted (n 5 162) HR (95% CI)
Adjusteda (n 5 157) HR (95% CI)
P
P
............................................................................................................................................................................... Hospitalization for HF Age (years)
1.00 (1.00– 1.08)
0.07
Age ≤65 Age 66–75
1.00 1.17 (0.47– 2.87)
0.74
1.00 1.44 (0.49–4.24)
0.51
Age ≥76
2.60 (1.04– 6.51)
0.04
1.40 (0.46–4.31)
0.56
Gender, men Non-paroxysmal AF
1.54 (0.71– 3.34) 1.38 (0.65– 2.94)
0.28 0.41
1.37 (0.60–3.14) 1.34 (0.54–3.35)
0.46 0.54
QRS duration ≥120 ms [1]
3.30 (1.55– 7.05)
0.002
2.77 (1.18–6.54)
0.02
QRS duration (ms) [1] CHADS2 ≥2
1.03 (1.01– 1.04) 1.60 (0.73– 3.48)
,0.001 0.24
CHA2DS2-VASc≥2
1.50 (0.67– 3.33)
0.32
Hypertension Diabetes
0.93 (0.43– 2.01) 0.72 (0.22– 2.39)
0.85 0.59
1.79 (0.70–4.54) 0.56 (0.14–2.18)
0.22 0.40
0.006
2.27 (0.82–6.27)
0.11
3.04 (1.37– 6.72)
LVEF,35% [1] Left atrial diameter [5]
5.92 (2.37– 14.79) 1.13 (1.07– 1.19)
,0.001 ,0.001
1.11 (1.03–1.19)
0.007
Previous HF
6.20 (2.93– 13.11)
,0.001
2.81 (1.00–7.89)
0.05
Previous pacemaker Centre, Odense
1.61 (0.77– 3.39) 0.64 (0.29– 1.41)
0.21 0.27
1.54 (0.66–3.62) 1.09 (0.38–3.11)
0.32 0.87
Age (years) Age ≤65
1.06 (1.02– 1.09) 1.00
0.004
Age 66–75
2.03 (0.93– 4.44)
0.07
2.00 (0.85–4.70)
0.11
Age ≥76 Gender, men
3.38 (1.42– 8.04) 0.91 (0.47– 1.78)
0.006 0.79
2.30 (0.80–6.63) 1.18 (0.56–2.48)
0.12 0.30
Non-paroxysmal AF
2.18 (1.11– 4.28)
0.02
2.00 (0.91–4.40)
0.08
QRS duration ≥120 ms [1] QRS duration (ms) [1]
0.57 (0.20– 1.60) 0.99 (0.98– 1.00)
0.28 0.30
0.56 (0.19–1.68)
0.30
All-cause mortality 1.00
CHADS2 ≥2
2.99 (1.53– 5.86)
0.001
CHA2DS2-VASc≥2 Hypertension
3.47 (1.51– 8.00) 2.08 (1.07– 4.06)
0.003 0.03
2.26 (1.08–4.75)
0.03
Diabetes
2.29 (1.07– 4.89)
0.03
1.86 (0.77–4.46)
0.17
Coronary artery disease LVEF ,35% [1]
1.27 (0.53– 3.07) 1.53 (0.37– 6.41)
0.59 0.56
0.74 (0.27–2.03)
0.56
Left atrial diameter
1.07 (1.01– 1.13)
0.02
1.05 (0.99–1.12)
0.11
Previous HF Previous pacemaker
2.27 (1.09– 4.74) 1.30 (0.66– 2.54)
0.03 0.45
2.63 (1.01–6.82) 1.43 (0.66–3.11)
0.047 0.37
Centre, Odense
0.68 (0.33– 1.42)
0.30
1.84 (0.72–4.69)
0.20
1.42 (0.29– 7.05)
0.67
0– 24 monthsb
CI, confidence interval; HR, hazard ratio. [] defines number of missing values. a Adjusted for all variables except LVEF ,35%, CHADS2 and CHA2DS2-VASc b Evaluated as a time-dependent factor 0–24 months.
higher percentage of patients treated with warfarin, probably in part dictated by the PVI procedures, but had the same proportion of hospitalization for HF as the group with failed pharmacological treatment. The latter group had nearly twice as many patients with known HF before the AVJA, indicating a higher incidence of new-onset HF in the PVI group, although the difference was nonsignificant. The mortality was slightly higher in the group with failed
pharmacological treatment compared with the PVI group, indicating a subgroup of sicker patients.
Medications The present study showed a statistically significant reduction of treatment with b-blockers, calcium-channel blockers, digoxin and antiarrhythmics 1 year after the AVJA. A low proportion of patients were
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Coronary artery disease
1778
A. Bjo¨rkenheim et al.
Conclusions 1.0
Long-term RV pacing was not harmful in the majority of AF patients after AVJA. Hypertension and previous HF were identified as independent predictors of all-cause mortality, and prolonged QRS duration and left atrial diameter as predictors of hospitalization for HF during long-term follow-up. When selecting a patient for AVJA, it is important to take the QRS duration into account and to consider treatment with CRT. Atrioventricular junction ablation remains a valid treatment option for otherwise therapy refractory AF, including patients with unsuccessful repeated PVI.
95% CI
All-cause mortality
0.8
0.6
0.4
0.2
0.0 0
36
48
Number of subjects at risk All patients 159 155 134 117
99
12
24
60 72 84 96 Months of follow-up 83
63
57
50
108 120 132 144
34
23
8
0
Figure 2 Cumulative incidence of all-cause mortality estimated
Conflict of interest: none declared.
Funding ¨ rebro Heart Foundation and the ReA.B. received funding from the O ¨ search Committee of Orebro University Hospital.
by the Kaplan – Meier method.
References
Table 5 Causes of death No. of patients (%)
Arrhythmias (sudden cardiac death) HF
3 (9) 6 (17)
Myocardial infarction
5 (14)
Stroke Cancer
2 (6) 6 (17)
Infections
4 (11)
Respiratory failure Other
2 (6) 7 (20)
................................................................................
on warfarin treatment both before and after the AVJA, especially in the subgroup with pharmacological failure, which is surprising. This fact is possibly due to the unusually high proportion of paroxysmal AF.
Limitations The study was retrospective in design. The study parameters are based on hospital medical records, echocardiography was not performed in all patients after AVJA and the time of the echocardiography varied among patients. Nearly half of all patients had previous pacemaker treatment for other reasons than the AVJA. The study included two centres and, while the criteria for AVJA were the same, the selection still turned out somewhat differently. This did not, however, result in any relevant statistical differences. During the first years of the enrolment period, AVJA was also offered to younger patients, and even patients with paroxysmal AF, in whom PVI had become a first-line treatment later in the enrolment period.
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Cause of death
1. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010;12:1360 –420. 2. Tan ES, Rienstra M, Wiesfeld AC, Schoonderwoerd BA, Hobbel HH, Van Gelder IC. Long-term outcome of the atrioventricular node ablation and pacemaker implantation for symptomatic refractory atrial fibrillation. Europace 2008;10:412 –8. 3. Wood MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clinical outcomes after ablation and pacing therapy for atrial fibrillation: a meta-analysis. Circulation 2000;101: 1138 –44. 4. Fitzpatrick AP, Kourouyan HD, Siu A, Lee RJ, Lesh MD, Epstein LM et al. Quality of life and outcomes after radiofrequency His-bundle catheter ablation and permanent pacemaker implantation: impact of treatment in paroxysmal and established atrial fibrillation. Am Heart J 1996;131:499–507. 5. Vernooy K, Dijkman B, Cheriex EC, Prinzen FW, Crijns HJ. Ventricular remodeling during long-term right ventricular pacing following His bundle ablation. Am J Cardiol 2006;97:1223 –7. 6. Brignole M, Botto G, Mont L, Iacopino S, De Marchi G, Oddone D et al. Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial. Eur Heart J 2011;32:2420 –9. 7. Tops LF, Schalij MJ, Holman ER, van Erven L, van der Wall EE, Bax JJ. Right ventricular pacing can induce ventricular dyssynchrony in patients with atrial fibrillation after atrioventricular node ablation. J Am Coll Cardiol 2006;48:1642 – 8. 8. Poci D, Backman L, Karlsson T, Edvardsson N. New or aggravated heart failure during long-term right ventricular pacing after AV junctional catheter ablation. Pacing Clin Electrophysiol 2009;32:209 –16. 9. Nielsen JC, Andersen HR, Thomsen PE, Thuesen L, Mortensen PT, Vesterlund T et al. Heart failure and echocardiographic changes during long-term follow-up of patients with sick sinus syndrome randomized to single-chamber atrial or ventricular pacing. Circulation 1998;97:987 –95. 10. Stavrakis S, Garabelli P, Reynolds DW. Cardiac resynchronization therapy after atrioventricular junction ablation for symptomatic atrial fibrillation: a meta-analysis. Europace 2012;14:1490 –7. 11. Zhang XH, Chen H, Siu CW, Yiu KH, Chan WS, Lee KL et al. New-onset heart failure after permanent right ventricular apical pacing in patients with acquired high-grade atrioventricular block and normal left ventricular function. J Cardiovasc Electrophysiol 2008;19:136 –41. 12. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H et al. Dualchamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the dual chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002;288:3115 –23. 13. Szili-Torok T, Bountioukos M, Muskens AJ, Theuns DA, Poldermans D, Roelandt JR et al. The presence of contractile reserve has no predictive value for the evolution of left ventricular function following atrio-ventricular node ablation in patients with permanent atrial fibrillation. Eur J Echocardiogr 2005;6:344 – 50. 14. Ozcan C, Jahangir A, Friedman PA, Patel PJ, Munger TM, Rea RF 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 –51. 15. Iuliano S, Fisher SG, Karasik PE, Fletcher RD, Singh SN. QRS duration and mortality in patients with congestive heart failure. Am Heart J 2002;143:1085 –91.
