Cardiac resynchronization therapy in atrial fibrillation

INTRODUCTION — In patients with ventricular dyssynchrony due to intrinsic conduction disease or permanent right ventricular pacing, cardiac resynchronization therapy (CRT) with biventricular pacing can improve ventricular synchrony. This is accomplished with an additional pacemaker lead, typically implanted lateral to the left ventricle via a coronary vein. Among selected patients with heart failure (HF) who are in sinus rhythm, CRT improves cardiac performance, symptoms, and overall survival. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".)

In patients who are in sinus rhythm, the pacing mode during CRT is programmed to an atrial tracking mode such as DDD(R) or VDD(R) with an atrioventricular (AV) delay short enough to coordinate depolarization of the ventricles with pacing. However, in patients with atrial fibrillation (AF), atrial tracking is not possible, so other pacing modes are required. AF is common in patients with HF, with a prevalence ranging from 5 percent in patients with New York Heart Association (NYHA) functional class I HF to 40 percent in patients with NYHA class IV HF (table 1) [1]. (See 'Practical considerations' below.)

The use of CRT in patients with AF will be reviewed here. The general use of CRT in patients in sinus rhythm and the rationale for and mechanisms of benefit of CRT are discussed further separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.)

RATIONALE AND MECHANISM OF BENEFIT

Hemodynamic benefit — CRT is useful to restore intra- and interventricular synchrony when ventricular contraction is dyssynchronous due to intrinsic conduction disease (typically manifest as a broad QRS complex, often with left bundle branch block), or ventricular pacing. The rationale and theoretical mechanism of benefit of CRT in patients with AF is similar to that in patients with sinus or atrial-paced rhythm. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT' and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Mechanisms of benefit'.)

There are sufficient data to evaluate the role of CRT in patients with AF, as discussed below, although most major clinical trials evaluating the benefit of CRT have been performed predominantly or exclusively in patients in sinus or atrial-paced rhythms. (See 'Cardiac resynchronization therapy outcomes in patients with atrial fibrillation' below.)

Effect of cardiac resynchronization therapy on atrial fibrillation — CRT is not indicated to reduce the burden of AF [2]. Although CRT has a favorable impact on potential risk factors for AF such as neurohormonal activation, left ventricular systolic dysfunction, atrial size, and degree of mitral regurgitation [3-6], CRT has not been shown to decrease the incidence of new or recurrent AF in clinical trials. Although AF was not a prespecified endpoint of the large randomized trials, CRT was not observed to decrease the incidence of AF [7,8]. However, some patients with AF that is considered "permanent" may convert to sinus rhythm after placement of CRT devices, with factors predictive of a higher conversion rate including smaller left ventricular diastolic dimension, narrower post-CRT QRS complex, smaller left atrial size, and AV nodal ablation [9]. Some observational studies suggested an association between CRT and reduced AF burden [10,11].

CLINICAL SETTINGS FOR USE — Among patients with chronic AF, CRT may be considered in three overlapping clinical settings: AV block due to conduction system disease, following AV node ablation, and systolic HF with evidence of ventricular dyssynchrony (based on QRS width and morphology).

Atrioventricular block — Among patients requiring pacemaker therapy for AV block caused by conduction system disease, CRT may ameliorate the negative effects of dyssynchrony induced by right ventricular (RV) pacing alone. Evidence supporting this approach in patients with AF or sinus rhythm is discussed below. This clinical setting overlaps with the HF setting since the study population included patients with AV block and concomitant HF with reduced systolic function. (See 'Patients requiring a pacemaker for atrioventricular block' below.)

Atrioventricular node ablation — Among patients with AF treated with AV node ablation to achieve definitive rate control, CRT may ameliorate the negative effects of dyssynchrony induced by RV pacing alone. This clinical setting overlaps with the HF setting since patients with HF and/or left ventricular (LV) systolic dysfunction may be most likely to benefit from CRT following AV node ablation. (See 'Following AV node ablation' below.)

The most common nonpharmacologic approach to ventricular rate control in AF is catheter-based radiofrequency ablation of the AV node and/or the His bundle with subsequent electronic pacing. Because the procedure is invasive and results in pacemaker dependency, it is generally reserved for patients in whom pharmacologic rate control therapy is unsuccessful. The majority of well-selected patients for AV node ablation to address inadequate rate control in AF improve hemodynamically following AV node ablation and standard RV pacing. However, RV pacing causes the RV to contract before the LV (interventricular dyssynchrony) and causes the interventricular septum to contract before the lateral wall (intraventricular dyssynchrony). Thus, chronic ventricular pacing, by inducing ventricular dyssynchrony [12,13], may impair LV systolic function, reduce functional status, and increase mortality. Patients with moderate or severe mitral regurgitation and/or LV dysfunction appear to be at the highest risk of clinical deterioration with chronic RV pacing. CRT may ameliorate the negative effects of RV pacing. (See "Atrial fibrillation: Atrioventricular node ablation" and "Overview of pacemakers in heart failure".)

Heart failure — While patients with AF and concomitant HF may benefit from CRT, the evidence to support this therapy in patients with AF is not as strong as that for patients in sinus rhythm. This clinical setting overlaps with the AV block clinical scenario as well as the AV node ablation clinical scenario, since AV node ablation appears to promote the efficacy of CRT by eliminating native AV conduction, thereby ensuring almost 100 percent biventricular pacing. (See 'Patients with heart failure' below.)

OUR APPROACH

Indications for cardiac resynchronization therapy in patients with atrial fibrillation — Our approach for this patient population is consistent with major society guideline recommendations [2]:

●For patients with AF undergoing AV node ablation or strict pharmacologic rate control. In patients with AF and an LV ejection fraction (LVEF) ≤35 percent who require ventricular pacing or otherwise meet CRT criteria and in whom AV nodal ablation or pharmacologic rate control will allow near 100 percent ventricular pacing with CRT, we suggest CRT.

"Otherwise meets CRT criteria" in this context means either the patient has left bundle branch block (LBBB), a QRS duration ≥120 ms, and NYHA functional class II, III; or ambulatory class IV HF symptoms on optimal recommended medical therapy or has a non-LBBB pattern with a QRS duration ≥150 and NYHA class III or ambulatory class IV HF symptoms.

This recommendation is based upon data in patients with HF receiving CRT with or without prior AV node ablation. (See 'Following AV node ablation' below and 'Patients with heart failure' below.)

A similar recommendation is included in major society guidelines [14-17].

●For patients with AV block requiring pacemaker placement, we suggest CRT for patients with NYHA functional class I, II, or III HF who have LVEF ≤50 percent and AV block (with AF or sinus rhythm) who are expected to require a high percentage of ventricular pacing.

●Patients with AF treated with effective rhythm control (either with antiarrhythmic drugs or AF ablation resulting in successful maintenance of sinus rhythm) are generally treated the same as patients in sinus rhythm in regard to indications for CRT (see "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT' and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Mechanisms of benefit'). It is notable that studies of AF ablation have shown improvement in LVEF with maintenance of sinus rhythm [18,19]. Therefore, reassessment of LVEF several months after restoration of sinus rhythm is achieved is recommended before determining candidacy for CRT.

Practical considerations — In patients with AF with AV block or a slow ventricular response during AF, CRT can be achieved with a VVIR setting for those with chronic AF or DDDR setting with mode switching for those with paroxysmal AF. Procedural risks of CRT placement in AF patients are comparable to risks in patients with sinus rhythm, although an atrial lead (and its attendant risks) can be avoided in patients in permanent AF for whom there is no future plan to try to achieve sinus rhythm.

A high rate of biventricular pacing is required to achieve maximum benefit from CRT, which may be difficult to achieve in patients with AF without AV block. The biventricular pacing rates reported by the CRT device may be misleading since these rates include fusion and pseudofusion (ventricular complexes representing a combination of paced and intrinsically conducted beats) [20]. Ambulatory rhythm monitoring may be required to adequately assess the extent of biventricular pacing in patients with intact AV conduction.

Many patients who have the above indications for CRT are also candidates for an implantable cardioverter-defibrillator and should receive CRT-D rather than CRT-P. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

CARDIAC RESYNCHRONIZATION THERAPY OUTCOMES IN PATIENTS WITH ATRIAL FIBRILLATION

Patients requiring a pacemaker for atrioventricular block — Evidence supporting the use of CRT in patients undergoing pacemaker placement for AV block comes from the BLOCK HF trial [21]. The trial randomly assigned 691 patients with indications for pacing for AV block and an LVEF ≤50 percent with NYHA class I, II, or III HF to standard RV or biventricular pacing following CRT device implantation. Of note, over 50 percent of trial subjects had AF at baseline. The following results were reported:

●Biventricular pacing reduced the composite outcome (mortality, urgent care visit for HF requiring intravenous therapy, or a ≥15 percent increase in LV end-systolic index) compared with RV pacing during average 37-month follow-up (45.8 versus 55.6 percent; hazard ratio 0.74; 95% credible interval 0.60 to 0.90).

●LV lead complications occurred in 6.4 percent of patients.

Following AV node ablation — A randomized trial found that CRT improves HF symptoms in selected patients with chronic AF who have undergone AV node ablation and have NYHA functional class II or III HF or LVEF ≤45 percent [22].

Observational studies and small randomized trials support the value of CRT in patients with AF who undergo AV node ablation, particularly for patients with reduced LV systolic function or HF [23-25].

In the randomized PAVE trial, 184 patients with chronic AF (83 percent with NYHA class II or III HF) underwent AV node ablation to treat medically refractory rapid ventricular rates and were randomly assigned to receive a standard RV pacing or CRT pacing system [25]. At six-month follow-up, the following results were noted:

●CRT resulted in significantly greater increases in six-minute walking distance, peak oxygen consumption with exercise, and exercise duration compared with standard RV pacing (31 versus 24 percent improvement, respectively).

●The improvement in six-minute walk distance with CRT was limited to patients with an LVEF ≤45 percent or NYHA class II or III HF.

●CRT resulted in more frequent preservation of the LVEF compared with RV pacing.

Based upon these observations, society guidelines recommend CRT system placement in patients who have undergone AV node ablation for chronic AF and have NYHA class II or III HF.

Patients with heart failure — The limited data on CRT in patients with AF and HF suggest a benefit from CRT (particularly among patients with high rates of ventricular pacing), though the benefit of CRT may be less in patients with AF than that in patients in sinus rhythm.

Patients with atrial arrhythmias were excluded from most of the major CRT trials, such as CARE-HF and COMPANION [26]. In the CARE-HF trial comparing CRT with pharmacologic therapy alone, although mortality was higher among patients who developed new AF during follow-up, this subgroup benefitted from CRT for all major study endpoints [7]. In the RAFT trial comparing implantable cardioverter-defibrillator (ICD) with CRT plus ICD (CRT-D), CRT-D provided no benefit compared with ICD alone in the subgroup of 229 patients with AF [27,28]. However, less than one-third of patients treated with CRT received ≥95 percent ventricular pacing during the first six months of follow-up. In comparison with other trials suggesting CRT benefit in patients with AF, this negative result in the RAFT study is generally interpreted to relate to the low percentage of biventricular pacing achieved in the study.

Observational studies and small randomized trials suggest a benefit from CRT in individuals with AF [3,29-33]. A meta-analysis of observational data from five studies (four prospective cohort studies and the MUSTIC randomized trial [30]) compared responses to CRT in 797 patients in sinus rhythm and 367 patients with AF [29]. The overall use of AV node ablation in patients with AF was 56 percent. The NYHA functional class improved similarly in patients with sinus rhythm and those with AF, although relative improvements in the six-minute walk test and health status were greater in patients with sinus rhythm.

A later meta-analysis of 23 observational studies included 7495 CRT recipients, 25.5 percent of whom had AF [34]. The meta-analysis compared outcomes in patients with AF to outcomes in patients in sinus rhythm but did not address the question of CRT efficacy in patients with AF.

●Patients with AF had higher rates of clinical non-response to CRT (34.5 versus 26.7 percent) and higher risks of death (10.8 versus 7.1 percent per year) than patients in sinus rhythm.

●AF was also associated with less improvement in quality of life, six-minute walk distance, and LV end-systolic volume, but not LVEF.

●Among patients with AF, those undergoing AV node ablation had a lower risk of clinical non-response and lower mortality rate than those who did not undergo AV node ablation.

The MUSTIC-AF trial was not included in the larger meta-analysis since the trial did not include patients in sinus rhythm. This study included 59 patients with HF and chronic AF with a wide QRS complex requiring a permanent pacemaker because of a slow ventricular rate; the patients were randomly assigned to either single site RV pacing or biventricular pacing in a crossover design [3,30]. Sixty-three percent of patients had undergone AV node ablation. Only 39 patients completed the six-month crossover trial, which limits interpretation [3]. Using an intention-to-treat analysis, there were no significant differences in exercise tolerance or peak oxygen consumption. In contrast, among the 37 patients who received effective therapy (97 to 100 percent paced rhythm), biventricular pacing was associated with a significant increase in six-minute walk distance and peak oxygen consumption.

A later observational registry study compared outcomes in patients with HF with QRS duration of ≥120 ms and LVEF of ≤35 percent receiving CRT (n = 4471) with patients with these characteristics receiving no device therapy (n = 4888) [33]. CRT-D use was associated with lower risks of mortality and hospital readmission in the study population, including the subgroup of 3357 patients with AF.

Role of atrioventricular node ablation in patients with heart failure and atrial fibrillation — For patients with LV dyssynchrony, benefit from CRT requires biventricular pacing to occur most of the time (ie, intrinsic dyssynchronous conduction should be rare). This can be difficult to accomplish in patients with AF if conduction through the AV node is rapid despite optimal medical therapy for rate control. However, AV node ablation eliminates intrinsic conduction, resulting in ventricular pacing 100 percent of the time. (See "The management of atrial fibrillation in patients with heart failure", section on 'Atrioventricular node ablation with pacing'.)

The role of AV node ablation in combination with CRT was evaluated in an observational series of 673 patients receiving a CRT device for conventional indications (LVEF ≤35 percent, NYHA class ≥II, and a QRS duration >120 msec) [35]. Among the 162 patients in the cohort with chronic AF, 48 received medical therapy for rate control and 114 underwent AV node ablation. In contrast to the above-described studies in which AV node ablation was necessary for rate control, AV node ablation in this study was performed to ensure frequent biventricular pacing (>85 percent of the time).

At four-year follow-up, the following findings were noted:

●Patients with AF and sinus rhythm had similar improvements in LVEF, reverse remodeling, and exercise tolerance.

●Among patients with AF, the improvements with CRT were observed only in those who had undergone AV node ablation. Despite biventricular pacing more than 85 percent of the time, patients with AF treated with medications for rate control experienced no improvement in LV function or functional capacity.

Another observational study suggested that AV node ablation plus CRT may significantly improve survival compared with CRT alone [36]. Among 1285 patients treated with CRT, 243 were in AF. Rate control was achieved by AV node ablation in 188 and medical therapy in 55; all had at least 85 percent biventricular pacing. During 34-month median follow-up, mortality was significantly lower in patients treated with AV node ablation (4.3 versus 15.2 percent in patients treated with drugs for rate control, adjusted hazard ratio 0.26 for all-cause mortality and 0.15 for HF mortality).

These results suggest that clinicians should target complete (100 percent) biventricular pacing in patients with AF for CRT to achieve maximum benefit. A study reporting on 36,935 patients whose CRT devices were followed in a remote monitoring network found that higher proportions of biventricular pacing were associated with a lower risk of death. The optimal cut-point was 98.4 percent, and patients with a biventricular pacing percentage above 99.6 percent experienced up to a 24 percent lower mortality risk compared with those with lesser percentages of CRT [37]. This observation has not been confirmed by randomized trials. Until such data are available, the indications for biventricular pacing in combination with AV node ablation are uncertain. This approach may be considered particularly in patients with significant LV dysfunction at baseline and those who deteriorate with RV pacing [23,38].

Patients with symptomatic atrial fibrillation or refractory heart failure — The APAF trial found that CRT reduced HF-related morbidity in a mixed population of patients with AF. The trial enrolled patients with permanent AF with either symptomatic AF with poorly controlled ventricular rate or drug-refractory HF, LV systolic dysfunction, and wide QRS who underwent AV node ablation and placement of a biventricular pacemaker [39]. The 186 patients were randomly assigned to programming of either RV apical pacing or CRT with median 20-month follow-up.

●CRT reduced the composite primary endpoint of death from HF, hospitalization due to HF, or worsening HF (11 percent in the CRT group versus 26 percent in the RV group).

●CRT reduced rates of HF hospitalization or clinically worsening HF. Total mortality was similar in the two groups.

ROLE OF CONDUCTION SYSTEM PACING — In patients with AF, it is unknown whether conduction system pacing (ie, achieving cardiac resynchronization by pacing the His bundle or the left bundle branch area) is superior to traditional CRT with an LV lead. Additional information on conduction system pacing can be found separately. (See "Overview of pacemakers in heart failure".)

COMPARISON WITH PULMONARY VEIN ISOLATION — The decision to use pulmonary vein isolation to reestablish normal sinus rhythm versus CRT with or without AV node ablation should be made on a case-by-case basis, depending on several factors, including the institutional success rates with catheter ablation and patient preference. Limited data are available comparing CRT with or without AV node ablation with other therapies for patients with AF and HF. Although a small randomized trial found that pulmonary vein isolation improved symptoms compared with CRT with AV node ablation at six-month follow-up, longer-term data are not available. (See "Atrial fibrillation: Catheter ablation" and "The management of atrial fibrillation in patients with heart failure".)

The PABA-CHF trial of 81 patients with antiarrhythmic drug-resistant AF and NYHA class II or III HF and LVEF ≤40 percent compared pulmonary vein isolation with CRT with AV node ablation [18]. At six months, the pulmonary vein isolation group had significantly better Minnesota Living with Heart Failure questionnaire scores (60 versus 82), longer six-minute walk distance (340 versus 297 m), and higher LVEF (35 versus 28 percent).

Later trials of AF ablation versus drug therapy in patients with HF demonstrated clinical benefits of ablation; in CASTLE-AF, the primary composite endpoint of death from any cause or hospitalization for HF occurred in fewer patients in the ablation group [19]. These studies are discussed in detail separately (see "The management of atrial fibrillation in patients with heart failure", section on 'Catheter ablation'). Although these studies did not compare AF ablation with CRT (with or without AV nodal ablation), the evidence of clinical benefit of AF ablation compared with drug therapy in HF patients supports AF ablation as an option for HF patients, which in some cases may obviate the need for CRT.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Cardiac resynchronization therapy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Effect of cardiac resynchronization on atrial fibrillation – Although cardiac resynchronization therapy (CRT) improves some potential risk factors for atrial fibrillation (AF), such as atrial size and left ventricular (LV) systolic function, CRT has not been shown to decrease the incidence of new or recurrent AF. (See 'Effect of cardiac resynchronization therapy on atrial fibrillation' above.)

●Indications for cardiac resynchronization therapy in patients with atrial fibrillation

•In patients with AF and an LV ejection fraction (LVEF) ≤35 percent who require ventricular pacing or otherwise meet CRT criteria and in whom atrioventricular (AV) nodal ablation or pharmacologic rate control will allow near 100 percent ventricular pacing with CRT, we suggest CRT (Grade 2B). (See 'Indications for cardiac resynchronization therapy in patients with atrial fibrillation' above.)

"Otherwise meets CRT criteria" in this context means either left bundle branch block (LBBB) and a QRS duration ≥120 ms and New York Heart Association (NYHA) functional class II, III, or ambulatory class IV heart failure (HF) symptoms on optimal recommended medical therapy; or a non-LBBB pattern with a QRS duration ≥150 and NYHA class III or ambulatory class IV HF symptoms.

•For patients with AV block requiring pacemaker placement, we suggest CRT for patients with NYHA functional class I, II, or III HF who have LVEF ≤50 percent and AV block (with AF or sinus rhythm) who are expected to require a high percentage of ventricular pacing (Grade 2B). (See 'Indications for cardiac resynchronization therapy in patients with atrial fibrillation' above.)

●Role of defibrillator placement – Most patients who are candidates for CRT are also candidates for an implantable cardioverter-defibrillator and should receive a combined device. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".)

●Comparison of CRT and pulmonary vein isolation – Pulmonary vein isolation is another potential treatment option in patients with AF and HF. The decision to use pulmonary vein isolation aimed at reestablishing normal sinus rhythm versus CRT with or without AV node ablation should be made on a case-by-case basis depending on several factors, including the likelihood of successful maintenance of sinus rhythm after AF ablation, the institutional success rates with catheter ablation, and patient preference. Pulmonary vein isolation may result in better symptom control compared with CRT plus AV node ablation at short-term follow-up, but comparative long-term effects are not known. (See 'Comparison with pulmonary vein isolation' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges Leonard I Ganz, MD, FHRS, FACC, Michael Cao, MD, and Leslie A Saxon, MD, who contributed as authors to earlier versions of this topic review.

The UpToDate editorial staff acknowledges Wilson Colucci, MD, who contributed as section editor to earlier versions of this topic review.