Cardiac Resynchronization Therapy in Permanent Atrial Fibrillation
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.
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.
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.
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).
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.
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.
- Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845-1853.
- Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-2150.
- Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-1549.
- Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA, 3rd, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329-1338.
- Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;51:e1-e62.
- Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91:2D-8D.
- Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R, Healey JS, Rouleau JL; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010;363:2385-2395.
- 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.
- Brignole M, Botto G, Mont L, Iacopino S, De Marchi G, Oddone D, Luzi M, Tolosana JM, Navazio A, Menozzi C. Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial. Eur Heart J 2011;32:2420-2429.
- Gasparini M, Auricchio A, Metra M, Regoli F, Fantoni C, Lamp B, Curnis A, Vogt J, Klersy C; Multicentre Longitudinal Observational Study (MILOS) Group. Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation. Eur Heart J 2008;29:1644-1652.
- Delnoy PP, Ottervanger JP, Luttikhuis HO, Elvan A, Misier AR, Beukema WP, van Hemel NM. Comparison of usefulness of cardiac resynchronization therapy in patients with atrial fibrillation and heart failure versus patients with sinus rhythm and heart failure. Am J Cardiol 2007;99:1252-1257.
- Wilton SB, Leung AA, Ghali WA, Faris P, Exner DV. Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm 2011;8:1088-1094.
- Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S, McKenna W, Fitzgerald M, Deharo JC, Alonso C, Walker S, Braunschweig F, Bailleul C, Daubert JC. Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002;40:111-118.
- Leon AR, Greenberg JM, Kanuru N, Baker CM, Mera FV, Smith AL, Langberg JJ, DeLurgio DB. Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing. J Am Coll Cardiol 2002;39:1258-1263.
- Valls-Bertault V, Fatemi M, Gilard M, Pennec PY, Etienne Y, Blanc JJ. Assessment of upgrading to biventricular pacing in patients with right ventricular pacing and congestive heart failure after atrioventricular junctional ablation for chronic atrial fibrillation. Europace 2004;6:438-443.
- Doshi RN, Daoud EG, Fellows C, Turk K, Duran A, Hamdan MH, Pires LA; PAVE Study Group. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol 2005;16:1160-1165.
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