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Managing atrial fibrillation in the CRT patient: Controversy or consensus?
Managing atrial fibrillation in the CRT patient: Controversy or consensus? Gaurav A. Upadhyay, MD,* Jonathan S. Steinberg, MD† From the *Department of Medicine and the Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, and †Arrhythmia Institute of the Valley Health System, Columbia University College of Physicians & Surgeons, New York, New York. The cumulative incidence of new onset atrial fibrillation (AF) in patients undergoing cardiac resynchronization therapy (CRT) is substantial, exceeding 25% in multiple recent studies. Although AF patients undergoing CRT show improved echocardiographic parameters, functional status, and quality of life in, they benefit to a lesser degree than do patients in normal sinus rhythm. They also exhibit a trend toward increased mortality. Understanding the barriers to response from CRT among AF patients is critical to addressing the needs of growing populations of patients with AF and HF. Foremost among these are suboptimal biventricular pacing, often characterized by fusion or pseudo-fusion complexes, leading to inefficient CRT delivery. Furthermore, AF increases the risk of inappropriate shocks, which lead to substantial psychiatric morbidity, increased risk of heart failure hospitalization, and may also increase mortality. Assiduous rate control is reasonable for all AF patients receiving CRT, but there is a paucity of data regarding specific antiarrhythmic drug therapy recommendations. For patients with permanent AF and severe symptoms, atrioventricular
Introduction Atrial fibrillation (AF) and heart failure (HF) have been characterized as the twin epidemics of modern cardiovascular medicine.1 In individuals ⱖ40 years of age, the lifetime risk of developing HF is 1 in 5.2 The prevalence of HF exceeds 5.7 million in the United States,3 and in 2010 HF accrued estimated direct and indirect costs totaling $39.2 billion.4 Similar in magnitude to HF, AF affects ⬎2.2 million Americans. The lifetime risk for AF in adults aged ⱖ40 years is 1 in 4.3,5 Worse, AF is a marker of increased mortality: one-fourth of all Medicare beneficiaries diagnosed with AF die within 1 year.6 AF also clearly tracks with New York Heart Association (NYHA) HF class. It is
Dr. Upadhyay has no financial disclosures that are relevant to this publication. Dr. Steinberg is on the speakers’ bureau for Sanofi-Aventis; receives consultant fees/honoraria from Biosense Webster, Cameron Health, Ambucor, Medtronic, St. Jude Medical, and Sanofi-Aventis; and receives research/research grants from Biosense Webster and Medtronic. Address reprint requests and correspondence: Dr. Gaurav A. Upadhyay, Division of Cardiology and the Cardiac Arrhythmia Service, Massachusetts General Hospital, Gray Bigelow 109, Boston, MA 02114. E-mail address: [email protected].
junction ablation appears effective in improving response by ensuring biventricular capture and reducing implantable cardioverter-defibrillator shock burden in selected patients. Catheterbased techniques such as pulmonary vein isolation appear more attractive and in the future may offer further advantages and lower risks, particularly for patients with paroxysmal AF. KEYWORDS Atrial fibrillation; Cardiac resynchronization therapy; Heart failure; Treatment strategies ABBREVIATIONS AF ⫽ atrial fibrillation; AV ⫽ atrioventricular; AVJ ⫽ atrioventricular junction; BiV ⫽ biventricular; CFAE ⫽ complex fractionated atrial electrogram; CRT ⫽ cardiac resynchronization therapy; EF ⫽ ejection fraction; HF ⫽ heart failure; ICD ⫽ implantable cardioverter-defibrillator; LV ⫽ left ventricular; NYHA ⫽ New York Heart Association; PVI ⫽ pulmonary vein isolation; VRR ⫽ ventricular rate regularization (Heart Rhythm 2012;9:S51–S59) © 2012 Heart Rhythm Society. All rights reserved.
present in 5% of NYHA class I patients and in up to 50% of NYHA class IV patients.7 In the past decade, cardiac resynchronization therapy (CRT) has emerged as a viable new treatment option for an important subset of HF patients. However, although CRT now has an established role as a safe and efficacious devicebased therapy for HF patients with severe systolic dysfunction, intraventricular conduction delay, and normal sinus rhythm, its optimal use in patients with HF and AF remains uncertain.8 –10 Indeed, although HF patients with AF who undergo CRT demonstrate improvement in echocardiographic parameters, functional status, and quality of life, they benefit less than their counterparts in normal sinus rhythm, and they exhibit a trend toward increased mortality.11,12 Understanding the barriers to response to CRT among HF patients with AF and identifying strategies to overcome these barriers are critical to addressing the needs of growing populations of patients with HF and AF.
Scope of the problem The first reported randomized, large-trial data regarding the incidence of AF in HF patients who received CRT devices came from analysis of the CArdiac REsynchronization in Heart Failure (CARE-HF) study.13 The analysis by Hoppe
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et al14 found that 16.1% of the 409 patients assigned to optimal medical therapy plus CRT developed new-onset AF, which was nonsignificantly different from the 14.4% found in the medication-only treatment arm (P ⫽ .79). Data estimates from another large randomized trial, the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) study, suggested a similar rate of new-onset AF.15 Interestingly, Hoppe et al14 reported that in the CARE-HF study, an additional 93 patients (22%) in the CRT group demonstrated AF when assessed using device diagnostics rather than through routine ECG monitoring. Following this trend, modern trials have increasingly used data available from device-based diagnostics rather than periodic ECG assessments at disparate follow-up visits to quantify overall degree of AF burden.16 –21 Evaluated in this fashion, the overall cumulative incidence of AF in HF patients treated with CRT is greater than what had previously been suspected: between 21% and 42% of CRT patients who initially exhibit normal sinus rhythm (Table 1). In addition to increased incidence, the presence of AF, as measured by device diagnostics, has been shown to correlate with worse clinical outcome. Puglisi et al20 found a statistically significant and deleterious impact on patients’ activity levels, a higher average nighttime heart rate, and reduced heart rate variability for patients with paroxysmal AF once they had returned to normal sinus rhythm. In addition, there is concern that time spent in AF increases the risk of stroke. Indeed, the AF burden measured by device diagnostics in antitachycardia pacemakers has been found to be associated with an increased risk of arterial embolic events, although this has yet to be conclusively shown in patients who have received CRT devices.18,21 Interestingly, although AF appears relatively common after initiation of CRT, the degree of AF burden appears to be modified by device therapy. Among patients with paroxysmal AF, the burden of AF shrinks over time during the first 3 months with CRT22 and remains significantly reduced for CRT responders for up to 6 months after implant.23 Furthermore, Gasparini et al24 found that up to 1 in 10 patients with permanent AF who receive a CRT device will resume normal sinus rhythm, mostly within 4 months of implantation. This finding is novel and remains to be reproduced in future trials. With that said, it is clear that, the Table 1
Cumulative incidence of AF in recent CRT trials Patients (%) with new-onset AF/AT according to diagnosis from CRT device
Study (Year) Leclercqetal17 Borleffsetal19 Marijonetal16 Caldwelletal18 Borianietal21 Puglisietal20
(2010) (2009) (2010) (2009) (2011) (2008)
21 25 27 27 32 42
AF ⫽ atrial fibrillation; AT ⫽ atrial tachycardia; CRT ⫽ cardiac resynchronization therapy.
interplay of AF incidence and AF progression after CRT is complex and difficult to predict.
Barriers to CRT response during AF Insufficient biventricular pacing It is axiomatic that there is no possibility of benefit after CRT if biventricular (BiV) pacing does not reliably occur. This is because the physiological impact of CRT is postulated to occur through synchronizing ventricular contraction, leading to improvement in left ventricular (LV) filling and pumping efficiency and reduction in the extent of functional mitral regurgitation. In patients with HF and AF, atrioventricular (AV) synchrony does not exist; thus, any clinical benefit is predicated on BiV synchronization. However, in patients with AF, erratic electric activity of the atria occasionally will penetrate the AV node and override, interrupt, or disrupt BiV capture. This leads to fusion or pseudo-fusion beats and suboptimal CRT delivery,1,11,25 particularly in situations of increased myocardial demand, as occurs from increased adrenergic tone during stress or exercise. Perhaps even more problematic than lack of BiV capture is that the percentage of BiV pacing recorded by internal CRT device counters often is artificially inflated during AF, due to erroneous counting of fusion and pseudo-fusion complexes.1,25,26 Although a clinician might believe that adequate delivery of CRT has occurred because of an apparently high percentage of BiV pacing, a patient with AF may not have received the full benefit of synchronized BiV capture. This dichotomy between device counters estimation of percentage BiV pacing and true BiV capture was elegantly illustrated in a study by Kamath et al26 utilizing 12-lead ambulatory Holter monitoring in 19 AF patients who received CRT devices. In their study, less than half of the patients in AF received effective pacing (defined as ⬎90% genuine BiV capture). More disturbingly, patients who were ineffectively paced demonstrated an astonishing 40% rate of fusion and pseudo-fusion complexes despite internal device counters suggesting that ⬎90% BiV capture had been achieved. The authors were also able to establish the clinical relevance of truly realized BiV capture, correlating CRT response with a significantly higher percentage of fully paced beats. The findings of Kamath et al26 are in line with recent observations suggesting that a high degree of BiV capture may be the single most important variable in predicting improvement after CRT, reducing HF decompensation, and, most importantly, increasing survival (Figure 1).27,28 Indeed, a recent study by Hayes et al28 evaluating the association between the percentage of BiV capture assessed by device diagnostics and survival found that only when measured BiV pacing percentage rates were ⬎98.5% did AF patients demonstrate survival similar to that of their counterparts in normal sinus rhythm.
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Figure 1 Probability of survival in biventricular pacing patients, with or without atrial fibrillation, as a function of percentage of biventricular pacing capture. Patients with biventricular pacing ⬎99.6% experienced a 24% reduction in mortality compared with the other groups (hazard ratio 0.76, P ⬍.001). (Adapted from Hayes DL, Boehmer JP, Day JD, et al. Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival. Heart Rhythm 2011;8:1469 –1475.28)
Increased risk of implantable cardioverterdefibrillator shocks The second most significant barrier to AF patients deriving full benefit from CRT is an increased risk of appropriate and inappropriate defibrillator therapies.29 Based on prior investigations of patients with an implantable cardioverter-defibrillator (ICD), AF is associated with an increased risk of appropriate and inappropriate defibrillator therapy and also an increased risk of HF deterioration (Figure 2).30,31 While it is well-known that appropriate shocks are associated with an increased risk of death, subgroup
analysis of two major ICD trials and a large national registry have further suggested that inappropriate ICD shocks are also associated with increased mortality.32–34 However, published data regarding the impact of newonset AF in recipients of combined CRT plus ICD devices (ie, CRT-D) are more limited. In a study of 223 consecutive patients treated with CRT-D, Borleffs et al19 found that new-onset AF after CRT predisposed to an increased risk of both appropriate and inappropriate shocks, as well as hospitalizations, but did not lead to a significantly increased risk of mortality (Figure 3).19
Figure 2 Increasingly severe atrial fibrillation (AF) is associated with increased probability of implantable cardioverter-defibrillator (ICD) shocks (left) and increased risk of congestive heart failure (HF) deterioration (right). (Adapted from Rienstra M, Smit MD, Nieuwland W, et al. Persistent atrial fibrillation is associated with appropriate shocks and heart failure in patients with left ventricular dysfunction treated with an implantable cardioverter defibrillator. Am Heart J 2007;153:120 –126.31)
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Figure 3 New-onset atrial fibrillation (AF) is associated with statistically significant increases in risk of both appropriate and inappropriate implantable cardioverter-defibrillator shocks (A, B) as well as hospitalization (C). There is no statistically significant difference in risk of mortality (D). SR ⫽ sinus rhythm. (Modified from Borleffs CJ, Ypenburg C, van Bommel RJ, et al. Clinical importance of new-onset atrial fibrillation after cardiac resynchronization therapy. Heart Rhythm 2009;6:305–310.19)
Clearly, further investigation of the impact of AF and shock burden in CRT-D patients is necessary.
Antiarrhythmic drug therapy and CRT The crucial decision point for managing AF in patients with HF has been “rate vs rhythm” control strategies, and this question has been a source of ongoing controversy. The landmark and frequently cited Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study concluded that there is no survival advantage for a rhythmcontrol strategy over rate control.35 However, only 23% of patients enrolled in the AFFIRM study demonstrated a history of congestive HF, and subgroup analysis revealed no difference with respect to the primary endpoint for these patients. In post hoc analysis, Corley et al36 found that the presence of normal sinus rhythm was associated with significant survival benefit, irrespective of rate or rhythm strategy. Guglin et al37 further demonstrated that patients in the rhythm-control arm had fewer HF symptoms than did those in the rate-control arm and that stable sinus rhythm was associated with the best functional status. These contradictory findings in AFFIRM are supported by observations on the benefit of antiarrhythmic drug therapy for AF in other trials of HF patients. In a substudy of the Congestive Heart Failure: Survival Trial of Antiarrhythmic Therapy (CHF-STAT), Deedwania et al38 generated significant interest in the potential benefit of amiodarone when they reported that AF patients who converted to sinus rhythm demonstrated a mortality benefit. Similar findings of mortality benefit were also reported with a different antiarrhythmic agent in a substudy of the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND).39
Indeed, even in a prespecified analysis of patients with mild-to-moderate chronic HF in the RAte Control versus Electrical cardioversion (RACE) study, a trend toward a mortality benefit was found in patients maintaining sinus rhythm.40 In light of these findings, the results of the larger and more recent Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial have been surprising. The AF-CHF trial was a prospective, multicenter trial of 1376 patients with NYHA class III–IV HF and systolic dysfunction. No mortality or morbidity benefit was found for a rhythm-control over a rate-control strategy with respect to the primary endpoint of cardiovascular mortality or the secondary endpoints of allcause mortality and worsening HF.41 Critics have noted that the rhythm-control arm relied almost exclusively on amiodarone (82% of patients) and that ⬎20% of the rhythmcontrol patients crossed over to the rate-control arm. In addition, only 73% of patients in the rhythm-control arm achieved and actually maintained sinus rhythm at 4 years of follow-up (Figure 4). Nevertheless, the AF-CHF trial raises important questions as to whether a rhythm-control strategy, and its associated drug-related toxicities, is worth the risk for the general HF patient. Perhaps the reality is that the decision of rhythm vs rate control for AF in the CRT patient is a false choice. Given that the primary barriers to response to CRT-D in AF patients are insufficient BiV capture and the increased risks associated with ICD therapies, it may be that ventricular rate control with negative chronotropic drugs is insufficient to address the harm from ventricular dyssynchronization.
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Figure 4 Results from the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial found that 27% of patients in the rhythm-control arm still demonstrated atrial fibrillation at 4 years of follow-up.
Some authors have suggested the use of device-derived features, such as ventricular rate regularization (VRR), in addition to rate-control drug therapy.42 Gasparini et al42 described how VRR might increase retrograde concealed penetration of the AV node through rate-adaptive BiV pacing and reduce short cycles. They also have found the “ventricular sense response”— or the “trigger” function that produces LV pacing after a premature right ventricular sense event— has been helpful in their patients with AF.42 Establishing the thresholds for adequate rate control is also uncertain in patients with AF who receive CRT, and, for the typical AF patient, there may be a trend toward acceptance of more liberal rate goals. In the recent Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient versus Strict Rate Control II (RACE II) study, a resting heart rate goal of ⬍110 bpm was found to result in a clinical outcome similar to that of a conventional goal of ⬍80 bpm.43 However, this study was not focused on HF patients and had a relatively short follow-up; therefore, this result should not be taken as an evidence-based recommendation. Clearly, this is not a “onesize-fits-all” situation, and taking such an approach would lead to significant harm for patients receiving CRT-D devices, due to inappropriate shocks alone. Conversely, an “as low-as-you-can-go” strategy for rate control has not been formally assessed in the CRT population, although it has remained an attractive concept in the electrophysiology community, particularly when addressing patients with HF. There is a relative paucity of data regarding the role of antiarrhythmic drug therapy in CRT patients. In a study of 263 consecutive patients enrolled in a prospective registry, Delnoy et al44 reported that they were able to achieve a high percentage of BiV pacing (ⱖ90%) in ⬎90% of AF patients. They suggested that higher rates of amiodarone prescription, which doubled from 12% to 23% for AF patients treated with CRT and was associated with spontaneous cardioversion, allowed for this response. It is noteworthy that the rate of amiodarone prescription seen in Delnoy’s cohort is not substantially different than that observed in
other prospective trials11 or reported in a substudy of the only randomized CRT trial enrolling patients with AF, the MUltisite STimulation In Cardiomyopathy (MUSTIC) study.45 The purported association between increased use of amiodarone and adverse events was not noted in Delnoy’s group. Indeed, in recent meta-analyses of CRT and AF studies, no significant signal of antiarrhythmic drug therapy–related toxicity was observed.11,12
Role for AV junction ablation The role of an “ablate and pace” strategy, as an alternative to classic rhythm-control or rate-control strategies, has been of considerable interest in CRT trials. Atrioventricular junction (AVJ) ablation is attractive because it affords the opportunity to guarantee essentially 100% BiV capture. Typically reserved for patients with medication-refractory symptoms and rapid heart rates, the procedure is considered by many to be a palliative or “last resort” option because it is associated with multiple disadvantages, not the least of which is pacemaker dependence (Table 2). Reports on the benefit of AVJ ablation in the treatment of AF in CRT patients are conflicting. In a large prospective observational cohort study of 673 patients, 162 (24%) of whom were in permanent AF, Gasparini et al25 reported that only those patients who underwent AVJ ablation showed significant improvement in venTable 2 Disadvantages of atrioventricular junction ablation and permanent pacemaker placement in the treatment of atrial fibrillation Continued atrial fibrillation Risk of thromboembolism ● Loss of A-V synchrony ● Procedure is irreversible Patient is rendered pacemaker-dependent Patient is made vulnerable to catastrophic complications in case of device/lead failure Rapid battery drain (constant pacing) ● More generator replacements and potential complications
S56 tricular volumes, exercise capacity, and clinical response to CRT. The same group conducted a more extensive multicenter observational study of 1285 consecutive patients, 243 (19%) of whom were in permanent AF, and found that AVJ ablation was associated with a survival benefit driven by reduction in HF-associated mortality.46 These results have been replicated by Ferreira et al47 and Dong et al,48 who found significantly improved clinical outcome and survival among CRT patients with AF who received AVJ ablation vs those who did not. However, other investigators have argued that sufficiently high degrees of ventricular capture can be achieved with the use of medications alone, thus avoiding the risk associated with AVJ ablation.44,49,50 A further criticism of this approach is that patient selection has not been random, because CRT studies usually restrict the procedure to patients in permanent AF with severe symptomatology. The role of AVJ ablation for persistent, and certainly for paroxysmal, AF is much less certain.
Pulmonary vein isolation—A case for a hybrid strategy? There has been considerable interest in recent years about the role of catheter-based therapies for the treatment of AF, particularly with respect to pulmonary vein isolation (PVI) utilizing radiofrequency ablation or cryoablation. PVI is significantly less invasive than the surgical Cox maze procedure. Published success rates for PVI range between 41% and 94%, with most large studies reporting 80% freedom from paroxysmal AF.51 Indeed, in a meta-analysis examining PVI vs optimal medical therapy, Piccini et al52 found a cumulative odds ratio of close to 16 for freedom from paroxysmal AF at 12 months after PVI (Figure 5). In studies evaluating the success of PVI in the treatment of persistent AF, however, success rates have been lower. Published studies have reported that freedom from persistent AF occurs in as few as 20% to 61% of cases and frequently requires multiple PVI procedures.51 Techniques are continuously being modified, however, and early
Heart Rhythm, Vol 9, No 8S, August Supplement 2012 evidence suggests that addition of ablation of complex fractionated atrial electrograms (CFAEs) or piggybacking ablation to periods of sinus rhythm–induced reversed remodeling might improve freedom from AF in nonparoxysmal AF patients.53,54 Certainly, there is a role for the simultaneous use of PVI and antiarrhythmic drug therapy for refractory patients. The success rate of PVI in patients with HF due to systolic dysfunction vs those with normal systolic function has recently been evaluated. In an abstract presented at the 2011 American College of Cardiology Scientific Sessions, a meta-analysis of 7 studies of PVI in patients with AF and LV dysfunction found similar success of PVI in patients with LV dysfunction and those with normal ejection fraction (EF) (RR 1.00, 95% confidence interval 0.96 –1.04; Figure 6a).55 Additionally, a significant improvement in LVEF was seen after PVI (Figure 6b).55 The relative efficacy of PVI vs AVJ ablation was assessed in randomized fashion in the Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure (PABA-CHF) trial. This was an intriguing study that evaluated the role of PVI in NYHA class II and III HF patients vs AVJ ablation and CRT therapy in the treatment of severe, symptomatic AF.56 About half of the patients were in persistent AF and half in paroxysmal AF. Patients in this trial did not have significant intraventricular conduction delay; mean QRS width was approximately 90 ms in both study arms. However, the results of PABA-CHF revealed a clear advantage for PVI over AVJ ablation plus CRT, with freedom from AF in nearly 80% of PVI patients. More significantly, LVEF and 6-minute walk were substantially increased after PVI. Taken together, there are promising data regarding the use of PVI to ameliorate symptoms and improve echocardiographic parameters in AF patients, particularly in those with paroxysmal AF. In addition, some data suggest that the
Figure 5 Meta-analysis of 5 trials of pulmonary vein isolation (PVI) vs optimal medical therapy found a cumulative odds ratio ⬃16 for freedom from paroxysmal atrial fibrillation at 12 months after PVI. (Modified from Piccini JP, Lopes RD, Kong MH, Hasselblad V, Jackson K, Al-Khatib SM. Pulmonary vein isolation for the maintenance of sinus rhythm in patients with atrial fibrillation: a meta-analysis of randomized, controlled trials. Circ Antiarrhythm Electrophysiol 2009;2:626 – 633.52)
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Figure 6 Meta-analysis of 7 studies shows similar success with pulmonary vein isolation (PVI) in patients with left ventricular dysfunction and those with normal ejection fraction (RR 1.00; A). In addition, there was a significant improvement in left ventricular ejection fraction after PVI (B). (From an abstract presented at the 2011 American College of Cardiology Scientific Sessions by Garikipati NV, Avula A, Verma P, Mittal S, Steinberg J. Pulmonary vein isolation in patients with left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2011;57:E16.55)
efficacy for PVI in patients with LV dysfunction is similar to that of PVI in those with normal EF. What has not yet been sufficiently explored, however, is the role of PVI in patients with LV dysfunction and intraventricular conduction delay (ie, typical candidates for CRT). Whether modification of the standard PVI approach may be required in CRT patients in order to yield similar results, either with regard to the extent or the location of ablation lines or the use of additional CFAE modification, remains to be evaluated. Based on the data acquired thus far, it seems reasonable to consider PVI as a means to improve symptoms, reduce the risk of antiarrhythmic drug toxicity, and improve response through increased BiV capture in CRT patients with paroxysmal AF who are nonresponders to conventional therapies. Selected patients with persistent or permanent AF and favorable left atrial anatomy also might be targeted, but the data remain limited at this time. Further prospective cohort investigation and randomized trials are needed to better approach this group of patients.
ensure that pseudo-fused and fused beats are not being miscounted as those associated with BiV capture. This process should be undertaken periodically throughout follow-up and whenever clinical response is suboptimal. Next, rate control is an initial and simple means to reduce degree of fusion and should be attempted in all patients. Although no single “rate goal” has been identified as optimal in patients receiving CRT, based on data from HF literature, lower rates (resting mean ⬍80 bpm) appear reasonable. Rhythm control through antiarrhythmic therapy should be pursued as a second-line approach should rate control fail to address lack of capture. PVI is another increasingly attractive option for suppression of AF to increase CRT effective delivery and decrease shocks for AF, particularly for patients with paroxysmal AF. In patients with permanent AF who cannot be adequately rate-controlled, AVJ ablation may be a necessary means of guaranteeing CRT response and should be an active consideration for virtually all such patients.
Summary recommendations
There has been increasing recognition of the epidemics of HF and AF, conditions often present in the same patient. Initially validated in populations in normal sinus rhythm, CRT now has an established role in the treatment of HF patients with LV dysfunction and intraventricular conduction delay. The incidence of new AF in patients who have been implanted with a CRT device is substantial, exceeding one-fourth of patients in multiple recent studies utilizing device diagnostics, making maximization of BiV capture and the reduction of fusion and pseudo-fusion beats imper-
Based on the available data, we feel confident that AF patients can enjoy similar benefits from CRT as do those with normal sinus rhythm, but careful and attentive management is essential. There are two unifying principles for optimizing CRT benefit in patients with AF: (1) ensure and maximize biventricular capture, and (2) reduce and attempt to minimize inappropriate tachyarrhythmia therapies. First, reliance on device counters alone can be misleading, and we recommend reviewing device diagnostic and Holter data to
Conclusion
S58 ative for treatment success. For patients with permanent AF and severe symptoms, AVJ ablation may be an additional means to improve response by guaranteeing BiV capture and reducing ICD shock burden. Newer catheter-based techniques such as PVI offer theoretical advantages and potentially reduced risks, particularly for patients with paroxysmal AF. Prospective cohort and randomized investigations of these techniques in CRT patients are critically important to definitively validating and establishing future management approaches.
Acknowledgement Editorial assistance (referencing, production of graphics, copyediting, and proofreading) for the articles in this publication was provided by David Good, Independent Publishing Solutions, LLC, and support for this editorial assistance and for publication of this open-access article was provided by St. Jude Medical.
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Boriani G, Gasparini M, Landolina M, et al. Incidence and clinical relevance of uncontrolled ventricular rate during atrial fibrillation in heart failure patients treated with cardiac resynchronization therapy. EurJ Heart Fail 2011;13:868 – 876. 22. Hugl B, Bruns HJ, Unterberg-Buchwald C, et al. Atrial fibrillation burden during the post-implant period after CRT using device-based diagnostics. J Cardiovasc Electrophysiol 2006;17:813– 817. 23. Lellouche N, De Diego C, Vaseghi M, et al. Cardiac resynchronization therapy response is associated with shorter duration of atrial fibrillation. Pacing Clin Electrophysiol 2007;30:1363–1368. 24. Gasparini M, Steinberg JS, Arshad A, et al. Resumption of sinus rhythm in patients with heart failure and permanent atrial fibrillation undergoing cardiac resynchronization therapy: a longitudinal observational study. Eur Heart J 2010; 31:976 –983. 25. Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol 2006;48:734 –743. 26. Kamath GS, Cotiga D, Koneru JN, et al. The utility of 12-lead Holter monitoring in patients with permanent atrial fibrillation for the identification of nonresponders after cardiac resynchronization therapy. J Am Coll Cardiol 2009;53: 1050 –1055. 27. Koplan BA, Kaplan AJ, Weiner S, Jones PW, Seth M, Christman SA. Heart failure decompensation and all-cause mortality in relation to percent biventricular pacing in patients with heart failure: is a goal of 100% biventricular pacing necessary? J Am Coll Cardiol 2009;53:355–360. 28. Hayes DL, Boehmer JP, Day JD, et al. Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival. Heart Rhythm 2011;8:1469 –1475. 29. Sweeney MO, Wathen MS, Volosin K, et al. Appropriate and inappropriate ventricular therapies, quality of life, and mortality among primary and secondary prevention implantable cardioverter defibrillator patients: results from the Pacing Fast VT Reduces Shock Therapies (PainFREE RX II) trial. Circulation 2005;111:2898 –2905. 30. Gronefeld GC, Mauss O, Li YG, Klingenheben T, Hohnloser SH. Association between atrial fibrillation and appropriate implantable cardioverter defibrillator therapy: results from a prospective study. J Cardiovasc Electrophysiol 2000;11: 1208 –1214. 31. Rienstra M, Smit MD, Nieuwland W, et al. Persistent atrial fibrillation is associated with appropriate shocks and heart failure in patients with left ventricular dysfunction treated with an implantable cardioverter defibrillator. Am Heart J 2007;153:120 –126. 32. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008;359:1009 –1017. 33. Daubert JP, Zareba W, Cannom DS, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Coll Cardiol 2008;51:1357–1365. 34. van Rees JB, Borleffs CJ, de Bie MK, et al. Inappropriate implantable cardioverter-defibrillator shocks: incidence, predictors, and impact on mortality. J Am Coll Cardiol 2011;57:556 –562. 35. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825– 1833. 36. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Circulation 2004;109:1509 –1513. 37. Guglin M, Chen R, Curtis AB. Sinus rhythm is associated with fewer heart failure symptoms: Insights from the AFFIRM trial. Heart Rhythm 2010;7:596 – 601. 38. Deedwania PC, Singh BN, Ellenbogen K, Fisher S, Fletcher R, Singh SN. Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: observations from the Veterans
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Affairs Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT). Circulation 1998;98:2574 –2579. Pedersen OD, Bagger H, Keller N, Marchant B, Kober L, Torp-Pedersen C. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) substudy. Circulation. 2001;104: 292–296. Hagens VE, Crijns HJ, Van Veldhuisen DJ, et al. Rate control versus rhythm control for patients with persistent atrial fibrillation with mild to moderate heart failure: results from the Rate Control versus Electrical Cardioversion (RACE) study. Am Heart J 2005;149:1106 –1111. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667–2677. Gasparini M, Regoli F, Galimberti P, Ceriotti C, Cappelleri A. Cardiac resynchronization therapy in heart failure patients with atrial fibrillation. Europace]?2009;11/sb:volume-nrSuppl 5):v82–v86. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363– 1373. Delnoy PP, Ottervanger JP, Luttikhuis HO, et al. Comparison of usefulness of cardiac resynchronization therapy in patients with atrial fibrillation and heart failure versus patients with sinus rhythm and heart failure. Am J Cardiol 2007;99:1252–1257. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the Multisite Stimulation in Cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002;40:111–118. Gasparini M, Auricchio A, Metra M, et al. Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation. Eur Heart J 2008;29:1644 –1652.
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47. Ferreira AM, Adragao P, Cavaco DM, et al. Benefit of cardiac resynchronization therapy in atrial fibrillation patients vs. patients in sinus rhythm: the role of atrioventricular junction ablation. Europace 2008;10:809 – 815. 48. Dong K, Shen WK, Powell BD, et al. Atrioventricular nodal ablation predicts survival benefit in patients with atrial fibrillation receiving cardiac resynchronization therapy. Heart Rhythm 2010;7:1240 –1245. 49. Khadjooi K, Foley PW, Chalil S, et al. Long-term effects of cardiac resynchronisation therapy in patients with atrial fibrillation. Heart 2008;94:879 – 883. 50. Schutte F, Ludorff G, Grove R, Kranig W, Thale J. Atrioventricular node ablation is not a prerequisite for cardiac resynchronization therapy in patients with chronic atrial fibrillation. Cardiology 2009;16:246 –249. 51. Nault I, Miyazaki S, Forclaz A, et al. Drugs vs. ablation for the treatment of atrial fibrillation: the evidence supporting catheter ablation. Eur Heart J 2010; 31:1046 –1054. 52. Piccini JP, Lopes RD, Kong MH, Hasselblad V, Jackson K, Al-Khatib SM. Pulmonary vein isolation for the maintenance of sinus rhythm in patients with atrial fibrillation: a meta-analysis of randomized, controlled trials. Circ Antiarrhythm Electrophysiol 2009;2:626 – 633. 53. Hayward RM, Upadhyay GA, Mela T, et al. Pulmonary vein isolation with complex fractionated atrial electrogram ablation for paroxysmal and nonparoxysmal atrial fibrillation: a meta-analysis. Heart Rhythm 2011;8:994 –1000. 54. Khan A, Mittal S, Kamath GS, Garikipati NV, Marrero D, Steinberg JS. Pulmonary vein isolation alone in patients with persistent atrial fibrillation: an ablation strategy facilitated by antiarrhythmic drug induced reverse remodeling. J Cardiovasc Electrophysiol 2011;22:142–148. 55. Garikipati NV, Avula A, Verma P, Mittal S, Steinberg J. Pulmonary vein isolation in patients with left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2011;57:E16. 56. Khan MN, Jais P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008;359:1778 –1785.
Introduction Atrial fibrillation (AF) and heart failure (HF) have been characterized as the twin epidemics of modern cardiovascular medicine.1 In individuals ⱖ40 years of age, the lifetime risk of developing HF is 1 in 5.2 The prevalence of HF exceeds 5.7 million in the United States,3 and in 2010 HF accrued estimated direct and indirect costs totaling $39.2 billion.4 Similar in magnitude to HF, AF affects ⬎2.2 million Americans. The lifetime risk for AF in adults aged ⱖ40 years is 1 in 4.3,5 Worse, AF is a marker of increased mortality: one-fourth of all Medicare beneficiaries diagnosed with AF die within 1 year.6 AF also clearly tracks with New York Heart Association (NYHA) HF class. It is
Dr. Upadhyay has no financial disclosures that are relevant to this publication. Dr. Steinberg is on the speakers’ bureau for Sanofi-Aventis; receives consultant fees/honoraria from Biosense Webster, Cameron Health, Ambucor, Medtronic, St. Jude Medical, and Sanofi-Aventis; and receives research/research grants from Biosense Webster and Medtronic. Address reprint requests and correspondence: Dr. Gaurav A. Upadhyay, Division of Cardiology and the Cardiac Arrhythmia Service, Massachusetts General Hospital, Gray Bigelow 109, Boston, MA 02114. E-mail address: [email protected].
junction ablation appears effective in improving response by ensuring biventricular capture and reducing implantable cardioverter-defibrillator shock burden in selected patients. Catheterbased techniques such as pulmonary vein isolation appear more attractive and in the future may offer further advantages and lower risks, particularly for patients with paroxysmal AF. KEYWORDS Atrial fibrillation; Cardiac resynchronization therapy; Heart failure; Treatment strategies ABBREVIATIONS AF ⫽ atrial fibrillation; AV ⫽ atrioventricular; AVJ ⫽ atrioventricular junction; BiV ⫽ biventricular; CFAE ⫽ complex fractionated atrial electrogram; CRT ⫽ cardiac resynchronization therapy; EF ⫽ ejection fraction; HF ⫽ heart failure; ICD ⫽ implantable cardioverter-defibrillator; LV ⫽ left ventricular; NYHA ⫽ New York Heart Association; PVI ⫽ pulmonary vein isolation; VRR ⫽ ventricular rate regularization (Heart Rhythm 2012;9:S51–S59) © 2012 Heart Rhythm Society. All rights reserved.
present in 5% of NYHA class I patients and in up to 50% of NYHA class IV patients.7 In the past decade, cardiac resynchronization therapy (CRT) has emerged as a viable new treatment option for an important subset of HF patients. However, although CRT now has an established role as a safe and efficacious devicebased therapy for HF patients with severe systolic dysfunction, intraventricular conduction delay, and normal sinus rhythm, its optimal use in patients with HF and AF remains uncertain.8 –10 Indeed, although HF patients with AF who undergo CRT demonstrate improvement in echocardiographic parameters, functional status, and quality of life, they benefit less than their counterparts in normal sinus rhythm, and they exhibit a trend toward increased mortality.11,12 Understanding the barriers to response to CRT among HF patients with AF and identifying strategies to overcome these barriers are critical to addressing the needs of growing populations of patients with HF and AF.
Scope of the problem The first reported randomized, large-trial data regarding the incidence of AF in HF patients who received CRT devices came from analysis of the CArdiac REsynchronization in Heart Failure (CARE-HF) study.13 The analysis by Hoppe
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et al14 found that 16.1% of the 409 patients assigned to optimal medical therapy plus CRT developed new-onset AF, which was nonsignificantly different from the 14.4% found in the medication-only treatment arm (P ⫽ .79). Data estimates from another large randomized trial, the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) study, suggested a similar rate of new-onset AF.15 Interestingly, Hoppe et al14 reported that in the CARE-HF study, an additional 93 patients (22%) in the CRT group demonstrated AF when assessed using device diagnostics rather than through routine ECG monitoring. Following this trend, modern trials have increasingly used data available from device-based diagnostics rather than periodic ECG assessments at disparate follow-up visits to quantify overall degree of AF burden.16 –21 Evaluated in this fashion, the overall cumulative incidence of AF in HF patients treated with CRT is greater than what had previously been suspected: between 21% and 42% of CRT patients who initially exhibit normal sinus rhythm (Table 1). In addition to increased incidence, the presence of AF, as measured by device diagnostics, has been shown to correlate with worse clinical outcome. Puglisi et al20 found a statistically significant and deleterious impact on patients’ activity levels, a higher average nighttime heart rate, and reduced heart rate variability for patients with paroxysmal AF once they had returned to normal sinus rhythm. In addition, there is concern that time spent in AF increases the risk of stroke. Indeed, the AF burden measured by device diagnostics in antitachycardia pacemakers has been found to be associated with an increased risk of arterial embolic events, although this has yet to be conclusively shown in patients who have received CRT devices.18,21 Interestingly, although AF appears relatively common after initiation of CRT, the degree of AF burden appears to be modified by device therapy. Among patients with paroxysmal AF, the burden of AF shrinks over time during the first 3 months with CRT22 and remains significantly reduced for CRT responders for up to 6 months after implant.23 Furthermore, Gasparini et al24 found that up to 1 in 10 patients with permanent AF who receive a CRT device will resume normal sinus rhythm, mostly within 4 months of implantation. This finding is novel and remains to be reproduced in future trials. With that said, it is clear that, the Table 1
Cumulative incidence of AF in recent CRT trials Patients (%) with new-onset AF/AT according to diagnosis from CRT device
Study (Year) Leclercqetal17 Borleffsetal19 Marijonetal16 Caldwelletal18 Borianietal21 Puglisietal20
(2010) (2009) (2010) (2009) (2011) (2008)
21 25 27 27 32 42
AF ⫽ atrial fibrillation; AT ⫽ atrial tachycardia; CRT ⫽ cardiac resynchronization therapy.
interplay of AF incidence and AF progression after CRT is complex and difficult to predict.
Barriers to CRT response during AF Insufficient biventricular pacing It is axiomatic that there is no possibility of benefit after CRT if biventricular (BiV) pacing does not reliably occur. This is because the physiological impact of CRT is postulated to occur through synchronizing ventricular contraction, leading to improvement in left ventricular (LV) filling and pumping efficiency and reduction in the extent of functional mitral regurgitation. In patients with HF and AF, atrioventricular (AV) synchrony does not exist; thus, any clinical benefit is predicated on BiV synchronization. However, in patients with AF, erratic electric activity of the atria occasionally will penetrate the AV node and override, interrupt, or disrupt BiV capture. This leads to fusion or pseudo-fusion beats and suboptimal CRT delivery,1,11,25 particularly in situations of increased myocardial demand, as occurs from increased adrenergic tone during stress or exercise. Perhaps even more problematic than lack of BiV capture is that the percentage of BiV pacing recorded by internal CRT device counters often is artificially inflated during AF, due to erroneous counting of fusion and pseudo-fusion complexes.1,25,26 Although a clinician might believe that adequate delivery of CRT has occurred because of an apparently high percentage of BiV pacing, a patient with AF may not have received the full benefit of synchronized BiV capture. This dichotomy between device counters estimation of percentage BiV pacing and true BiV capture was elegantly illustrated in a study by Kamath et al26 utilizing 12-lead ambulatory Holter monitoring in 19 AF patients who received CRT devices. In their study, less than half of the patients in AF received effective pacing (defined as ⬎90% genuine BiV capture). More disturbingly, patients who were ineffectively paced demonstrated an astonishing 40% rate of fusion and pseudo-fusion complexes despite internal device counters suggesting that ⬎90% BiV capture had been achieved. The authors were also able to establish the clinical relevance of truly realized BiV capture, correlating CRT response with a significantly higher percentage of fully paced beats. The findings of Kamath et al26 are in line with recent observations suggesting that a high degree of BiV capture may be the single most important variable in predicting improvement after CRT, reducing HF decompensation, and, most importantly, increasing survival (Figure 1).27,28 Indeed, a recent study by Hayes et al28 evaluating the association between the percentage of BiV capture assessed by device diagnostics and survival found that only when measured BiV pacing percentage rates were ⬎98.5% did AF patients demonstrate survival similar to that of their counterparts in normal sinus rhythm.
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Figure 1 Probability of survival in biventricular pacing patients, with or without atrial fibrillation, as a function of percentage of biventricular pacing capture. Patients with biventricular pacing ⬎99.6% experienced a 24% reduction in mortality compared with the other groups (hazard ratio 0.76, P ⬍.001). (Adapted from Hayes DL, Boehmer JP, Day JD, et al. Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival. Heart Rhythm 2011;8:1469 –1475.28)
Increased risk of implantable cardioverterdefibrillator shocks The second most significant barrier to AF patients deriving full benefit from CRT is an increased risk of appropriate and inappropriate defibrillator therapies.29 Based on prior investigations of patients with an implantable cardioverter-defibrillator (ICD), AF is associated with an increased risk of appropriate and inappropriate defibrillator therapy and also an increased risk of HF deterioration (Figure 2).30,31 While it is well-known that appropriate shocks are associated with an increased risk of death, subgroup
analysis of two major ICD trials and a large national registry have further suggested that inappropriate ICD shocks are also associated with increased mortality.32–34 However, published data regarding the impact of newonset AF in recipients of combined CRT plus ICD devices (ie, CRT-D) are more limited. In a study of 223 consecutive patients treated with CRT-D, Borleffs et al19 found that new-onset AF after CRT predisposed to an increased risk of both appropriate and inappropriate shocks, as well as hospitalizations, but did not lead to a significantly increased risk of mortality (Figure 3).19
Figure 2 Increasingly severe atrial fibrillation (AF) is associated with increased probability of implantable cardioverter-defibrillator (ICD) shocks (left) and increased risk of congestive heart failure (HF) deterioration (right). (Adapted from Rienstra M, Smit MD, Nieuwland W, et al. Persistent atrial fibrillation is associated with appropriate shocks and heart failure in patients with left ventricular dysfunction treated with an implantable cardioverter defibrillator. Am Heart J 2007;153:120 –126.31)
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Figure 3 New-onset atrial fibrillation (AF) is associated with statistically significant increases in risk of both appropriate and inappropriate implantable cardioverter-defibrillator shocks (A, B) as well as hospitalization (C). There is no statistically significant difference in risk of mortality (D). SR ⫽ sinus rhythm. (Modified from Borleffs CJ, Ypenburg C, van Bommel RJ, et al. Clinical importance of new-onset atrial fibrillation after cardiac resynchronization therapy. Heart Rhythm 2009;6:305–310.19)
Clearly, further investigation of the impact of AF and shock burden in CRT-D patients is necessary.
Antiarrhythmic drug therapy and CRT The crucial decision point for managing AF in patients with HF has been “rate vs rhythm” control strategies, and this question has been a source of ongoing controversy. The landmark and frequently cited Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study concluded that there is no survival advantage for a rhythmcontrol strategy over rate control.35 However, only 23% of patients enrolled in the AFFIRM study demonstrated a history of congestive HF, and subgroup analysis revealed no difference with respect to the primary endpoint for these patients. In post hoc analysis, Corley et al36 found that the presence of normal sinus rhythm was associated with significant survival benefit, irrespective of rate or rhythm strategy. Guglin et al37 further demonstrated that patients in the rhythm-control arm had fewer HF symptoms than did those in the rate-control arm and that stable sinus rhythm was associated with the best functional status. These contradictory findings in AFFIRM are supported by observations on the benefit of antiarrhythmic drug therapy for AF in other trials of HF patients. In a substudy of the Congestive Heart Failure: Survival Trial of Antiarrhythmic Therapy (CHF-STAT), Deedwania et al38 generated significant interest in the potential benefit of amiodarone when they reported that AF patients who converted to sinus rhythm demonstrated a mortality benefit. Similar findings of mortality benefit were also reported with a different antiarrhythmic agent in a substudy of the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND).39
Indeed, even in a prespecified analysis of patients with mild-to-moderate chronic HF in the RAte Control versus Electrical cardioversion (RACE) study, a trend toward a mortality benefit was found in patients maintaining sinus rhythm.40 In light of these findings, the results of the larger and more recent Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial have been surprising. The AF-CHF trial was a prospective, multicenter trial of 1376 patients with NYHA class III–IV HF and systolic dysfunction. No mortality or morbidity benefit was found for a rhythm-control over a rate-control strategy with respect to the primary endpoint of cardiovascular mortality or the secondary endpoints of allcause mortality and worsening HF.41 Critics have noted that the rhythm-control arm relied almost exclusively on amiodarone (82% of patients) and that ⬎20% of the rhythmcontrol patients crossed over to the rate-control arm. In addition, only 73% of patients in the rhythm-control arm achieved and actually maintained sinus rhythm at 4 years of follow-up (Figure 4). Nevertheless, the AF-CHF trial raises important questions as to whether a rhythm-control strategy, and its associated drug-related toxicities, is worth the risk for the general HF patient. Perhaps the reality is that the decision of rhythm vs rate control for AF in the CRT patient is a false choice. Given that the primary barriers to response to CRT-D in AF patients are insufficient BiV capture and the increased risks associated with ICD therapies, it may be that ventricular rate control with negative chronotropic drugs is insufficient to address the harm from ventricular dyssynchronization.
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Figure 4 Results from the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial found that 27% of patients in the rhythm-control arm still demonstrated atrial fibrillation at 4 years of follow-up.
Some authors have suggested the use of device-derived features, such as ventricular rate regularization (VRR), in addition to rate-control drug therapy.42 Gasparini et al42 described how VRR might increase retrograde concealed penetration of the AV node through rate-adaptive BiV pacing and reduce short cycles. They also have found the “ventricular sense response”— or the “trigger” function that produces LV pacing after a premature right ventricular sense event— has been helpful in their patients with AF.42 Establishing the thresholds for adequate rate control is also uncertain in patients with AF who receive CRT, and, for the typical AF patient, there may be a trend toward acceptance of more liberal rate goals. In the recent Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient versus Strict Rate Control II (RACE II) study, a resting heart rate goal of ⬍110 bpm was found to result in a clinical outcome similar to that of a conventional goal of ⬍80 bpm.43 However, this study was not focused on HF patients and had a relatively short follow-up; therefore, this result should not be taken as an evidence-based recommendation. Clearly, this is not a “onesize-fits-all” situation, and taking such an approach would lead to significant harm for patients receiving CRT-D devices, due to inappropriate shocks alone. Conversely, an “as low-as-you-can-go” strategy for rate control has not been formally assessed in the CRT population, although it has remained an attractive concept in the electrophysiology community, particularly when addressing patients with HF. There is a relative paucity of data regarding the role of antiarrhythmic drug therapy in CRT patients. In a study of 263 consecutive patients enrolled in a prospective registry, Delnoy et al44 reported that they were able to achieve a high percentage of BiV pacing (ⱖ90%) in ⬎90% of AF patients. They suggested that higher rates of amiodarone prescription, which doubled from 12% to 23% for AF patients treated with CRT and was associated with spontaneous cardioversion, allowed for this response. It is noteworthy that the rate of amiodarone prescription seen in Delnoy’s cohort is not substantially different than that observed in
other prospective trials11 or reported in a substudy of the only randomized CRT trial enrolling patients with AF, the MUltisite STimulation In Cardiomyopathy (MUSTIC) study.45 The purported association between increased use of amiodarone and adverse events was not noted in Delnoy’s group. Indeed, in recent meta-analyses of CRT and AF studies, no significant signal of antiarrhythmic drug therapy–related toxicity was observed.11,12
Role for AV junction ablation The role of an “ablate and pace” strategy, as an alternative to classic rhythm-control or rate-control strategies, has been of considerable interest in CRT trials. Atrioventricular junction (AVJ) ablation is attractive because it affords the opportunity to guarantee essentially 100% BiV capture. Typically reserved for patients with medication-refractory symptoms and rapid heart rates, the procedure is considered by many to be a palliative or “last resort” option because it is associated with multiple disadvantages, not the least of which is pacemaker dependence (Table 2). Reports on the benefit of AVJ ablation in the treatment of AF in CRT patients are conflicting. In a large prospective observational cohort study of 673 patients, 162 (24%) of whom were in permanent AF, Gasparini et al25 reported that only those patients who underwent AVJ ablation showed significant improvement in venTable 2 Disadvantages of atrioventricular junction ablation and permanent pacemaker placement in the treatment of atrial fibrillation Continued atrial fibrillation Risk of thromboembolism ● Loss of A-V synchrony ● Procedure is irreversible Patient is rendered pacemaker-dependent Patient is made vulnerable to catastrophic complications in case of device/lead failure Rapid battery drain (constant pacing) ● More generator replacements and potential complications
S56 tricular volumes, exercise capacity, and clinical response to CRT. The same group conducted a more extensive multicenter observational study of 1285 consecutive patients, 243 (19%) of whom were in permanent AF, and found that AVJ ablation was associated with a survival benefit driven by reduction in HF-associated mortality.46 These results have been replicated by Ferreira et al47 and Dong et al,48 who found significantly improved clinical outcome and survival among CRT patients with AF who received AVJ ablation vs those who did not. However, other investigators have argued that sufficiently high degrees of ventricular capture can be achieved with the use of medications alone, thus avoiding the risk associated with AVJ ablation.44,49,50 A further criticism of this approach is that patient selection has not been random, because CRT studies usually restrict the procedure to patients in permanent AF with severe symptomatology. The role of AVJ ablation for persistent, and certainly for paroxysmal, AF is much less certain.
Pulmonary vein isolation—A case for a hybrid strategy? There has been considerable interest in recent years about the role of catheter-based therapies for the treatment of AF, particularly with respect to pulmonary vein isolation (PVI) utilizing radiofrequency ablation or cryoablation. PVI is significantly less invasive than the surgical Cox maze procedure. Published success rates for PVI range between 41% and 94%, with most large studies reporting 80% freedom from paroxysmal AF.51 Indeed, in a meta-analysis examining PVI vs optimal medical therapy, Piccini et al52 found a cumulative odds ratio of close to 16 for freedom from paroxysmal AF at 12 months after PVI (Figure 5). In studies evaluating the success of PVI in the treatment of persistent AF, however, success rates have been lower. Published studies have reported that freedom from persistent AF occurs in as few as 20% to 61% of cases and frequently requires multiple PVI procedures.51 Techniques are continuously being modified, however, and early
Heart Rhythm, Vol 9, No 8S, August Supplement 2012 evidence suggests that addition of ablation of complex fractionated atrial electrograms (CFAEs) or piggybacking ablation to periods of sinus rhythm–induced reversed remodeling might improve freedom from AF in nonparoxysmal AF patients.53,54 Certainly, there is a role for the simultaneous use of PVI and antiarrhythmic drug therapy for refractory patients. The success rate of PVI in patients with HF due to systolic dysfunction vs those with normal systolic function has recently been evaluated. In an abstract presented at the 2011 American College of Cardiology Scientific Sessions, a meta-analysis of 7 studies of PVI in patients with AF and LV dysfunction found similar success of PVI in patients with LV dysfunction and those with normal ejection fraction (EF) (RR 1.00, 95% confidence interval 0.96 –1.04; Figure 6a).55 Additionally, a significant improvement in LVEF was seen after PVI (Figure 6b).55 The relative efficacy of PVI vs AVJ ablation was assessed in randomized fashion in the Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure (PABA-CHF) trial. This was an intriguing study that evaluated the role of PVI in NYHA class II and III HF patients vs AVJ ablation and CRT therapy in the treatment of severe, symptomatic AF.56 About half of the patients were in persistent AF and half in paroxysmal AF. Patients in this trial did not have significant intraventricular conduction delay; mean QRS width was approximately 90 ms in both study arms. However, the results of PABA-CHF revealed a clear advantage for PVI over AVJ ablation plus CRT, with freedom from AF in nearly 80% of PVI patients. More significantly, LVEF and 6-minute walk were substantially increased after PVI. Taken together, there are promising data regarding the use of PVI to ameliorate symptoms and improve echocardiographic parameters in AF patients, particularly in those with paroxysmal AF. In addition, some data suggest that the
Figure 5 Meta-analysis of 5 trials of pulmonary vein isolation (PVI) vs optimal medical therapy found a cumulative odds ratio ⬃16 for freedom from paroxysmal atrial fibrillation at 12 months after PVI. (Modified from Piccini JP, Lopes RD, Kong MH, Hasselblad V, Jackson K, Al-Khatib SM. Pulmonary vein isolation for the maintenance of sinus rhythm in patients with atrial fibrillation: a meta-analysis of randomized, controlled trials. Circ Antiarrhythm Electrophysiol 2009;2:626 – 633.52)
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Figure 6 Meta-analysis of 7 studies shows similar success with pulmonary vein isolation (PVI) in patients with left ventricular dysfunction and those with normal ejection fraction (RR 1.00; A). In addition, there was a significant improvement in left ventricular ejection fraction after PVI (B). (From an abstract presented at the 2011 American College of Cardiology Scientific Sessions by Garikipati NV, Avula A, Verma P, Mittal S, Steinberg J. Pulmonary vein isolation in patients with left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2011;57:E16.55)
efficacy for PVI in patients with LV dysfunction is similar to that of PVI in those with normal EF. What has not yet been sufficiently explored, however, is the role of PVI in patients with LV dysfunction and intraventricular conduction delay (ie, typical candidates for CRT). Whether modification of the standard PVI approach may be required in CRT patients in order to yield similar results, either with regard to the extent or the location of ablation lines or the use of additional CFAE modification, remains to be evaluated. Based on the data acquired thus far, it seems reasonable to consider PVI as a means to improve symptoms, reduce the risk of antiarrhythmic drug toxicity, and improve response through increased BiV capture in CRT patients with paroxysmal AF who are nonresponders to conventional therapies. Selected patients with persistent or permanent AF and favorable left atrial anatomy also might be targeted, but the data remain limited at this time. Further prospective cohort investigation and randomized trials are needed to better approach this group of patients.
ensure that pseudo-fused and fused beats are not being miscounted as those associated with BiV capture. This process should be undertaken periodically throughout follow-up and whenever clinical response is suboptimal. Next, rate control is an initial and simple means to reduce degree of fusion and should be attempted in all patients. Although no single “rate goal” has been identified as optimal in patients receiving CRT, based on data from HF literature, lower rates (resting mean ⬍80 bpm) appear reasonable. Rhythm control through antiarrhythmic therapy should be pursued as a second-line approach should rate control fail to address lack of capture. PVI is another increasingly attractive option for suppression of AF to increase CRT effective delivery and decrease shocks for AF, particularly for patients with paroxysmal AF. In patients with permanent AF who cannot be adequately rate-controlled, AVJ ablation may be a necessary means of guaranteeing CRT response and should be an active consideration for virtually all such patients.
Summary recommendations
There has been increasing recognition of the epidemics of HF and AF, conditions often present in the same patient. Initially validated in populations in normal sinus rhythm, CRT now has an established role in the treatment of HF patients with LV dysfunction and intraventricular conduction delay. The incidence of new AF in patients who have been implanted with a CRT device is substantial, exceeding one-fourth of patients in multiple recent studies utilizing device diagnostics, making maximization of BiV capture and the reduction of fusion and pseudo-fusion beats imper-
Based on the available data, we feel confident that AF patients can enjoy similar benefits from CRT as do those with normal sinus rhythm, but careful and attentive management is essential. There are two unifying principles for optimizing CRT benefit in patients with AF: (1) ensure and maximize biventricular capture, and (2) reduce and attempt to minimize inappropriate tachyarrhythmia therapies. First, reliance on device counters alone can be misleading, and we recommend reviewing device diagnostic and Holter data to
Conclusion
S58 ative for treatment success. For patients with permanent AF and severe symptoms, AVJ ablation may be an additional means to improve response by guaranteeing BiV capture and reducing ICD shock burden. Newer catheter-based techniques such as PVI offer theoretical advantages and potentially reduced risks, particularly for patients with paroxysmal AF. Prospective cohort and randomized investigations of these techniques in CRT patients are critically important to definitively validating and establishing future management approaches.
Acknowledgement Editorial assistance (referencing, production of graphics, copyediting, and proofreading) for the articles in this publication was provided by David Good, Independent Publishing Solutions, LLC, and support for this editorial assistance and for publication of this open-access article was provided by St. Jude Medical.
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