Editor's Note: This Article of the Month is based on Healy JS, Hohnloser SH, Exner DV, et al. Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the resynchronization for ambulatory heart failure trial (RAFT). Circ Heart Fail 2012;Published online before print August 14, 2012.

Introduction

Cardiac resynchronization therapy (CRT) has become an integral treatment modality for patients with heart failure (HF), diminished left ventricular ejection fraction, and a wide QRS complex, conferring symptomatic relief, functional improvement, and survival benefit to the majority of recipients.^1-4 CRT indications⁵ were initially restricted to patients in sinus rhythm, yet as atrial fibrillation (AF) is the most common sustained arrhythmia in HF patients, with a prevalence that increases with more advanced HF symptoms,⁶ much attention has focused on expanding the CRT indications to patients with permanent AF. Despite the fact that approximately a quarter of HF patients eligible for CRT therapy have permanent AF,⁶ the overwhelming majority of multicenter, randomized CRT trials have only included patients in sinus rhythm.^1-4 The majority of our knowledge regarding the role of CRT in patients with permanent AF is therefore based on non-randomized, observational data.

The Resynchronization for Ambulatory Heart Failure (RAFT) trial⁷ randomized patients with New York Heart Association classes II and III who also had a low left ventricular ejection fraction (LVEF ≤30%) and a wide QRS complex (≥120 ms) on surface electrocardiogram to receiving a CRT defibrillator (CRT-ICD) versus a regular ICD. This study allowed the enrolment of patients with permanent AF and stratified randomization by AF status. Healy et al.⁸ analyzed the results of RAFT in the 229 patient with permanent AF.

Methods

Patients with permanent AF in the RAFT trial were randomized to CRT-ICD (n=114) versus regular ICD (n=115). Both the original RAFT trial and its AF sub-study used a composite of all-cause mortality or hospitalization for HF as the primary endpoint.

Results

There were no differences in baseline characteristics of patients randomized to the two arms of this study.⁸ The mean age of patients was about 71 years, with male predominance (88%). Their mean LVEF was 23% and mean QRS width 152 ms. Seventy-two percent of patients belonged to NYHA HF class II. During a mean follow-up of about 40 months, 42.6% of patients in the ICD group and 48.2% in the CRT-ICD group reached the composite primary endpoint of death or HF hospitalization (p=0.82). When examining the secondary endpoint of HF hospitalization alone, there was a strong trend towards less events in the CRT-ICD group compared to the ICD group (Hazard ratio = 0.58; 95% confidence intervals 0.38-1.01, p=0.052). Although the change in 6-minute walk was not different between the two study arms, patients in the CRT-ICD group had a trend towards more improvement in their Minnesota Living with Heart Failure Questionnaire scores (p=0.057).

Conclusion

The authors⁸ conclude that permanent AF patients who are otherwise candidates for CRT appear to gain minimal benefit from CRT-ICD compared to standard ICD.

Perspective

There are special considerations that are pertinent to CRT patients with permanent AF. First, in the absence of large, randomized, prospective trials of 'CRT' versus 'no CRT' in the AF population, it is not firmly established whether patients with AF derive survival, symptomatic, and structural benefits from CRT and if these benefits do occur, whether they are comparable in magnitude to those seen in sinus rhythm patients. Second, it is not completely established how best to ensure a high burden of biventricular pacing in CRT recipients who also have AF, although the role of atrio-ventricular nodal ablation in this context seems to be widely accepted.^{9, 10}

From a survival perspective, there are no randomized, prospective trials examining the effect of CRT on mortality in patients with AF. Early prospective, non-randomized, observational data¹¹ showed no difference in total mortality after CRT in 96 patients with permanent AF compared to 167 patients in sinus rhythm. A retrospective analysis of the CARE-HF trial³ identified 124 out of 813 (15%) patients with a diagnosis of AF, in whom the presence of AF did not diminish the decrease in all-cause mortality conferred by CRT. A more recent meta-analysis, however, suggested an attenuated survival benefit from CRT in AF patients compared to patients in sinus rhythm.¹²

From a symptomatic perspective, CRT seems to benefit patients with AF. In the MUSTIC-AF trial,¹³ 41 patients with slow, permanent AF of > 3 months duration and a paced QRS duration of > 200 ms were randomized in a single-blinded, cross-over study design (3 months for each phase) to right ventricular versus biventricular pacing. At the end of six months, 85% of patients who were blinded to their pacing mode preferred biventricular pacing to right ventricular pacing. With the preferred mode of pacing adopted for the following 6 months, patients had significant improvement in their 6-minute walk tests, quality of life scores, and New York Heart Association HF class compared to baseline values. Other studies have also documented improved symptoms in HF patients with permanent AF and chronic right ventricular pacing after undergoing device upgrade to biventricular pacing.^{14, 15} A more recent meta-analysis, however, suggests an attenuated symptomatic response to CRT in AF patients compared to patients in sinus rhythm.¹²

As documented by echocardiography, CRT also improves systolic function and induces reverse remodeling in patients with permanent AF and diminished LV function. Prospective, non-randomized, observational data¹¹ demonstrated similar rates of left ventricular reverse remodeling (defined as >10% decrease in left ventricular end-systolic volume) between CRT patients with permanent AF versus sinus rhythm. Similarly, in HF patients chronically paced in the right ventricle, upgrading to CRT increased left ventricular ejection fraction¹⁴ and reduced left ventricular end-systolic diameter and the severity of mitral regurgitation.¹⁵ A more recent meta-analysis, however, suggests an attenuated echocardiographic response to CRT in AF patients compared to patients in sinus rhythm.¹²

Preventative CRT also appears to be beneficial in patients with permanent AF and normal left ventricular function undergoing radiofrequency ablation of the atrioventricular node. In this population, CRT after atrioventricular nodal ablation seems to prevent a decline in left ventricular ejection fraction and improve measures of the 6-minute walk test and peak myocardial oxygen consumption compared to right ventricular pacing.¹⁶ Compared to right ventricular pacing, CRT in permanent AF patients was also recently shown in a small, prospective, randomized trial⁹ to reduce the rates of worsening of HF as well as HF hospitalizations when performed after atrioventricular nodal ablation.

Of particular concern in this RAFT subanalysis⁸ is that optimal biventricular pacing (>95%) was achieved in only one third of the patients, since only one patient underwent atrioventricular nodal ablation while the rest of the AF patients randomized to the CRT arm had the unproven 'Conducted AF Response' feature activated. Moreover, Healy et al.⁸ do not report any follow-up echocardiographic data in their study. Favorable effects of CRT on structural and functional echocardiographic parameters, if present, may add insight into whether CRT may actually be clinically beneficial in permanent AF patients.

So, do patients in permanent AF extract any benefit from CRT? The answer is probably yes. They do derive symptomatic benefit and experience reverse remodeling from CRT as previously shown in the MUSTIC-AF trial¹³ and other studies.^{14, 15} These data have formed the basis for the current ACC/AHA/HRS guidelines⁵ published in 2008 that recommend (with a class IIa indication) the use of CRT pacing in AF in patients meeting other accepted criteria. Although underpowered and lacking optimal CRT delivery, the present study by Healy et al.⁸ further supports the benefit of CRT in permanent AF patients as far as reducing HF hospitalizations, albeit with a level of certainty reaching 94.8% as opposed to 95%, which is conventionally used as the threshold cutoff for statistical significance.

The study by Healy et al.⁸ is a welcome addition to the growing literature on the role of CRT in permanent AF. Because of its important shortcomings, however, it has failed to answer definitively whether permanent AF patients benefit from CRT. Taken in the context of the growing literature on this subject, our conclusion, contrary to that of Healy et al.⁸ is that CRT does benefit AF patients when biventricular pacing is ensured. We do agree with the authors in their assertion that further randomized trials are needed in the sizable group of HF patients who also have permanent AF.

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References

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Keywords: Atrial Fibrillation, Cardiac Resynchronization Therapy, Echocardiography, Heart Failure, Minnesota, Oxygen Consumption

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