Atrial Fibrillation in Heart Failure: Rate or Rhythm Control Strategy

Abstract

Atrial fibrillation and heart failure are intimately related as they shared the same risk factors, unsurprisingly they commonly coexist and complicate each other. Management of atrial fibrillation in heart failure is usually simplified into rate or rhythm control strategy, as each offers its advantages and limitations. Pharmacological rate and rhythm control strategy has been compared for the last decades; however, as more nonpharmacological approach raised as viable option has driven the management strategy discussion even further. On the other hand, heart failure understanding is also evolving and more detailed classification has been made based on left ventricular function. Justification for rate or rhythm control strategy should be individualized predicated on clinical phenotype. Moreover, the chosen strategy should be flexible and can be adjusted if the preferred strategy is ineffective.

1. Introduction

Atrial fibrillation (AF) and heart failure (HF) commonly coexist that frequently complicate one another and exert a significant detrimental effect on cardiovascular health and well-being [1]. Altered left ventricular (LV) functions may be the substrate for most HF spectrum, heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), but in some instances, HFpEF may be the consequence of a failing left atrium (LA) including AF. It is believed that AF can induced and worsened HF due to: (1) elevated resting heart rate and exaggerated response during exercise result in reduction of diastolic filling time, leading to cardiac output reduction. Irregularity of the ventricular response will affect the cardiac output even further [2]. (2) Heart rate irregularity with calcium mishandling, even in AF with the absence of tachycardia we can observe potential deleterious interaction of AF and LV function; (3) loss of atrial contraction associated with sympathetic activation contributing to limited ventricular filling and increased filling pressures, functional mitral regurgitation, and diastolic function [3, 4]. Studies in AF patients have shown the atria structural remodeling changes; however, the impact of arrhythmia chronicity and the structural remodeling is not well understood; adaptive (dedifferentiation of cardiomyocytes) and maladaptive (degeneration of cells with replacement fibrosis) features are the changes mainly concern [5].

Management strategy of rate or rhythm control strategy has been thoroughly discussed over the last decades. Rate control strategy is considered as first-line therapy in most AF; however, the evidence keeps evolving. The decision to treat AF with a rate versus rhythm control strategy depends on multiple factors, including: medical comorbidities, age, and lifetime exposure to the risks and side effects of treatments; the duration and type of AF; and concomitant medications. Based on recent clinical trials, treatment strategies for patients with AF are increasingly focused on rhythm control by catheter ablation compared with rate control therapy [1, 3]. This chapter will discuss each strategy further.

2. Role of rate control strategy

AF is frequently considered a primary cause of arrhythmia-induced cardiomyopathy. AF by itself in the absence of tachycardia causes impaired excitation-contraction coupling associated with increased levels of reactive oxygen species and CaMKII-dependent depression of systolic Ca²⁺ release, clinically frequently observed as impaired ventricular function [3]. Furthermore, limited evidence suggests that controlled ventricular rate during AF does not predict the reversibility of cardiomyopathy. This has raised the question whether well-controlled heart rate in AF can reverse this process. However, early studies failed to demonstrate rhythm control superiority over rate control strategy [4, 6].

Traditionally rate control strategy is the primary option in AF with or without HF [7, 8]. AFFIRM is the landmark trial to exposed rhythm control strategy and offers no survival benefit over rate control strategy while more adverse drug effects were also seen. These findings were later confirmed by other studies [6, 9]. Nevertheless, extrapolation from these studies to patients with HF should be done with caution.

In patients with HF, similar results were also observed in landmark AF trials. AF-CHF (rhythm control vs. rate control for atrial fibrillation and heart failure) trial was the first randomized study to examine the effect of rate versus rhythm control strategy in a heart failure population; it showed pharmacological rhythm control is not superior to rate control for the prevention of cardiac death and hospitalization for heart failure, therefore extends the findings of AF without HF. Of note, most of these trials were performed before the era of catheter ablation for AF. The need for effective therapy to maintain sinus rhythm while minimizing toxicity is the highlight of the difficulty with currently available antiarrhythmic drug (AAD) [2, 4, 10, 11]. Nevertheless, up-to-date rate control strategy remained as first option in AF with HF.

2.1 Drug selection for rate control strategy

There are several atrioventricular nodal blockers that can be used to obtain rate control; beta-blockers, non-dyhidropyridine calcium channel blockers, cardiac glycosides, and (in rare circumstances) low-dose amiodarone. Pharmacological rate control strategies are different for patients with HFrEF and HFpEF.

Beta-blockers and digoxin can be used in those with HFrEF. Beta-blockers are well known as of the HFrEF management pillars, suited well in HF with AF comorbidity. Beta-blockers may both control the ventricular rate to AF and improve survival of HFrEF. A meta-analysis showed that the effect of beta-blockers on outcome in HF patients with reduced left ventricular ejection fraction (LVEF) who have AF is less than in those who have sinus rhythm. This result does not suggest that there is no benefit of beta-blockers in HF and AF, but rather highlights the benefits of sinus rhythm in patients with HF [8, 12, 13]. Digoxin slows ventricular response to AF through enhancement of vagal tone and therefore is less effective in states of increased sympathetic tone such as exercise or worsening heart failure. However, digoxin may be used as adjunct therapy to beta-blockers as it exerts a synergistic effect with beta-blockers after single therapeutic option failed to achieve optimal target heart rate. Of note, digoxin should be used with caution because of its potential deleterious effects [2, 7, 14, 15].

The non-dihydropyridine calcium-channel blockers include diltiazem and verapamil, beta-blockers, and digoxin are all viable options in HFpEF. The non-dihydropyridine calcium-channel blockers are effective rate control agents; however, because of their negative inotropic effect, they may be not tolerated at optimal dose required for optimal ventricular rate control and increased mortality in HFrEF. Beta-blockers were more successful than calcium-channel blockers in achieving rate control (70% vs. 54%, consecutively) when used alone or in combination with digitalis. Amiodarone is also another option for rate control in both forms of HF, but limited only to acute settings [1, 8, 16].

2.2 Optimal AF target heart rate in HF

Optimal target heart rate in AF is informed by several factors, including symptom management, optimization of functional capacity, and preventing HF exacerbation and tachycardia-induced cardiomyopathy. High ventricular rates are clearly harmful and can result in symptoms and especially in patients with preexisting HF [17]. The decision to use of strict or lenient as optimal level of heart rate control in AF and HF is essential in management strategy.

A major concern with lenient heart rate control is the decompensation episode of HF may occur; however, this concern was not confirmed [18]. Strict rate control cannot be advocated over lenient rate control for patients with preserved LV function; however, it potentially offers clinical benefit in patients with AF and HFrEF, but this remains unproven. The latest European Society of Cardiology (ESC) guidelines recommend a lenient rate control of <100–110 bpm as initial approach; however, tight rate control strategy can be considered in case with persistent symptoms or cardiac dysfunction likely related to tachycardia. It should be noted that these criteria were not based on strong clinical evidence [7, 8].

2.3 Pace and ablate strategy

Atrioventricular node ablation with permanent pacemaker placement remains an important option, it should be undertaken with caution. One concern of pharmacological rate and rhythm control strategies is the risk of pauses or symptomatic bradycardia during AF or at the time of AF conversion to sinus (conversion pauses). Another common scenario is patient coexists with sinus node dysfunction, a permanent pacemaker is usually required during significant bradycardia [1, 19].

Effective rate control is often hard to achieve in patients with or without pacemaker in situ. In patients without pacemaker, symptomatic pauses during AF or at the time of conversion of paroxysmal AF to sinus rhythm make effective rate control not possible. Ineffectiveness of rate controlling drugs or intolerance to the drugs at doses that result in adequate rate control is indication for the use of permanent pacemaker. In these strategies, combination of AV nodal radiofrequency ablation and permanent pacemaker implantation can be performed as definitive strategy with a high success rate [19, 20].

In patients with symptomatic AF and rapid ventricular response refractory to pharmacological therapy, radiofrequency atrioventricular nodal ablation with subsequent pacemaker placement can improve cardiac performance. In the subgroup of patients with heart failure, the degree of improvement for LVEF and NYHA class was even greater [21]. However, long-term outcomes of the “pace and ablate” strategy have been less favorable [22]. AV nodal ablation typically results in nearly 100% right ventricular (RV) pacing, which can induce ventricular dyssynchrony and worsen systolic function. A large body of evidence has emerged recently that underscores the harmful effects of long-term right ventricular pacing.

A study showed that patients who underwent AV nodal ablation with cardiac resynchronization (CRT) achieved significantly better symptomatic relief with improvement in their LV function [23]. The CRT impact on new onset AF is controversial. CRT can reverse the remodeling of the ventricle, improve the regurgitation of the mitral valve, and theoretically reduce the incidence of new-onset AF [2]. Recently, multiple studies showed conduction system pacing (His bundle pacing and left bundle branch area pacing) is not inferior to CRT. However, the current evidence of conduction system pacing is still limited and neither has been evaluated as robustly as CRT [24, 25, 26]. AV nodal ablation in the presence of let bundle branch area pacing lead is associated with a higher success rate and fewer acute and chronic lead related complications compared with His bundle pacing [27].

AV nodal ablation and pacing for patients with AF have not been found to worsen survival in comparison with drug therapy for AF [28]. Unfortunately, this pace and ablate strategy results in permanent pacemaker dependence and irreversible. It should be performed only as a last resort when other rate and/or rhythm control strategies have been failed or are contraindicated.

3. Role of rhythm control strategy

Previous trials cast skepticism over the hard end point benefit of sinus-rhythm maintenance in patients with and without heart failure. Trials including patients with HF and comparing rate control and rhythm control strategies with the pharmacological approach failed to show mortality benefit of one strategy over the other [10, 29]. Consequently, previous guidelines have limited recommendations for catheter ablation (CA) in patients with HF: when tachycardiomyopathy is suspected, with pharmacological rate control the accepted standard treatment [30].

CA for AF has emerged as alternative strategy to pharmacological rhythm control, as it significantly reduces the risk of death, stroke, and hospitalization compared with medical therapy alone [13, 31, 32]. It is a well-established option for symptomatic AF that is resistant to drug therapy in patients with otherwise normal cardiac function [8].

EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) has emphasized that aggressive rhythm control (with either CA or drugs) early in the course of AF reduced adverse cardiovascular outcomes compared with usual care. The effects of an early rhythm-control strategy on the primary outcome appeared to be generally consistent across predefined subgroups, including patients with or without HF [33].

In the field of CA in HF, various studies have shown that ablation is associated with positive outcomes in patients with HF. Important to note is that initial series were often single-center studies that included a limited number of patients with limited follow-up, and its effectiveness in improving rates of hard primary end points such as death or the progression of HF was not tested [34, 35]. More recently, larger trials with substantial longer duration of follow-up and cardiovascular endpoints as well as sinus rhythm maintenance have been conducted.

3.1 Medical vs catheter ablation for rhythm control

AF-CHF and DIAMOND-CHF trials found no difference in mortality between AAD therapy and rate control. The mortality benefit of AADs in previous trials may have been limited by their adverse effects [10, 29]. AADs may not be as efficacious as catheter ablation in providing freedom from AF in patients with HF, and there is increasing evidence that the maintenance of sinus rhythm is the key determinant of survival [11].

Several trials have reported improvements in soft end points with catheter ablation. The AATAC and CAMTAF trials showed that CA was superior to medical treatment in maintaining sinus rhythm and improving LVEF. The trial also showed a favorable effect on rates of death and hospitalization for HF [36, 37].

CASTLE-AF is notable because previous trials comparing CA versus standard medical therapy predominantly reported improvement in soft endpoints (symptoms, QOL, or surrogate endpoints). In the CASTLE-AF trial, ablation for AF in HF was superior to medical therapy in reducing composite death and hospitalization. The benefit of all-cause mortality in the ablation group was driven by lower rate of cardiovascular mortality. The mortality benefit of ablation did not emerge until after 3 years. Pursuing rhythm control with catheter ablation proved to be of significant benefit with regard to outcomes [38].

However, CASTLE-AF enrolled a highly selected population, 363 of 3013 patients were not blinded, had crossovers between the two treatment strategies, and the number of events observed was low. Both CASTLE-AF and CABANA showed a highly significant effect of catheter ablation on patients’ symptoms [38, 39, 40].

CASTLE-AF trial’s results are likely driven by two factors: Firstly, CA procedural risks have fewer risks and long-term toxicities than medical therapy. Secondly, ablation is more effective in reducing AF burden. One of the proposed mechanisms behind the improvement in prognosis in the patients treated with CA is that it significantly reduced total AF burden. Post-hoc analysis showed that AF burden below 50% after 6 months of CA was associated with an improved outcome. Another potential explanation is that part of the patients had a tachycardiomyopathy. Longer periods of sinus rhythm may, therefore, be a mechanism to improve outcome eventually [11, 38].

Furthermore, the absence of ventricular LGE on cardiac MRI imaging was associated with a greater improvement in LVEF and a higher likelihood of normalization of left ventricular function. These findings indicate that in these patients, AF may either significantly contribute to, or indeed be entirely responsible for, ventricular dysfunction [13]. Meta-analyses showed that AF ablation was associated with average LVEF improvement ranged between 11% and 13% illustrating the advantage of AF ablation. Improvement in LVEF was most pronounced in patients with non-ischemic cardiomyopathy [41, 42, 43].

Another interesting observation was seen in AF and HFpEF. Both conditions shared similar risk factors, including hypertension, sleep apnea, advanced age diastolic dysfunction, and obesity. The prevalence of HFpEF in AF ranges from 8% to 24%, and AF was found in ~20–30% patients with HFpEF [40]. Restoration and maintenance of sinus rhythm in patients with comorbid AF and HFpEF improve hemodynamic parameters, BNP, and symptoms associated with HFpEF [44].

4. Potential deleterious effects of pharmacological therapy

Understanding and identification of drug deleterious effects are also another important issue for management consideration. Digoxin’s ability to reduce heart rate and improving LV function is very tempting; however, digoxin’s potential deleterious effects such as arrhythmogenic potential, narrow therapeutic window, increased sympathetic activity, and risk for serious drug interaction. A meta-analysis of nonrandomized trials showed digoxin used in HF and AF is associated with an increased risk of all-cause mortality [15]. Moreover, the use of pharmacological rhythm control also brings risk. Amiodarone carries the risk of thyroid, pulmonary, and hepatic toxicity. Dofetilide therapy is also known for prolonging QT interval and higher rate of torsade de pointes [45, 46].

5. Catheter ablation vs pace and ablate

Biventricular pacing was found to be superior to right ventricular pacing after atrioventricular-node ablation [47]. However, PABA-CHF trial has shown that CA for AF provides superior morphological and functional improvements compared with atrioventricular-node ablation with biventricular pacing in patients with HF who had drug-refractory AF [20].

6. Catheter ablation strategy

The improvement in LVEF observed following CA may largely be dependent on successful rhythm restoration, rather than the mode of restoration, which enables regular ventricular filling time and coordinated atrial contraction [46]. CA by pulmonary vein isolation (PVI) is proven as the best technique for AF ablation, as no proven benefit shown by additional ablation.

After Haissaguerre et al. found that radiofrequency ablation on PV is efficient in treating AF in 1998, no additional ablation technique (posterior wall ablation, linear lines or ablation of complex fractional aytrial electrograms) has been proven consistently to improve ablation efficacy; however, additional ablation can be done up to the operator’s discretion. Future research endeavors should be performed into the field of high-power short duration, pulsed field ablation, and hybrid/convergent AF ablation strategies in patients with AF and HF [11, 48].

7. Catheter ablation patient selection

In selecting patients with HF for catheter ablation of AF, the increased risk of major peri-procedural events must be carefully weighed against the potential improvement in systolic function, quality of life, and functional status.

AF ablation can be performed safely and long-term prognosis can improve, especially in patients with a tachycardiomyopathy, that is, without other demonstrable underlying heart disease. Based on the post-hoc analysis of CASTLE-AF, patients with NYHA I/II and non-ischemic etiology of HF appear to benefit the most, suggesting that early intervention might be beneficial [49].

Furthermore, enlargement of the atria and evidence of fibrosis on CMR are an indication of poor candidate for CA. A trial of cardioversion with electrical cardioversion and/or amiodarone can be used if there is a doubt whether patients may benefit from sinus rhythm [11].

8. Catheter ablation for AF limitation

There are small but nonzero procedural risks that must be taken into account when considering CA, including risks of stroke (0.5–1%) and tamponade (1–2%); however, a second ablation is frequently required [1]. CA for AF and HF was performed at centers with experienced ablationists in most landmark trials, and the results thus may not be reproducible in all centers [20].

9. Conclusion

In the management of AF in HFrEF, there is insufficient evidence in favor of a strategy of rhythm control with antiarrhythmic drugs vs. rate control in patients with HF and AF. Pharmacological rate control strategy remained as leading option in AF and HF. More evidence is needed to weigh the short-term risks of catheter ablation versus the long-term risks associated with antiarrhythmic therapy in those with AF and HFrEF. Notably, this has led to recent guideline changes suggesting that CA may be considered as first-line therapy in patients with AF and HFrEF (Class I recommendation). Pace and ablate option should be keep as last resort, because this becomes pacemaker-dependent and irreversible. Conduction system pacing as alternative pacing site in AF and HF should be an interesting area to watch in the future. On the other hand, pharmacological approach remained as preferred strategy in HFpEF; non-dihydropyridine calcium-channel blockers are the additional alternative medication compared with HFrEF. Evidence on nonpharmacological approach for AF in HFpEF is still limited.