Authors

• Dubravko Petrač — Kardiološka poliklinika «Bogdan», Zagreb, Hrvatska — ORCID: 0000-0003-2623-1475

Abstract

Atrial fibrillation (AF) is often present in patients with cardiac resynchronization therapy (CRT), and may have a significant negative impact on the prognosis and CRT response. Management of AF in CRT patients includes the optimal pharmacological heart failure therapy, anticoagulation therapy, and rate or rhythm control therapy with specific goal to ensure a high percentage (≥98%) of biventricular (BiV) pacing. In heart failure patients with AF, a rhythm control with antiarrhythmic drugs has failed to show any survival benefit compared with a rate control drugs. In this context, a rate control with drugs is preferred as first-line therapy in CRT patients with persistent or permanent AF. However, the observational prospective studies and meta-analyses indicate that AV junction ablation is superior to rate control drugs in achieving adequate BiV pacing and reducing mortality. Therefore, an ablation of AV junction should be considered as the first therapeutic choice in CRT patients with permanent AF. Amiodarone and dofetilide are the lone antiarrhythmic drugs suitable for the rhythm control in CRT patients, but with a moderate efficacy and significant side effects. Catheter ablation of AF is another option for the rhythm control, which can improve CRT response by promoting adequate atrioventricular and interventricular synchrony. According to randomized controlled studies in heart failure patients, AF ablation should be considered in CRT patients with paroxysmal AF, who are non-responders to antiarrhythmic drugs, or in selected patients with persistent AF before accepting a rate control therapy.

Keywords

Ključne riječi: fibrilacija atrija, resinkronizacijska terapija srca, terapijske mogućnosti, atrial fibrillation, cardiac resynchronization therapy, therapeutic options

DOI

Full Text

## Introduction Cardiac resynchronization therapy (CRT) is an efficient way of treatment for patients with mild to severe heart failure, sinus rhythm, left ventricular (LV) dyysynchrony, and impaired LV systolic function. (1) With regard to clinical profile, atrial fibrillation (AF) is often present in these patients and its prevalence rises as the severity of heart failure increases. The ability of CRT devices to detect and store AF episodes offers the opportunity to have a more realistic insight in overall AF burden in this group of patients. Evaluated in this fashion, the cumulative incidence of new onset AF in patients treated with CRT ranges from 21% to 42%. (2) Development of AF in patients with CRT leads to symptomatic deterioration, predisposes to episodes of worsening heart failure, increases the risk of thromboembolic incidents, reduces the percent of biventricular (BiV) pacing and increases the risk of shock therapy in patients with an implanted CRT-defibrillator. (2-5) The aim of this review is to: 1) summarize the main negative effects of AF in patients with CRT, and 2) present the current therapeutic options for the treatment of AF in this patient population. ## Does AF increase mortality in patients with CRT? Data on prognostic implications of AF following CRT are scarce. In a current report of the European CRT Survey, (6) patients with AF have a poorer 1-year survival than those with sinus rhythm (86% vs. 91%, p = 0.0038). Wilton et al. (7) performed a meta-analysis of 23 studies, which have compared the outcomes of CRT patients with (n = 1912) and patients without (n = 5583) AF. After a mean follow-up of 33 months, AF was associated with an increased risk of all-cause mortality (10.8% vs 7.1% per year, p = 0.015). Ousdigian et al. (4) investigated the impact of AF on survival in >50,000 patients with CRT-defibrillators during a follow-up period 2.3 years. In comparison to patients with no/little AF, patients with paroxysmal AF, persistent AF or permanent AF had an increase in mortality of 32%, 51% and 28% respectively (p 0.01% was associated with decreased survival compared with no AF (p7 days. These data suggest that there is significant mortality risk associated with a broad range of AF burden and duration. ## Impact of AF on biventricular pacing The basic goal of CRT is to restore left ventricular synchrony in patients with heart failure and LV dyysynchrony. In sinus rhythm patients, CRT resynchronizes cardiac contractions by optimizing of atrioventricular (AV) timing and by BiV pacing. In patients with AF, AV synchrony does not exist, and therefore, clinical benefit of CRT is predicated only on BiV synchronization. However, AF causes irregular ventricular rate which is often faster than paced rate resulting in spontaneous, fusion or pseudo-fusion beats, and may reduce effective CRT delivery. This is further exacerbated when patients with AF have intermittent or consistently accelerated ventricular rates. Recently, Hayes et al. (9) examined the association between the percentage of BiV pacing and survival in a large cohort of >30,000 CRT patients who were followed up in the remote monitoring network. Mortality was inversely correlated with the percentage of BiV pacing in the presence of both normal sinus rhythm and paced atrial rhythm, and when the atrial rhythm was AF. The BiV pacing >98.5% was found as a cut-point value for the significant benefit in survival. Patients with BiV pacing >99.6% experienced a 24% reduction in mortality (p 98%) was not achieved in two thirds of 8686 patients with persistent or permanent AF, and these patients had an increased risk of death. In a multivariable analysis, reduced percentage of BiV pacing (≤98%) was an independent risk factor of higher mortality. Relative to patients with high BiV pacing (>98%), patients with moderate (90-98%) BiV pacing had a 20% increase in mortality (p2DS2-VASc score at least 2. However, the balance between benefit of anticoagulants and the risk of bleeding should be evaluated in every patient. Non-vitamin K antagonist oral anticoagulants (NOACs) are preferred for CRT patients with nonvalvular AF, as NOACs compared with vitamin K antagonists seem to be at least similarly effective and even safer, especially in reducing intracranial hemorrhage (**Table 1**). (12, 13) In CRT patients who have mechanical heart valves or at least moderate mitral stenosis, only oral vitamin K antagonists should be used for prevention of thromboembolic stroke. (14) It is important to note that the doses of NOACs should be reduced in older patients (age ≥80 years) and those with a poor renal function. ### Table 1: The hazard ratio (HR) and 95% confidence interval of the efficacy and safety outcomes of the non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin in patients with atrial fibrillation and heart failure. | **NOAC** | **Risk of stroke/embolism** | **Risk of major bleeding** | **Risk of intracranial hemorrhage** | | --- | --- | --- | --- | | Dabigatran 150 mg bid | HR 0.75 (0.51−1.10) | HR 0.79 (0.60−1.03) | HR 0.39 (0.17−0.89) | | Dabigatran 110 mg bid | HR 0.99 (0.69−1.42) | HR 0.83 (0.64−1.09) | HR 0.34 (0.14−0.80) | | Rivaroxaban 20 mg od | HR 0.91 (0.74−1.13) | NA | HR 0.63 (0.40−1.02) | | Apixaban 5 mg bid | HR 0.55 (0.34−0.91) | HR 0.81 (0.58−1.14) | HR 0.25 (0.08−0.73) | [†] bid = twice daily, od = once daily, NA = not available. ## Rhythm control or rate control for atrial fibrillation? Multiple studies have demonstrated that rhythm control and rate control with antiarrhythmic drugs have comparable efficacy in the treatment of AF with regard to cardiovascular mortality and stroke. (15) In the AF-CHF (Atrial Fibrillation and Congestive Heart Failure) study, (16) >1300 patients with a left ventricular ejection fraction (LVEF) ≤35%, NYHA class II-IV, and a paroxysmal or persistent AF were randomized to rhythm control (82% with amiodarone) or rate control (88% with beta-blockers). At a mean follow-up of 37 months, there was no significant difference in the primary outcome of death from cardiovascular causes between the rhythm and rate control groups (27% vs. 25%, p = 0.59). There was also no advantage with regard to stroke prevention, heart failure hospitalization and all- cause mortality in the rhythm control group. In a subsequent on treatment-efficacy analysis of the AF-CHF study, (17) the presence of sinus rhythm or rhythm control strategy was not associated with better clinical outcome. Patients with high prevalence of sinus rhythm had similar rates of cardiovascular death, total mortality, and worsening heart failure as the patients with low prevalence of sinus rhythm. The main reasons for these results were limited efficacy and adverse effects of the antiarrhythmic drugs, or delayed therapeutic intervention that was unable to reverse cumulative effects of AF on atria. (18) Thus, the limiting factor was not necessarily the rhythm-control strategy, but the inadequate tools available to maintain the sinus rhythm. (19) Whether modern rhythm control management involving catheter ablation, combination therapy, and early therapy leads to a reduction in major cardiovascular events is currently under investigation. (11, 20) ## Rate control Rate control includes treatment options which effectively reduce and regularize heart rate in CRT patients, who have permanent or persistent AF which cannot be readily converted to sinus rhythm. Pharmacological rate control is an initial treatment option in these patients, but the drugs for rate control are rarely adequate to ensure that a high percentage of beats are paced without fusion. (21) Beta-blockers are recommended as first-line therapy to control ventricular rate because of their effectiveness at high sympathetic tone. (12) Digoxin should be considered when ventricular rate remains high despite beta-blockers or when beta-blockers are not tolerated or contraindicated. Beta-blockers reduce better ventricular rate during periods of activity, while digoxin exerts a greater effect at night because it slows ventricular rate by increasing parasympatethic tone on the AV node. (22) Regarding to results from the recent meta-analyses, both drugs have a neutral effect on mortality in patients with AF and concomitant heart failure. (18, 23) Non-dichydropyridine calcium chanel blockers, verapamil and diltiazem, should not be given for ventricular rate control in patients with CRT because of their negative inotropic effects. Catheter ablation of the AV junction (AVJ) has emerged as an attractive adjunctive therapy for CRT patients with permanent or persistent AF to ensure a high percentage of BiV pacing. The potential benefits and negative effects of AVJ ablation are presented in **Table 2**. Several observational studies have shown that in CRT patients with permanent AF, those who underwent AVJ ablation showed an improvement in LVEF, reverse remodeling effect, improved exercise tolerance and might lead to improved survival, while those treated with drugs for rate control did not. (24-26) In a systematic review of 768 CRT patients with AF, Ganesan et al. (27) found that patients with additional AVJ ablation had a substantial reduction of all-cause mortality (risk ratio: 0.42, p<0.001) and cardiovascular mortality (risk ratio: 0.44, p<0.003), compared with those, who were treated with rate-controlling drugs. ### Table 2: Benefits and negative effects of atrioventricular junction ablation in patients with cardiac resynchronization therapy and atrial fibrillation. | **Benefits** | **Negative effects** | | --- | --- | | Cardiac rate regularization | Procedure is irreversible | | Elimination of rapid ventricular rates | Patient is rendered pacemaker-independent | | Discontinuation of rate control drugs | Possible SR restoration after CRT implantation | [†] Nearly 100% of biventricular pacing [†] SR = sinus rhythm, CRT = cardiac resynchronization therapy. The CERTIFY (Cardiac Resynchronization Therapy in Atrial Fibrillation Patients Multinational Registry) study (28) is multicenter, observational, prospective study, which was designed to determine whether patients with permanent AF undergoing CRT have better outcome with AVJ ablation or rate-slowing drugs. Three groups of CRT patients were included in the study: patients in sinus rhythm (n=6046), patients with AF plus AVJ ablation (n=443) and patients with AF plus rate controlling drugs (n=895). At a mean follow-up of 37 months, patients with AF plus AVJ ablation had 52% lower total mortality and 57% lower cardiac mortality than patients with AF plus rate-controlling drugs (**Figure 2**). No difference in mortality was observed between the patients with AF plus AVJ ablation and the patients in sinus rhythm. Moreover, the improvement in LVEF and reduction in LV end systolic volume in patients with AF plus AVJ ablation were comparable to that observed in sinus rhythm patients, and significantly better than that observed in patients with AF plus rate-controlling drugs (both p<0.001). The results of CERTIFY study strongly support recommendation that AVJ ablation should be performed in most, if not all, patients with CRT and permanent AF as well as those with frequent and prolonged episodes of paroxysmal AF. Figure 2. Kaplan-Meier survival after cardiac resynchronization therapy from total mortality for the three patient groups: sinus rhythm (SR, blue color), atrial fibrillation plus drugs (AFdrug, red color), and atrial fibrillation plus AVJ ablation (AFabl, green color) (Adapted from reference (28)). ## Rhythm control Current guidelines reserve pharmacological rhythm control for patients with heart failure whose symptoms or worsening heart failure persist despite rate control therapy, or for patients in whom the heart rate cannot be controlled. (11, 12) As in other heart failure patients, amiodarone and dofetilide are the lone drugs suitable for patients with AF and CRT. Amiodarone is the most effective antiarrhythmic drug with regard to restoring and maintaining sinus rhythm, (29, 30) and it can safely be initiated in an outpatient setting. Amiodarone has neutral impact on mortality and low proarrhythmia risk, but its long-term use is associated with significant pulmonary, hepatic, and thyroid toxicity. Despite its potency, the recurrence rate of AF in heart failure patients with implanted defibrillators can be such great as 64% over the 2-year follow-up. (31) Dofetilide is more effective than placebo in converting to and maintaing sinus rhythm in patients with AF and heart failure (hazard ratio for the recurrence of AF 0.35, p < 0.001). (32) Dofetilide has no negative inotropic effects and does not affect mortality. (33, 34) Because of the risk of torsade de points within first three days, therapy with dofetilide requires in-hospital initiation with close monitoring of the QT interval and dosage adjustments in patients with impaired renal function. (32, 34) Regarding to limitations of current pharmacological therapy for rhythm control and superiority of AF catheter ablation to antiarrhythmic drugs in patients with no heart failure and normal LV function, (35) the use of AF ablation is extended to patients with heart failure and reduced LV function. The role of catheter ablation in the treatment of AF in heart failure patients was examined in recent systematic review, that included 16 observational studies with 1253 patient. (36) All patients underwent pulmonary vein isolation (PVI), and 55% received an additional left atrial lesions. The efficacy of AF ablation in maintaining sinus rhythm was 75%, including redo procedures and antiarrhythmic drugs. Moreover, the improvement in LVEF following ablation was observed in all studies with a mean increase of 13%, while the rate of serious complications was 4.5%. To date, four randomized controlled studies were conducted to determine if the rhythm control with AF ablation is superior to the rate control therapy in heart failure patients with AF (**Table 3**). The PABA-CHF (Pulmonary-vein isolation for atrial fibrillation in patients with heart failure) study (37) compared AF ablation with the combination of AVJ ablation and CRT in 81 patients, who were in NYHA class II-III heart failure. After 6 months, 71% of patients who underwent AF ablation were free from AF of antiarrhythmic drugs and 88% were free from AF with antiarrhythmic drugs. The patients randomized to AF ablation had a greater improvement in LVEF, longer six-minute walk test, and better heart failure-related quality of life than those randomized to AVJ ablation and CRT. In the other three studies, the patients with persistent AF and heart failure were randomized to AF ablation or pharmacological rate control. Patients with a pharmacological rate control (beta-blockers and/or digoxin) were targeted to achieve a mean heart rate ≤80 beats/min at rest and ≤110 beats/min on moderate exertion. MacDonald et al. (38) reported lower success rates of AF ablation, and no improvement in LVEF or exercise tolerance in patients with ablation. However, it should be noted that patients included in this study had advanced heart failure, longer AF duration, and a worse NYHA class compared with patients in the other three studies. In contrast, two subsequent studies (39, 40) reported 88% and 81% freedom from AF with ablation, and a significant improvement in exercise capacity and quality of life in patients who underwent AF ablation compared with those who received pharmacological rate control. The results of these studies suggest that AF ablation is superior to rate control therapy in heart failure patients with persistent or drug refractory AF in improving LVEF, quality of life and functional capacity. For these reasons, AF ablation should be considered in these patients before accepting a rate control strategy. ### Table 3: Randomized clinical studies on catheter ablation versus a rate control therapy in patients with atrial fibrillation and heart failure. | **Study** | **N** | **Age (yrs)** | **Complications** | **Change in LVEF (%)** | **Outcomes** | | --- | --- | --- | --- | --- | --- | | Khan, 2008 (34) catheter ablation AVJA+CRT | 41 40 | 60 61 | 12% 15% | 27 → 35* 29 → 28 | 88% AF freedom with ablation at 6 mo; improvement in Qol and 6-MWT with ablation | | MacDonald, 2011 (35) catheter ablation rate control drug | 22 10 | 62 64 | 15% NA | 36 → 41 43 → 48 | 50% AF freedom with ablation at 6 mo; no difference in QoL and 6-MWT between groups | | Jones, 2013 (36) catheter ablation rate control drug | 26 26 | 64 62 | 8% NA | 22 → 33 25 → 30 | 88% AF freedom with ablation at 12 mo; improvement in Qol and peak VO2 with ablation | | Hunter, 2014 (37) catheter ablation rate control drug | 26 24 | 55 60 | 8% 8% | 32 → 40* 34 → 33 | 81% AF freedom with ablation at 12 mo; improvement in QoL and peak VO2 with ablation | [†] N = number of patients, yrs = years, LVEF = left ventricular ejection fraction, AF = atrial fibrillation, m = months, QoL = quality of life, 6-MWT = six minute walk test, AVJA = atrioventricular junction ablation, CRT = cardiac resynchronization therapy, NA = not available, VO2 = peak oxygen consumption. * = p <0.001 The AATAC (Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device) study (31) was designed to investigate whether catheter ablation is superior to amiodarone for the rhythm control in heart failure patients with persistent AF and implanted a dual chamber implantable defibrillator or CRT-defibrillator. The study included 203 patients, who were randomly assigned to AF ablation or amiodarone. Amiodarone was orally loaded and then dosed at 200 mg daily. AF ablation included pulmonary vein antrum isolation, and in the vast majority, isolation of the posterior wall of the left atrium. Freedom from AF or atrial tachycardia (AT) off antiarrhythmic drugs at 24 months was the primary endpoint. At the end of the study, 70% of patients in the ablation group were free of AF/AT recurrences in comparison with 34% of patients in the amiodarone group (p <0.001) (**Figure 3**). The rate of procedural complications in the ablation group was small (2%), while 10% of patients in the amiodarone group had to discontinue a therapy because of side effects. Over two years follow-up, the rates of unplanned hospitalization and mortality were substantially lower in the ablation group (31% vs 38%, p <0.001, and 8% vs 18%, p = 0.037, respectively). This is the first randomized study showing that catheter ablation of persistent AF is superior to amiodarone in achieving freedom from AF and reducing hospitalization and mortality in patients with heart failure, and to show that catheter ablation may have a beneficial effect in CRT patients with AF. Figure 3. Kaplan-Mayer curves comparing freedom from the recurrences of atrial fibrillation/atrial tachycardia in patients undergoing catheter ablation and those receiving amiodarone (Adapted from reference (31)). ## Clinical implications The treatment of AF in CRT patients depends on the type of AF, severity of symptoms, left atrium size, underlying heart disease and patient preference. The critical goal of this treatment is to ensure a high percentage of BiV pacing (≥98%). Therapeutic options for the management of AF in CRT patients regarding to type of AF are presented in **Figure 4**. Figure 4. Therapeutic options for atrial fibrillation (AF) in patients with cardiac resynchronization therapy (CRT) regarding to type of AF. % = percentage, BVP = biventricular pacing, AVJ = atrioventricular junction. Relative to ESC guidelines, (12, 13) the pharmacological rate control is the first-line therapy for persistent or permanent AF in heart failure patients treated with CRT, although the available drugs for rate control are rarely sufficient to ensure satisfactory BiV pacing. (21) On the other hand, the CERTIFY study (28) undoubtedly demonstrated the superiority of AVJ ablation over the rate control drugs in achieving a high BiV pacing and reducing morality. Consequently, there is strong recommendation that AVJ ablation should be performed in virtually all patients with CRT and permanent AF, and those who failed the rhythm control therapies. Current guidelines recommend rhythm control therapy for AF patients with heart failure who remain symptomatic on the rate control therapy. (11, 12) Amiodarone and dofetilide are the lone antiarrhythmic drugs suitable for rhythm control in CRT patients, but its use is limited by moderate efficacy and significant side effects. Catheter ablation of AF is another rhythm control option, which improves CRT response by affecting atrial function and by controlling the ventricular rate and/or regularity. According to the most recent evidence from the heart failure studies (36-40) and AATAC study, (31) AF ablation should be considered in CRT patients with paroxysmal AF, who are non-responders to antiarrhythmic drugs, and in selected patients with persistent AF before accepting a rate control strategy. Optimal management of concomitant cardiovascular conditions should be an integral part of rhythm control therapy in CRT patients with AF undergoing catheter ablation. (41) ## Conclusion AF is often present in patients with CRT and can have a significant negative impact on the prognosis and CRT response. All patients with AF and CRT should receive the optimal heart failure and optimal anti-thrombotic therapay, as well as the adequate rate or rhythm control therapy, whose aim is to achieve a high BiV pacing. Unfortunately, the antiarrhythmic drugs for rate and rhythm control have modrate efficacy and can not ensure a sufficient BiV pacing. In this context, the AVJ ablation can be used as the first option for the rate control in the majority of CRT patients with permanent AF. For now, catheter ablation of AF may be a second-line rhythm control option for CRT patients with paroxysmal or persistent AF refractory to antiarhythmic drugs, and should be performed in experienced center. Further prospective multicenter studies are needed to clearly define the true safety and efficacy of AF ablation in this group of patients.

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