A review of recommendations for cardiac resynchronisation therapy in patients with atrial fibrillation

Despite advances in treatment over the past decades, heart failure remains a highly prevalent, worldwide problem incurring high morbidity and mortality. Since its first clinical application in the 1990s, cardiac resynchronisation therapy (CRT) has become an essential therapeutic tool in the treatment of heart failure today (1-3). Its aim is to restore electrical synchrony, commonly impaired in these patients, and thus, restore cardiac function.
Although its results have been excellent (4), there are still 20-30% of patients who do not respond to therapy. Therefore, it is essential to make a careful selection of candidates. A number of randomised trials have supported its recommendation in patients in sinus rhythm, NYHA functional class III-IV, LVEF ≤ 35% and QRS ≥120 ms (5) (figure 1). While this indication is clear, there is some uncertainty with respect to various sub-populations underrepresented in clinical trials. In this article, we review the case of patients with atrial fibrillation.

1. Controversy on the convenience of cardiac resynchronisation therapy in advanced heart failure patients with atrial fibrillation

The prevalence of atrial fibrillation (AF) in patients with heart failure is high, especially in those with advanced forms of it. It has been reported that in patients in NYHA functional class I prevalence is 5%, it is from 10 to 25% in patients with NYHA class II or III, and up to 50% in patients in functional class IV6 (figure 2). However, only 2% (7) of patients in randomised studies supporting the benefits and indications for CRT have AF. This low representation is justified for several reasons. On the one hand, patients with AF are usually patients with higher comorbidity and therefore less likely to be included in a clinical trial. On the other hand, in the absence of atrioventricular node ablation, AF reduces the likelihood of obtaining adequate pacing percentage and introduces a reasonable element of confusion when interpreting the results of these studies.

There are other physiopathological arguments that prevent extrapolating evidence obtained in sinus rhythm patients to AF patients. During AF, atrioventricular synchrony, one of the main benefits of the CRT, is lost. This fact can be relevant when AF is permanent or persists for long periods. Moreover, the presence in varying degrees of salvos of high ventricular rate, not only make it difficult to ensure an adequate percentage of biventricular pacing, but should it even be obtained, it will be difficult to ensure that sequence of ventricular contraction is appropriate considering the possibility of fusion beats by partial capture through the conduction system of the patient. That is, an adequate percentage of stimulation does not guarantee an adequate capture and sequence of stimulation in AF patients. As a result we cannot directly assume the published evidence for patients in sinus rhythm.

2. Evidence for cardiac resynchronisation therapy in patients with atrial fibrillation

Over the last decade, studies aimed at patients with AF and heart failure have been carried out. In 1999, Etienne et al (8) published the results of a small series of 28 patients (17 in atrial fibrillation and 11 in sinus rhythm) with heart failure NYHA functional class III or IV, LVEF ≤ 35% and left bundle branch block. They noted that hemodynamic measures (systolic blood pressure, cardiac index and pulmonary capillary pressure) improved similarly in sinus rhythm and atrial fibrillation and that the improvement was independent of the length of the PR in patients in sinus rhythm. The latter observation was attributed to a lower than expected contribution of atrioventricular synchrony in these patients.

A year later, Leclerq et al (9) compared the long-term clinical effects of permanent biventricular pacing in 22 patients with stable sinus rhythm and 15 with chronic atrial fibrillation and atrioventricular junction ablation. They showed that the benefits in terms of functional class, oxygen consumption and LVEF were similar or greater in patients with AF (14 ± 9.4 months of follow-up).

This study provided the basis for one of the most relevant trials in cardiac resynchronisation therapy for patients both in sinus rhythm and atrial fibrillation: the MUltisite STImulation in Cardiomyopathies trial (MUSTIC). Investigators in this study performed the first randomised controlled crossover study in order to evaluate the clinical efficacy of ventricular resynchronisation in two distinct groups of patients: patients with stable sinus rhythm without indication for pacing (10) and patients with atrial fibrillation that required permanent ventricular pacing because of spontaneous or induced impairment of auriculoventricular conduction (11). In the sub-study of atrial fibrillation (AF MUSTIC), 64 NYHA class III patients with LVEF ≤ 35% who had permanent AF and the aforementioned pacemaker dependency were included. They compared the responses of these patients over two periods: a three month period of conventional right ventricular pacing and a three month period of biventricular pacing.

When the patients who completed the study were assessed, an increase in distance walked at 6 minutes and oxygen consumption and a reduction in hospitalisation rates at 6 months of follow-up was observed. A subsequent publication confirmed that this benefit remained at 9 and 12 months in both study cohorts (12). The main drawback of this study was the higher than expected drop out rate (27 patients or 42% withdrew before completing the 6-month crossover phase). The reasons for discontinuation were diverse: mortality (cardiovascular or not), failed implant, dislocation of the electrode and stimulated QRS <180 ms after randomisation. All analyses were based on the intention-to-treat principle, which limited the benefits of randomisation and reduced the sample size and, thus, its statistical power. A further objection was the existence of a baseline period of right ventricular pacing (8-14 weeks) since its unknown undesirable effects (13-16), particularly in a population with heart failure and systolic dysfunction, may have modified the characteristics of the population initially included. Despite its methodological difficulties, the benefits suggested by this study, precluded the further development of new randomised trials in this matter for ethical reasons.

Nevertheless, numerous observational studies (17-23) have shown similar benefits to those obtained in patients in sinus rhythm: improvement in functional class, quality of life, distance walked in 6 minutes, oxygen consumption and LVEF and, conversely, reductions in the ventricular end diastolic and systolic diameters, mitral regurgitation, heart failure hospitalisation and mortality. Moreover, these findings have been supported by a recent meta-analysis (24) conducted to determine the differential impact of CRT for patients in AF and sinus rhythm. Four prospective cohort studies and a subgroup of one randomised trial were analyzed. These studies included a total of 1164 patients of whom 797 were in sinus rhythm and 367 were in AF. They concluded that patients in AF show significant improvement after CRT, with similar or improved ejection fraction as sinus rhythm patients, but smaller benefits in regard to functional outcomes.

3. Current indications for cardiac resynchronisation therapy in advanced heart failure patients with atrial fibrillation

The European Society of Cardiology Guidelines for Cardiac Pacing and Cardiac Resynchronisation Therapy published in 2007 were the first to include patients with AF between the candidates for CRT. They considered it reasonable to implant a biventricular pacemaker in patients with LVEF ≤ 35%, NYHA III-IV despite optimal pharmacological treatment, left ventricular dilatation, permanent AF and indication for atrioventricular junction ablation (class IIa recommendation, level of evidence C).

In the recent update of these guidelines (5), and considering the results of new and more extensive observational studies, this indication remains with level of evidence B for patients dependent on ventricular pacing and C for those with slow ventricular response who are expected to achieve an adequate percentage of biventricular pacing (Figure 3). There are three additional considerations:

1. This is specifically aimed at reducing morbidity due to insufficient evidence regarding the effect of CRT in mortality in this subgroup of patients.
2. Its application is limited to patients with permanent atrial fibrillation. Although the available studies included patients on a permanent or long-standing persistent AF, this restriction leaves a significant gap regarding the management of patients with paroxysmal or persistent AF, especially taking into account the reported benefits on rhythm control.
3. Restriction of these recommendations to patients with QRS ≥ 130 ms: although this criterion may be justified by the presence of a very wide QRS in the few available trials, the figure itself is quite subjective considering two aspects. On one hand, in these studies, the mean QRS width of the patients was significantly higher than 130 ms (165-206 ms) 24 and not necessarily different from that of patients in sinus rhythm. Moreover, this reasoning is not applied to the group of patients in sinus rhythm. Several clinical trials have demonstrated that the benefit of CRT is greater in patients in sinus rhythm with broader QRS. Nevertheless, CRT is recommended in patients in sinus rhythm with QRS over 120 ms.

Figure 1. Modifications in the 2010 update of the European Society of Cardiology guidelines on device therapy in heart failure. Class I recommendation. CRT-P: Cardiac resynchronisation device. CRT-D device for cardiac resynchronisation and defibrillation. LVEF: Left ventricular ejection fraction. LV dilatation: LV diastolic diameter> 55 mm, LV end-diastolic diameter> 30 mm/m2, LV end-diastolic  diameter> 30 mm / m2 of height. Ambulatory class IV: Class IV patients who have not been hospitalised in the past month and with a life expectancy greater than 6 months.
 

Figure 2. Prevalence of atrial fibrillation according to NYHA function class. Modified from Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: Epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003; 91(suppl): 2D–8D6.




Figure 3. Modifications in the 2010 update of  the European Society of Cardiology guidelines on device therapy in heart failure. Recommendations in patients with heart failure and permanent atrial fibrillation. CRT-P: Cardiac resynchronisation device. CRT-D device for cardiac resynchronisation and defibrillation. LVEF: Left ventricular ejection fraction. LV dilatation: LV diastolic diameter> 55 mm, LV end-diastolic diameter> 30 mm/m2, LV end-diastolic  diameter> 30 mm / m2 of height. AF: atrial fibrillation. AV: atrioventricular.

Conclusion:

The prevalence of atrial fibrillation in patients with advanced heart failure is high. Only 2% of patients in randomised studies supporting the benefits and indications for CRT have AF.  The loss of atrioventricular synchrony and the difficulty to ensure effective biventricular pacing prevent extrapolation of evidence obtained in patients with a sinus rhythm. Several observational studies and a randomised study showed similar benefits to the patient with a sinus rhythm in terms of functional capacity and reverse remodelling in patients with permanent atrial fibrillation. Current guidelines recommend the use of CRT in patients in permanent AF with NYHA function class III-IV, LVEF < 35%, QRS ≥ 130 ms and who are likely to achieve an adequate percentage of biventricular pacing. This recommendation is specifically aimed at reducing morbidity due to insufficient evidence regarding the effect of CRT in mortality in this subgroup of patients.