- Email: [email protected]
Atrioventricular Node Ablation
Atrioventricular Node Ablation Maurizio Gasparini, MD KEYWORDS Cardiac resynchronization therapy Atrial fibrillation Atrioventricular junction ablation
KEY POINTS Every effort should be made in all patients receiving cardiac resynchronization therapy (CRT) to approach 100% biventricular (BIV) pacing by a correct device programming, a correct pharmacologic regimen, and atrioventricular (AV) nodal ablation in permanent atrial fibrillation (AF) patients. Currently, atrioventricular junction (AVJ) ablation should always be considered a fundamental step in a combined strategy to obtain the best results of CRT in the heart failure (HF) population affected by permanent AF. AF in patients with HF may have a significant negative impact on the clinical benefit conveyed by CRT, if not appropriately managed.
The prevalence of AF ranges from approximately 5% in patients with asymptomatic cardiac dysfunction to more than 50% of those with severe symptomatic HF.1–9 In some patients, the onset of HF and AF coincide, whereas the onset of AF in patients with preexisting HF indicates a poor prognosis. Patients who develop HF as a consequence of AF (approximately 75% of those admitted when these 2 conditions coexist) have a better outcome than those who develop AF after the onset of HF. AF and HF are believed to directly predispose to each other. They form a sinister synergy, and management of AF in the setting of HF is challenging. Even more problematic is the management of AF patients undergoing CRT. A distinction has to be made between the 3 forms of AF, namely paroxysmal, persistent, and permanent, the last one being frequent in the advanced phases of HF.
WHAT ARE THE TOOLS TO TREAT ATRIAL FIBRILLATION IN HEART FAILURE? Paroxysmal AF may be controlled by antiarrhythmic drugs, even if limited by their negative chronotropic effect, much dreaded in left ventricular (LV) dysfunction. Persistent AF may need repeated cardioversion. Paroxysmal and persistent AF, at least in an initial stage of AF, may be successfully treated with AF ablation (ie, pulmonary veins isolation). Treating AF substrate in the context of a cardiomyopathy, however, may achieve poor results in advanced HF, because during AF in failing hearts, there is a heterogeneous distribution of fibrosis that likely influences dynamic pattern of AF activation and signal complexity. Permanent AF requires a satisfying rate control and this is more true in HF.
MEDICAL THERAPY FOR RATE CONTROL IN PERMANENT ATRIAL FIBRILLATION The aim of the rate-control strategy is to lower heart rate (to allow better diastolic filling and stroke
The author has no conflict of interest. EP and Pacing Unit, Humanitas Research Hospital, 20089 Rozzano-Milano, Italy E-mail address: [email protected] Card Electrophysiol Clin - (2015) -–http://dx.doi.org/10.1016/j.ccep.2015.08.006 1877-9182/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
cardiacEP.theclinics.com
WHAT ARE THE INTERACTIONS BETWEEN ATRIAL FIBRILLATION AND HEART FAILURE (ATRIAL FIBRILLATION BEGETS HEART FAILURE AND VICE VERSA)?
2
Gasparini volume increase in hearts with conserved FrankStarling mechanism). Moreover, heart rate regularization further reinforces favorable effects on diastolic function. Rate-control drugs considered effective in HF patients with depressed LV function include digoxin, amiodarone, dronedarone, and b-blockers. Different randomized trials, however, have suggested caution in the use of digoxin and amiodarone in patients with HF due to increased morbidity and mortality.10
WHAT ARE THE INTERACTIONS BETWEEN ATRIAL FIBRILLATION AND CARDIAC RESYNCHRONIZATION THERAPY? AF poses several challenges to adequately deliver CRT because fast atrial rhythm conducted to the ventricles may easily override BIV pacing. An intrinsic, intermediate-to-high, irregular spontaneous AF rhythm reduces the percentage of effectively BIV-paced captured beats (BVP%), because there are phases of competing AF rhythm that cause spontaneous, fusion (hybrid between paced and intrinsic QRS morphologies), or pseudofusion (pacing artifacts delivered but intrinsic QRS morphology not altered) beats, not hemodynamically effective as pure BIV beats (Fig. 1). This phenomenon suggests that the global effective CRT dose may be markedly reduced compared with atrial-synchronous rhythm with a short AV interval (as is achieved during sinus rhythm [SR]). Moreover, in AF patients, during exertion, spontaneous ventricular rate tends to override BIV pacing rates, determining a further reduction of paced beats precisely when patients are most in need of having BIV capture, thus greatly limiting functional capacity. From a clinical standpoint, it is important to identify symptoms, such as palpitations, and, more importantly, worsening effort dyspnea, which may suggest that the resynchronization effect is reduced because of the interference of
underlying AF. Retrieving relevant information (BVP%, duration, numbers of mode switches episodes, and so forth) through device control may complement clinical data; this kind of information is important and is currently easily achieved with home monitoring systems. Some device-derived features may be helpful to improve rate control and thus improve CRT delivery. These algorithms try to maximize BIV% by stimulating in a BIV mode a native beat or by achieving BIV capture by a higher mean heart rate. They are only partially helpful, however, and not as efficacious as a complete BIV pacing modality. The recourse to rate-control drugs and/or activation of device-based algorithms is reasonable as a first-line approach when AF/AT burden is low/intermediate. Findings derived from different large observational cohort studies on the effects of CRT in patients with permanent AF have yielded contrasting results. It is worth emphasizing, however, that when the survival curves of the HF patients with AF treated with a combined device-based/drug regimen are compared, all-cause mortality remains remarkably high, amounting to more than 14% per year in both separate cohorts of nonablated patients (Fig. 2). It follows, therefore, that in HF patients treated with CRT who present with permanent AF or frequent persistent or paroxysmal episodes, the pursuit of an aggressive treatment strategy, such as AVJ ablation, may be warranted.
Atrioventricular Junction Ablation for Optimizing Cardiac Resynchronization Therapy in Permanent Atrial Fibrillation AVJ ablation is commonly performed in patients with symptomatic, drug-refractory, fast, permanent AF as part of the conventional ablate and pace strategy and has been shown to confer symptomatic relief. AVJ ablation in individuals with AF treated with CRT has initially mainly been confined to selected patients in whom high-rate
Fig. 1. In a patient with AF and HF treated with CRT, spontaneous irregular intrinsic beats alternate with fusion and pseudofusion beats, thus markedly reducing effective CRT. As shown in the figure, this may occur even during normal rate AF. (RV, right ventricle; EGM, intracavitary electrogram. From Gasparini M, Regoli F, Galimberti P, et al. Cardiac resynchronization therapy in heart failure patients with atrial fibrillation. Europace 2009;11(Suppl 5):v82–6; with permission.)
AV node ablation in AF/CRT patients Fig. 2. Comparison of Kaplan-Meier analysis for freedom from death for any cause between HF patients treated with drugs or with ablated AV node (abl). (From Gasparini M, Regoli F, Galimberti P, et al. Cardiac resynchronization therapy in heart failure patients with atrial fibrillation. Europace 2009;11(Suppl 5):v82–6; with permission.)
AF or atrial tachycardia (AT) jeopardizes satisfactory BIV stimulation, and, in CRT–implantable cardioverter-defibrillator (ICD) recipients, determines inappropriate ICD interventions. The problem of inappropriate ICD therapies during AF, constituting approximately 30% of all ICD interventions,11 is that it has an important negative impact on hospitalization rate and quality of life in patients and may be completely resolved after AVJ ablation. In the context of CRT in HF patients with concomitant AF, however, a growing body of evidence has demonstrated that AVJ ablation may be useful to optimize CRT delivery by eliminating the deleterious hemodynamic effects of underlying AF. In 2006, 1 large observational prospective investigation12 specifically evaluated the effects of AVJ ablation on CRT delivery using a predefined protocol. This study showed that only AF patients who underwent AVJ ablation showed significant improvements in LV ejection fraction, LV end-systolic volume, and exercise capacity. Furthermore, a significantly higher proportion of responders (response defined as a 10% reduction in LV end-systolic volume) were observed in the AVJ ablation group (68%) compared with the nonablated group (18%) at 12 months. As later observed by the same group13 in a more extensive observational multicenter study, CRT combined with AVJ ablation conferred a significant reduction of deaths for any cause compared with CRT alone, particularly by reducing HF. From this evidence, AVJ ablation was included in European Guidelines. In 2011 a metanalysis by Wilton and colleagues14 stated that AVJ ablation may improve CRT outcomes in patients with AF. In 2012, an elegant meta-analysis by Ganesan and colleagues15
included 6 studies and specifically compared CRT-AF patient outcomes according to AVJ ablation. Patients without AVJ ablation had higher allcause (relative risk [RR] 0.42) and cardiovascular (RR 0.44) mortality. A succeeding subanalysis of patients with AF enrolled in the Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT)16 showed, however, that, although CRT did reduce HF hospitalization (40% risk reduction), it had no influence on cardiovascular death (hazard ratio [HR] 0.97; 95% CI, 0.55–1.71; P 5 .91).16 The conclusion drawn by Healey and colleagues,16 even if formally absolutely correct, may be misleading. In the authors’ opinion, these conclusions do not adequately take into account that AVJ ablation has been performed in only 1 RAFT patient. Probably a more correct final message is simply that patients with AF, who are otherwise CRT candidates, not undergoing AVJ ablation do not reach effective BIV stimulation and, as a consequence, gain a minimal benefit from CRTwith a defibrillator compared with standard ICD. Definitive data on this topic, in particular strong endpoints of mortality showing clear benefits by AVJ ablation in CRT, have been recently provided by a large multicenter observational study, the Cardiac Resynchronization Therapy in Atrial Fibrillation Patients Multinational Registry (CERTIFY) study.17 This article reports data of a large cohort of patients (more than 7000) with a significantly long follow-up. The clinical outcome of CRT in patients with HF and permanent AF undergoing CRT in combination with either AVJ ablation (n 5 443) or rate-slowing drugs (n 5 895) were compared with patients in SR (n 5 6046). Over a
3
4
Gasparini median follow-up of 37 months (230,000 patient years), total mortality (6.8 vs 6.1), cardiac mortality (4.2 vs 4.0), and HF mortality (3.4 vs 3.5 per 100 person year) (all P 5 not significant) were similar in patients with AF plus AVJ ablation and patients in SR. In contrast, the AF plus drugs group had a higher total, cardiac, and HF mortality than the SR and the AF plus AVJ ablation groups (11.3, 8.1, and 7.4, respectively; P<.001). On multivariable analysis, AF plus AVJ ablation patients displayed values of total (HR 0.93), cardiac (HR 0.88), and HF mortality (HR 0.82) that were similar to those of to the SR group, independent of known confounders. The AF plus drugs group, however, presented higher total (HR 1.52), cardiac (HR 1.57), and HF mortality (HR 1.58) than both the SR and AF plus AVJ ablation groups (both P<.001). The study concluded that long-term survival after CRT in patients with AF plus AVJ ablation is similar to that observed in patients in SR whereas mortality is higher in AF patients treated with rate-slowing drugs. Last but not least, AVJ ablation has been also demonstrated by a multicenter longitudinal study18 to be the most powerful predictor of SR resumption (SRR) in permanent AF patients treated with CRT. SRR occurs in a significant percentage (10%) of permanent AF patients after CRT by positively affecting atrial electrophysiology (especially by lessening the stretch and change in local and systemic hormonal states). Other factors predicting SRR included smaller left atrial dimension, smaller LV dimension, and shorter QRS after CRT. SRR was usually within 6 months of implantation but observed even after 4 years. The coexistence of 3 predictors versus 0 to 2 predictors increases the likelihood of SRR by 3.5-fold, whereas the presence of all 4 factors improves the probability by a factor of 5.7. Critically, the subgroup of those who resumed SR went on to have a superb prognosis and a much lower death rate than those who remained in AF (0 vs 18 per 100 person-years). The issue of pacemaker dependency may represent a major problem in indicating AVJ ablation on a large scale. It must be stated, however, that CRT, through BIV pacing, offers dual pacing back-up. In addition, more novel device features (available with home monitoring) instantly detect any alteration in lead parameter. Effective failure of capture, therefore, seems unlikely.
though such designs may be difficult to implement for ethical and financial reasons, to definitively validate the need of AVJ ablation in this context. The need of AVJ ablation concept, however, has grown parallel to the concept that the highest BIV pacing percentage must be reached in CRT. After the retrospective analysis of Koplan and colleagues20 showing that the greatest magnitude of benefit was observed with greater than 92% BIV pacing, an elegant work of Hayes and colleagues21 of more than 30,000 patients followed up by home monitoring showed that mortality was inversely correlated to the percentage of BIV pacing both in SR or paced atrial rhythm and even in AF. The greatest magnitude mortality reduction was observed with a BIV pacing cutoff greater than 98%. AF patients with a BIV pacing percentage greater than 98.5% had a survival rate equivalent to that of their counterparts in normal SR. On the contrary, AF patients with a BIV pacing percentage less than 98.5% showed a significantly higher mortality with respect to SR patients. A recent article Ousdigian and coauthors22 assessed the impact of AF on BIV pacing (BIVP%), looking for a possible correlation between BIVP % and all-cause mortality on a wide population accounting for 54,019 patients with a follow-up of 2.3 1.2 years. A proportion as high as two-thirds of patients with permanent (daily mean AF burden 23 hours accounting for 69%) and persistent (1 day with AF 6 hours 62%) AF did not achieve high BIVP% (>98%). Relative to no/little AF, patients with AF had increased mortality after adjusting for age, gender, BIVP%, and shocks (permanent: HR 1.28 [1.19–1.38], P<.001; and persistent: HR 1.51 [1.41–1.61], P<.001). Relative to patients with BIVP% greater than 98%, patients with reduced BIVP% had increased mortality after adjusting for age, gender, AF, and shocks (90%– 98%: HR 1.20, P<.001 and <90%: HR 1.32, P<.001). High BIVP% was associated with the greatest mortality improvement in permanent AF among the AF classifications. All those data strongly indicate that physicians should always aim for a BIV% of 100% and in AF patients AVJ ablation may be the best (sometimes the only) tool for this scope.
SUMMARY THE IMPORTANCE OF MAXIMIZED BIVENTRICULAR PACING There is a great need to design randomized controlled trials with strong endpoints,19 even
AF in patients with HF may have a significant negative impact on the clinical benefit conveyed by CRT, if not appropriately managed. Careful overall evaluation is mandatory to precisely define the
AV node ablation in AF/CRT patients degree of AT/AF burden to articulate tailored diagnostic and therapeutic strategies. Based on recent observational extensive data, in patients presenting intermediate or elevated AT/AF burden, AVJ ablation may represent a fundamental tool to achieve full CRT delivery, thus conferring marked improvements in global cardiac function, and, by extension, in survival.
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REFERENCES 1. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344(12):873–80. 2. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346(24):1845–53. 3. Auricchio A, Stellbrink C, Sack S, et al. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol 2002;39(12):2026–33. 4. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350(21):2140–50. 5. Cleland JGF, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352(15):1539–49. 6. Auricchio A, Metra M, Gasparini M, et al. Long-term survival of patients with heart failure and ventricular conduction delay treated with cardiac resynchronization therapy. Am J Cardiol 2007;99(2):232–8. 7. Swedberg K, Cleland JGF, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur Heart J 2005;26(11):1115–40. 8. Vardas PE, Auricchio A, Blanc JJ, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy: the task force for cardiac pacing and cardiac resynchronization therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association. Eur Heart J 2007;28(18):2256–95. 9. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/ AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline update for implantation of cardiac pacemakers and antiarrhythmia devices): developed in
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Collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 2008;117(21):e350–408. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352(3): 225–37. 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(22):2898–905. 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(4):734–43. 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(13):1644–52. Wilton SB, Leung AA, Ghali WA, et al. Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm 2011;8(7): 1088–94. Ganesan AN, Brooks AG, Roberts-Thomson KC, et al. Role of AV nodal ablation in cardiac resynchronization in patients with coexistent atrial fibrillation and heart failure a systematic review. J Am Coll Cardiol 2012;59(8):719–26. Healey JS, Hohnloser SH, Exner DV. Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail 2012;5:566–70. Gasparini M, Leclercq C, Lunati M, et al. Cardiac resynchronization therapy in patients with atrial fibrillation: the CERTIFY study (Cardiac resynchronization therapy in atrial fibrillation patients multinational registry). JACC Heart Fail 2013;1(6):500–7. 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(8):976–83. Steinberg JS. Desperately seeking a randomized clinical trial of resynchronizationtherapy for patients with heart failure and atrial fibrillation. J Am Coll Cardiol 2006;48(4):744–6.
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Gasparini 20. Koplan BA, Kaplan AJ, Weiner S, et al. 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(4):355–60. 21. 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(9):1469–75. 22. Ousdigian KT, Borek PP, Koehler JL, et al. The epidemic of inadequate biventricular pacing in patients with persistent or permanent atrial fibrillation and its association with mortality. Circ Arrhythm Electrophysiol 2014;7(3):370–6.
KEY POINTS Every effort should be made in all patients receiving cardiac resynchronization therapy (CRT) to approach 100% biventricular (BIV) pacing by a correct device programming, a correct pharmacologic regimen, and atrioventricular (AV) nodal ablation in permanent atrial fibrillation (AF) patients. Currently, atrioventricular junction (AVJ) ablation should always be considered a fundamental step in a combined strategy to obtain the best results of CRT in the heart failure (HF) population affected by permanent AF. AF in patients with HF may have a significant negative impact on the clinical benefit conveyed by CRT, if not appropriately managed.
The prevalence of AF ranges from approximately 5% in patients with asymptomatic cardiac dysfunction to more than 50% of those with severe symptomatic HF.1–9 In some patients, the onset of HF and AF coincide, whereas the onset of AF in patients with preexisting HF indicates a poor prognosis. Patients who develop HF as a consequence of AF (approximately 75% of those admitted when these 2 conditions coexist) have a better outcome than those who develop AF after the onset of HF. AF and HF are believed to directly predispose to each other. They form a sinister synergy, and management of AF in the setting of HF is challenging. Even more problematic is the management of AF patients undergoing CRT. A distinction has to be made between the 3 forms of AF, namely paroxysmal, persistent, and permanent, the last one being frequent in the advanced phases of HF.
WHAT ARE THE TOOLS TO TREAT ATRIAL FIBRILLATION IN HEART FAILURE? Paroxysmal AF may be controlled by antiarrhythmic drugs, even if limited by their negative chronotropic effect, much dreaded in left ventricular (LV) dysfunction. Persistent AF may need repeated cardioversion. Paroxysmal and persistent AF, at least in an initial stage of AF, may be successfully treated with AF ablation (ie, pulmonary veins isolation). Treating AF substrate in the context of a cardiomyopathy, however, may achieve poor results in advanced HF, because during AF in failing hearts, there is a heterogeneous distribution of fibrosis that likely influences dynamic pattern of AF activation and signal complexity. Permanent AF requires a satisfying rate control and this is more true in HF.
MEDICAL THERAPY FOR RATE CONTROL IN PERMANENT ATRIAL FIBRILLATION The aim of the rate-control strategy is to lower heart rate (to allow better diastolic filling and stroke
The author has no conflict of interest. EP and Pacing Unit, Humanitas Research Hospital, 20089 Rozzano-Milano, Italy E-mail address: [email protected] Card Electrophysiol Clin - (2015) -–http://dx.doi.org/10.1016/j.ccep.2015.08.006 1877-9182/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
cardiacEP.theclinics.com
WHAT ARE THE INTERACTIONS BETWEEN ATRIAL FIBRILLATION AND HEART FAILURE (ATRIAL FIBRILLATION BEGETS HEART FAILURE AND VICE VERSA)?
2
Gasparini volume increase in hearts with conserved FrankStarling mechanism). Moreover, heart rate regularization further reinforces favorable effects on diastolic function. Rate-control drugs considered effective in HF patients with depressed LV function include digoxin, amiodarone, dronedarone, and b-blockers. Different randomized trials, however, have suggested caution in the use of digoxin and amiodarone in patients with HF due to increased morbidity and mortality.10
WHAT ARE THE INTERACTIONS BETWEEN ATRIAL FIBRILLATION AND CARDIAC RESYNCHRONIZATION THERAPY? AF poses several challenges to adequately deliver CRT because fast atrial rhythm conducted to the ventricles may easily override BIV pacing. An intrinsic, intermediate-to-high, irregular spontaneous AF rhythm reduces the percentage of effectively BIV-paced captured beats (BVP%), because there are phases of competing AF rhythm that cause spontaneous, fusion (hybrid between paced and intrinsic QRS morphologies), or pseudofusion (pacing artifacts delivered but intrinsic QRS morphology not altered) beats, not hemodynamically effective as pure BIV beats (Fig. 1). This phenomenon suggests that the global effective CRT dose may be markedly reduced compared with atrial-synchronous rhythm with a short AV interval (as is achieved during sinus rhythm [SR]). Moreover, in AF patients, during exertion, spontaneous ventricular rate tends to override BIV pacing rates, determining a further reduction of paced beats precisely when patients are most in need of having BIV capture, thus greatly limiting functional capacity. From a clinical standpoint, it is important to identify symptoms, such as palpitations, and, more importantly, worsening effort dyspnea, which may suggest that the resynchronization effect is reduced because of the interference of
underlying AF. Retrieving relevant information (BVP%, duration, numbers of mode switches episodes, and so forth) through device control may complement clinical data; this kind of information is important and is currently easily achieved with home monitoring systems. Some device-derived features may be helpful to improve rate control and thus improve CRT delivery. These algorithms try to maximize BIV% by stimulating in a BIV mode a native beat or by achieving BIV capture by a higher mean heart rate. They are only partially helpful, however, and not as efficacious as a complete BIV pacing modality. The recourse to rate-control drugs and/or activation of device-based algorithms is reasonable as a first-line approach when AF/AT burden is low/intermediate. Findings derived from different large observational cohort studies on the effects of CRT in patients with permanent AF have yielded contrasting results. It is worth emphasizing, however, that when the survival curves of the HF patients with AF treated with a combined device-based/drug regimen are compared, all-cause mortality remains remarkably high, amounting to more than 14% per year in both separate cohorts of nonablated patients (Fig. 2). It follows, therefore, that in HF patients treated with CRT who present with permanent AF or frequent persistent or paroxysmal episodes, the pursuit of an aggressive treatment strategy, such as AVJ ablation, may be warranted.
Atrioventricular Junction Ablation for Optimizing Cardiac Resynchronization Therapy in Permanent Atrial Fibrillation AVJ ablation is commonly performed in patients with symptomatic, drug-refractory, fast, permanent AF as part of the conventional ablate and pace strategy and has been shown to confer symptomatic relief. AVJ ablation in individuals with AF treated with CRT has initially mainly been confined to selected patients in whom high-rate
Fig. 1. In a patient with AF and HF treated with CRT, spontaneous irregular intrinsic beats alternate with fusion and pseudofusion beats, thus markedly reducing effective CRT. As shown in the figure, this may occur even during normal rate AF. (RV, right ventricle; EGM, intracavitary electrogram. From Gasparini M, Regoli F, Galimberti P, et al. Cardiac resynchronization therapy in heart failure patients with atrial fibrillation. Europace 2009;11(Suppl 5):v82–6; with permission.)
AV node ablation in AF/CRT patients Fig. 2. Comparison of Kaplan-Meier analysis for freedom from death for any cause between HF patients treated with drugs or with ablated AV node (abl). (From Gasparini M, Regoli F, Galimberti P, et al. Cardiac resynchronization therapy in heart failure patients with atrial fibrillation. Europace 2009;11(Suppl 5):v82–6; with permission.)
AF or atrial tachycardia (AT) jeopardizes satisfactory BIV stimulation, and, in CRT–implantable cardioverter-defibrillator (ICD) recipients, determines inappropriate ICD interventions. The problem of inappropriate ICD therapies during AF, constituting approximately 30% of all ICD interventions,11 is that it has an important negative impact on hospitalization rate and quality of life in patients and may be completely resolved after AVJ ablation. In the context of CRT in HF patients with concomitant AF, however, a growing body of evidence has demonstrated that AVJ ablation may be useful to optimize CRT delivery by eliminating the deleterious hemodynamic effects of underlying AF. In 2006, 1 large observational prospective investigation12 specifically evaluated the effects of AVJ ablation on CRT delivery using a predefined protocol. This study showed that only AF patients who underwent AVJ ablation showed significant improvements in LV ejection fraction, LV end-systolic volume, and exercise capacity. Furthermore, a significantly higher proportion of responders (response defined as a 10% reduction in LV end-systolic volume) were observed in the AVJ ablation group (68%) compared with the nonablated group (18%) at 12 months. As later observed by the same group13 in a more extensive observational multicenter study, CRT combined with AVJ ablation conferred a significant reduction of deaths for any cause compared with CRT alone, particularly by reducing HF. From this evidence, AVJ ablation was included in European Guidelines. In 2011 a metanalysis by Wilton and colleagues14 stated that AVJ ablation may improve CRT outcomes in patients with AF. In 2012, an elegant meta-analysis by Ganesan and colleagues15
included 6 studies and specifically compared CRT-AF patient outcomes according to AVJ ablation. Patients without AVJ ablation had higher allcause (relative risk [RR] 0.42) and cardiovascular (RR 0.44) mortality. A succeeding subanalysis of patients with AF enrolled in the Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT)16 showed, however, that, although CRT did reduce HF hospitalization (40% risk reduction), it had no influence on cardiovascular death (hazard ratio [HR] 0.97; 95% CI, 0.55–1.71; P 5 .91).16 The conclusion drawn by Healey and colleagues,16 even if formally absolutely correct, may be misleading. In the authors’ opinion, these conclusions do not adequately take into account that AVJ ablation has been performed in only 1 RAFT patient. Probably a more correct final message is simply that patients with AF, who are otherwise CRT candidates, not undergoing AVJ ablation do not reach effective BIV stimulation and, as a consequence, gain a minimal benefit from CRTwith a defibrillator compared with standard ICD. Definitive data on this topic, in particular strong endpoints of mortality showing clear benefits by AVJ ablation in CRT, have been recently provided by a large multicenter observational study, the Cardiac Resynchronization Therapy in Atrial Fibrillation Patients Multinational Registry (CERTIFY) study.17 This article reports data of a large cohort of patients (more than 7000) with a significantly long follow-up. The clinical outcome of CRT in patients with HF and permanent AF undergoing CRT in combination with either AVJ ablation (n 5 443) or rate-slowing drugs (n 5 895) were compared with patients in SR (n 5 6046). Over a
3
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Gasparini median follow-up of 37 months (230,000 patient years), total mortality (6.8 vs 6.1), cardiac mortality (4.2 vs 4.0), and HF mortality (3.4 vs 3.5 per 100 person year) (all P 5 not significant) were similar in patients with AF plus AVJ ablation and patients in SR. In contrast, the AF plus drugs group had a higher total, cardiac, and HF mortality than the SR and the AF plus AVJ ablation groups (11.3, 8.1, and 7.4, respectively; P<.001). On multivariable analysis, AF plus AVJ ablation patients displayed values of total (HR 0.93), cardiac (HR 0.88), and HF mortality (HR 0.82) that were similar to those of to the SR group, independent of known confounders. The AF plus drugs group, however, presented higher total (HR 1.52), cardiac (HR 1.57), and HF mortality (HR 1.58) than both the SR and AF plus AVJ ablation groups (both P<.001). The study concluded that long-term survival after CRT in patients with AF plus AVJ ablation is similar to that observed in patients in SR whereas mortality is higher in AF patients treated with rate-slowing drugs. Last but not least, AVJ ablation has been also demonstrated by a multicenter longitudinal study18 to be the most powerful predictor of SR resumption (SRR) in permanent AF patients treated with CRT. SRR occurs in a significant percentage (10%) of permanent AF patients after CRT by positively affecting atrial electrophysiology (especially by lessening the stretch and change in local and systemic hormonal states). Other factors predicting SRR included smaller left atrial dimension, smaller LV dimension, and shorter QRS after CRT. SRR was usually within 6 months of implantation but observed even after 4 years. The coexistence of 3 predictors versus 0 to 2 predictors increases the likelihood of SRR by 3.5-fold, whereas the presence of all 4 factors improves the probability by a factor of 5.7. Critically, the subgroup of those who resumed SR went on to have a superb prognosis and a much lower death rate than those who remained in AF (0 vs 18 per 100 person-years). The issue of pacemaker dependency may represent a major problem in indicating AVJ ablation on a large scale. It must be stated, however, that CRT, through BIV pacing, offers dual pacing back-up. In addition, more novel device features (available with home monitoring) instantly detect any alteration in lead parameter. Effective failure of capture, therefore, seems unlikely.
though such designs may be difficult to implement for ethical and financial reasons, to definitively validate the need of AVJ ablation in this context. The need of AVJ ablation concept, however, has grown parallel to the concept that the highest BIV pacing percentage must be reached in CRT. After the retrospective analysis of Koplan and colleagues20 showing that the greatest magnitude of benefit was observed with greater than 92% BIV pacing, an elegant work of Hayes and colleagues21 of more than 30,000 patients followed up by home monitoring showed that mortality was inversely correlated to the percentage of BIV pacing both in SR or paced atrial rhythm and even in AF. The greatest magnitude mortality reduction was observed with a BIV pacing cutoff greater than 98%. AF patients with a BIV pacing percentage greater than 98.5% had a survival rate equivalent to that of their counterparts in normal SR. On the contrary, AF patients with a BIV pacing percentage less than 98.5% showed a significantly higher mortality with respect to SR patients. A recent article Ousdigian and coauthors22 assessed the impact of AF on BIV pacing (BIVP%), looking for a possible correlation between BIVP % and all-cause mortality on a wide population accounting for 54,019 patients with a follow-up of 2.3 1.2 years. A proportion as high as two-thirds of patients with permanent (daily mean AF burden 23 hours accounting for 69%) and persistent (1 day with AF 6 hours 62%) AF did not achieve high BIVP% (>98%). Relative to no/little AF, patients with AF had increased mortality after adjusting for age, gender, BIVP%, and shocks (permanent: HR 1.28 [1.19–1.38], P<.001; and persistent: HR 1.51 [1.41–1.61], P<.001). Relative to patients with BIVP% greater than 98%, patients with reduced BIVP% had increased mortality after adjusting for age, gender, AF, and shocks (90%– 98%: HR 1.20, P<.001 and <90%: HR 1.32, P<.001). High BIVP% was associated with the greatest mortality improvement in permanent AF among the AF classifications. All those data strongly indicate that physicians should always aim for a BIV% of 100% and in AF patients AVJ ablation may be the best (sometimes the only) tool for this scope.
SUMMARY THE IMPORTANCE OF MAXIMIZED BIVENTRICULAR PACING There is a great need to design randomized controlled trials with strong endpoints,19 even
AF in patients with HF may have a significant negative impact on the clinical benefit conveyed by CRT, if not appropriately managed. Careful overall evaluation is mandatory to precisely define the
AV node ablation in AF/CRT patients degree of AT/AF burden to articulate tailored diagnostic and therapeutic strategies. Based on recent observational extensive data, in patients presenting intermediate or elevated AT/AF burden, AVJ ablation may represent a fundamental tool to achieve full CRT delivery, thus conferring marked improvements in global cardiac function, and, by extension, in survival.
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