Catheter ablation is a promising therapy for atrial fibrillation (AF), but its utility in patients with left ventricular systolic dysfunction (LVSD) is uncertain. The objectives of this study were to perform a systematic review and meta-analysis of randomized and observational studies comparing the rates of recurrent AF, atrial tachycardia (AT), and complications after AF catheter ablation in those with versus without LVSD and to summarize the impact of catheter ablation on the left ventricular ejection fraction. Seven observational studies and 1 randomized trial were included (total n = 1,851). Follow-up ranged from 6 to 27 months. In those with LVSD, 28% to 55% were free of AF or AT on follow-up after 1 AF catheter ablation, increasing to 64% to 96% after a mean of 1.4 procedures. The relative risk for recurrent AF or AT in those with versus without LVSD was 1.5 (95% confidence interval 1.2 to 1.8, p <0.001) after 1 procedure and 1.2 (95% confidence interval 0.9 to 1.5, p = 0.2) after multiple procedures. No difference in complications was observed in patients with (3.5%) versus without (2.5%) heart failure (p = 0.55). After catheter ablation, those with LVSD experienced a pooled absolute improvement in the left ventricular ejection fraction of 0.11 (95% confidence interval 0.07 to 0.14, p <0.001). In conclusion, patients with and without LVSD had similar risk for recurrent AF or AT after catheter ablation, but repeat procedures were required more often in those with LVSD. Significant improvements in left ventricular ejection fractions after ablation were observed in those with LVSD. Randomized trials are needed given the limitations of present data.
Whether to attempt to maintain sinus rhythm or control ventricular rate in patients with atrial fibrillation (AF) and systolic heart failure is uncertain. The available evidence does not support a benefit with medical rhythm control over rate control. However, some patients remain symptomatic with a rate-control approach, and the use of AF catheter ablation to restore sinus rhythm has attracted attention. In clinical trials of patients without significant structural heart disease, AF catheter ablation is superior to drug therapy for maintaining sinus rhythm. Extending this therapy to patients with left ventricular systolic dysfunction (LVSD) is appealing, because AF contributes to heart failure pathophysiology. However, ablation in these patients may be associated with higher risk for recurrent AF or complications, because of differences in atrial substrate and co-morbidities.
We performed a systematic review and meta-analysis to summarize the available evidence for AF catheter ablation in patients with LVSD. The specific objectives were to compare the risk for recurrent atrial arrhythmias and complications after AF catheter ablation in patients with versus without LVSD and to summarize the effects of AF catheter ablation on the left ventricular ejection fraction (LVEF) in those with LVSD.
Methods
We conducted a systematic review using a predefined protocol and in accordance with the Meta-Analysis of Observational Studies in Epidemiology statement. We identified reports in any language by searching Medline (1950 to March 2009), Embase (1980 to March 2009), and the Cochrane Registry of Controlled Trials (to the first quarter of 2009) for clinical studies evaluating AF catheter ablation in patients with LVSD. Our search combined 3 search themes: (1) terms related to AF, (2) terms related to catheter ablation, and (3) terms designed to identify randomized or observational clinical studies (see the Supplementary Materials for the complete search strategy). We supplemented the database search by scanning the bibliographies of reviews and abstracts from the American Heart Association (2007 and 2008) and the Heart Rhythm Society (2007 to 2009) scientific sessions.
Two reviewers (S.B.W. and A.F.) independently screened the titles and abstracts of all records. We retrieved reports for full-text review if either reviewer believed that they reported original data on patients with LVSD who underwent AF catheter ablation. Reports dealing with total atrioventricular node ablation or open surgical ablation were excluded. We then reviewed the full text of all retrieved studies in duplicate. Reports were included in the systematic review if they (1) reported original results of AF catheter ablation; (2) enrolled patients with LVSD, defined as an LVEF <0.50, either exclusively or in a separately reported group; (3) followed ≥25 patients (4) for ≥6 months; and (5) reported on ≥1 end point of interest. These end points included recurrence of AF or atrial tachycardia (AT), adverse events, and heart failure end points, including changes in LVEF, functional status, quality of life, or mortality. We extracted data about study design and patient characteristics, concomitant medical therapy, details of the ablation procedure, definitions of AF or AT recurrence, and adverse events. We recorded the absolute proportion of recurrent AF or AT as well as any effect measure (relative risk [RR], odds ratio, or hazard ratio) used to compare ablation outcomes in patients with and without LVSD. Finally, we extracted data relevant to study quality, using a published guide for evaluating the internal validity of observational studies. We considered sample selection, baseline clinical characteristics, measures taken to monitor for asymptomatic recurrence of AF or AT, blinding of outcome assessment, completeness of follow-up, and statistical methods used to minimize bias.
Measured data were recorded as mean ± SD. We calculated the Mantel-Haenszel pooled RR of recurrent AF or AT after ablation in patients with versus without LVSD. We also calculated the pooled absolute change in the LVEF during follow-up. We used Cochran’s Q statistic to assess between-study heterogeneity. In the absence of significant heterogeneity, fixed-effects models were used to calculate pooled effects. When heterogeneity was present, we used random-effects models and sought to identify its source(s) by performing stratified analyses on the basis of patient and study characteristics. A p value <0.05 was considered statistically significant. Stata version 11 (StataCorp LP, College Station, Texas) was used for analysis.
Results
The results of our search and selection are detailed in Figure 1 . The database search yielded 1,925 citations, 37 of which were selected for full-text review. Bibliographic hand search did not yield additional reports. One reviewed abstract met the inclusion criteria and has since been published. After full-text review, 8 reports were included. The reasons for exclusion of the others are listed in Figure 1 .
Table 1 outlines the characteristics of the included studies. The 8 reports, published from 2004 to 2009, followed a total of 1,851 patients who underwent AF catheter ablation, 483 of whom had LVSD. There were 7 single-center observational studies, most originating from centers whose investigators make frequent contributions to the published research on AF catheter ablation. The remaining study was the Pulmonary Vein Isolation Versus AV Nodal Ablation With Biventricular Pacing for Patients With Atrial Fibrillation With Congestive Heart Failure (PABA-CHF) randomized trial.
| Characteristic | Chen et al (2004) | Hsu et al (2004) | Tondo et al (2006) | Gentlesk et al (2007) | Nademanee et al (2008) | Khan et al (2008) | Lutomsky et al (2008) | De Potter et al (2010) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Prospective design | No | No | Yes | Yes | Yes | Yes (RCT) | Yes | No | |||||||
| Multicenter | No | No | No | No | No | Yes | No | No | |||||||
| Sample size | 377 | 116 | 105 | 366 | 635 | 81 | 70 | 72 | |||||||
| Low-LVEF sample | 94 (25%) | 58 (50%) | 40 (38%) | 67 (18%) | 129 (20%) | 81 (100%) | 18 (26%) | 36 (50%) | |||||||
| Patient characteristics | Low LVEF | Normal LVEF | Low LVEF | Normal LVEF | Low LVEF | Normal LVEF | Low LVEF | Normal LVEF | Abl | BiV | Low LVEF | Normal LVEF | Low LVEF | Normal LVEF | |
| Mean age (years) | 57 | 55 | 56 | 56 | 57 | 56 | 54 | 54 | 67 | 60 | 61 | — | — | 52 | 51 |
| Men | 80% | 78% | 88% | 88% | 70% | 88% | 93% | 76% | 67% | 95% | 88% | — | — | 89% | 94% |
| Mean AF duration (months) | 72 | 60 | 80 | 79 | 36 | 48 | 67 | 71 | 40 | 48 | 47 | — | — | 44 | 78 |
| Mean number of AADs used | 3 | 3 | 3 | 3 | 3 | 3 | — | — | 2.6 | — | — | — | — | — | — |
| Paroxysmal AF | 41% | 55% | 9% | 9% | 25% | 23% | 70% | 82% | 40% | 49% | 55% | 100% | 100% | 39% | — |
| CAD | 91% | 22% | 20% | 9% | 25% | 29% | 18% | 9% | 215 | 73% | 68% | — | — | 25% | — |
| Nonischemic CM | 66% | 7% | 50% | 3% | 74% | — | 11% | — | — | — | — | 50% | — | ||
| Valvular HD | 16% | 13% | 16% | 5% | 25% | 18% | 9% | 5% | 17% | — | — | — | — | 11% | — |
| Other structural HD | — | — | 6% | 0% | — | — | — | — | — | — | — | — | — | 14% | — |
| NYHA class ≥II | 100% | 5% | 100% | — | — | — | — | — | — | 100% | 100% | — | — | — | — |
| Mean LVEF | 0.36 | 0.54 | 0.35 | 0.66 | 0.33 | 0.64 | 0.42 | 0.61 | 0.30 | 0.27 | 0.29 | 0.41 | 0.60 | 0.41 | 0.63 |
| Mean LA diameter (mm) | 47 | 45 | 50 | 46 | 48 | 44 | 44 | 48 | — | 49 | 47 | — | — | 43 | 43 |
| Primary ablation procedure | PVI plus | PVI plus | PVI plus | PVI | CFAE | PVI plus | PVI | PVI plus | |||||||
| Mean number of procedures | 1.2 | 1.1 | 1.5 | 1.5 | 1.3 | 1.2 | 1.6 | 1.3 | 1.7 | 1.2 | N/A | 1.0 | 1.0 | 1.4 | 1.4 |
| Mean follow-up (months) | 14 | 15 | 12 | 12 | 14 | 14 | 20 | 20 | 27 | 6 | 6 | 6 | 6 | 14 | 17 |
| Definition of AF/AT recurrence | Any episode | Any episode | Any episode | Any episode | Any episode | Any episode | Any episode | Any episode | |||||||
| Blanking period (months) | 1 | 0 ⁎ | 1 | 1 | 3 | 2 | 1 | 3 | |||||||
| Detection of asymptomatic AF recurrence | |||||||||||||||
| ECG timing (months) | 2, 3, 6, 12 | — | 1, 3, 6, 12 | Per 3 | Per 3 | — | — | 3, 6, 12 | |||||||
| Holter monitoring (months) | 3, 6, 12 | 1, 3, 6, 12 | 1, 3, 6, 12 | — | Per 12 | — | — | 3, 6, 12 | |||||||
| TTM | At 1 month | — | 3 per week | — | Daily for 6 months | — | |||||||||
| ER | — | — | — | At 6 weeks and 6 months | — | At 2–6 months | — | — | |||||||
Table 1 also lists the baseline clinical characteristics, treatment, and follow-up of the patients. The mean age ranged from 52 to 67 years, and the proportion of men ranged from 70% to 95%. The mean duration of AF ranged from 38 to 80 months, and patients in all studies had recurrent symptomatic AF despite the use of ≥1 antiarrhythmic medication. The proportion of patients with paroxysmal AF varied from 9% to 100%. At baseline, mean left atrial diameter varied from 44 to 50 mm and did not differ in those with versus without LVSD. The mean baseline LVEF ranged from 0.27 to 0.41 in the LVSD groups and from 0.54 to 0.66 in the control groups. Reporting of the type of underlying heart disease was variable, and the criteria used to establish diagnoses were not reported. Ablation techniques were variable, although all but 1 report identified pulmonary vein isolation as the primary or only method. Many studies reported the use of atrial substrate modification techniques, including ablation of complex fractionated electrograms and linear ablation, at the investigators’ discretion. Mean follow-up ranged from 6 to 27 months.
Table 2 summarizes our assessments of several key determinants of study quality. Follow-up was complete in all studies. Because asymptomatic recurrence of AF is common after catheter ablation, adequate monitoring for its presence is important. All but 1 study met or exceeded the follow-up schedule recommended by the Heart Rhythm Society. Bias may also arise when individuals performing outcome assessments are aware of baseline characteristics or the results of ablation, in particular with assessment of the LVEF. Four studies took measures to reduce this type of bias. Improvement in heart failure end points could be due to changes in concomitant medical therapy rather than ablation. Only 3 studies addressed this issue. The PABA-CHF trial did so by requiring all patients to have optimal medical therapy for heart failure at enrollment, while 2 of the included observational studies reported no or minimal changes in heart failure therapy during follow-up. The included studies used various methods to detect confounding by differences in baseline characteristics, including performing stratified or multivariate regression analyses. The key results of these analyses are listed in Table 2 .
| Study | Complete Follow-Up | Adequate AF Monitoring | Reported HF Therapy | Blinded Outcome Assessors | Statistical Analyses to Reduce Bias | Key Results of Adjusted Analyses |
|---|---|---|---|---|---|---|
| Chen et al (2004) | + | + | 0 | 0 | Multivariate Cox model | LVEF, pulmonary vein size associated with recurrence |
| Hsu et al (2004) | + | + | 0 | 0 | Stratified analyses | Similar improvement in LVEF in those with and without poor rate control before ablation |
| Tondo et al (2006) | + | + | 0 | 0 | None | |
| Gentlesk et al (2007) | + | + | + | + | Stratified analyses | Maintenance of SR associated with more LVEF improvement |
| Khan et al (2008) | + ⁎ | + | + | + | Intention-to-treat analysis | |
| Lutomsky et al (2008) | + | + | + | 0 | None | |
| Nademanee et al (2008) | + | 0 | 0 | 0 | Multivariate logistic regression | Duration of AF, LA size >50 mm, not LVEF <40%, associated with recurrence Maintenance of SR predicts survival |
| De Potter et al (2010) | — | + | 0 | 0 | Multivariate Cox model | LA size, not LVEF or AF duration, associated with recurrence SR maintenance associated with ΔLVEF ΔLVEF similar in ischemic and nonischemic LVSD |
⁎ Differential follow-up in those requiring second ablation procedures.
Table 3 summarizes the results of AF catheter ablation in the included studies. All studies reported on the recurrence of AF or AT in follow-up (with a postprocedural “blanking period” of 1 to 3 months). Five studies reported on recurrence after a single procedure, which ranged from 45% to 73% in patients with LVSD and from 13% to 62% in those without LVSD. The pooled RR of AF or AT recurrence after a single ablation for those with versus without LVSD was 1.45 (95% confidence interval [CI] 1.20 to 1.75, p <0.0001; see Figure 2 ). Seven studies reported the proportion with recurrent AF or AT after ≥1 (weighted mean 1.4) procedure. These ranged from 4% to 31% in those with LVSD and from 6% to 31% in those without LVSD. Antiarrhythmic drugs were required to maintain sinus rhythm in 0% to 38% and 0% to 28% of patients with and without LVSD, respectively. In these studies, the pooled RR of recurrent AF or AT in those with versus without LVSD was 1.18 (95% CI 0.92 to 1.51, p = 0.18; see Figure 2 ). No evidence of between-study heterogeneity was identified in either of these analyses. In the PABA-CHF trial, 88% of patients in the ablation arm were free from AF or AT 6 months after the last procedure, 71% of them without the need for antiarrhythmic drugs, while all patients in the control arm had ongoing AF.
| Variable | Chen et al (2004) | Hsu et al (2004) | Tondo et al (2006) | Gentlesk et al (2007) | Khan et al (2008) | Lutomsky et al (2008) | Nademanee et al (2008) | De Potter et al (2010) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Low LVEF | Normal LVEF | Low LVEF | Normal LVEF | Low LVEF | Normal LVEF | Low LVEF | Normal LVEF | Abl | Biv | Low LVEF | Normal LVEF | Low LVEF | Normal LVEF | Low LVEF | Normal LVEF | |
| AF/AT recurrence | ||||||||||||||||
| Single procedure | 27% | 13% | 75% | 62% | 45% | 29% | — | — | — | — | 50% | 27% | — | — | 50% | 44% |
| ≥1 procedure | 4% | 6% | 22% | 16% | 12% | 11% | 13% | 13% | 12% | NA | 21% | 18% | 31% | 31% | ||
| SR with AAD | 3% | 6% | 9% | 13% | 38% | 23% | 31% | 28% | 17% | 0% | 0% | 0% | 11% | — | — | |
| Safety | ||||||||||||||||
| Total adverse events | 3 | 10 | 3 | 1 | 2 | 4 | — | 7 | 7 | 7 | 7 | 28 | 1 | 3 | ||
| Death | — | — | 1 | — | — | — | — | — | — | — | — | — | 0 ⁎ | — | — | |
| Stroke | 2 | 3 | 1 | — | — | — | — | — | — | — | — | — | 5 | — | 1 (TIA) | |
| Pulmonary vein stenosis | 1 | — | — | — | — | — | — | — | — | — | 2 | — | — | — | — | |
| Pericardial tamponade | — | 2 | 1 | 1 | — | 1 | — | — | — | — | — | — | 9 | — | — | |
| Significant bleeding | — | 5 | — | — | — | 3 | — | — | — | — | 3 | 2 | 1 | — | — | |
| Vascular complication | — | — | — | — | 2 | — | — | — | — | — | — | — | 13 | — | 2 | |
| Other | — | — | — | — | — | — | — | — | — | — | 2 | 5 | — | 1 | — | |
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