Is CRT Useful in Patients with Atrial Fibrillation? L. P

L. P

, M. C

, E. P

The Scale of the Problem

Despite improvements in the medical therapy of chronic heart failure (CHF) some patients remain refractory to full medical treatment, with limited ther- apeutic options and poor prognosis. Cardiac resynchronisation therapy (CRT) by biventricular pacing has recently been demonstrated to represent a valuable therapeutic strategy in improving the clinical course of patients with advanced heart failure and intraventricular conduction delay [1–5].

Atrial fibrillation (AF) is common in patients with CHF and its incidence increases with the severity progression of the syndrome. In all CHF patients, the prevalence of permanent AF is relatively high (approximately 20%) [6], but it may reach 40% in patients with advanced heart failure [7]. From an epidemiological point of view, AF in CHF is a relevant clinical problem. In fact the incidence of both CHF and AF markedly increases in the elderly, so that in the light of the ageing population these two diseases have been called

‘the new epidemics’ of cardiovascular disease. However, the prognostic sig- nificance of AF in the CHF population remains the subject of controversy.

While Middelkauf et al. [7] in 1991 reported an increased mortality associat- ed with AF in CHF patients, more recent data [8, 9] did not support the con- cept that the presence and/or development of AF correlates independently with an adverse outcome during long-term follow-up. The usually observed higher mortality in AF patients seems to be related to factors other than, but related to, AF (i.e. age, left ventricular ejection fraction, NYHA class, and serum urea) and closely linked to haemodynamic control of the syndrome.

Therefore the improvement in heart failure therapy might significantly reduce the prognostic impact of this pathological rhythm on CHF patients.

U.O. Cardiologia ed UTIC, Azienda USL 6, Livorno, Italy

Multivariate models may possibly underestimate the true effect of the arrhythmic disturbance. AF, per se, may lead to haemodynamic and patho- logical changes interacting with heart failure prognosis: loss of atrial contri- bution, irregular ventricular filling, and inappropriately high ventricular rates (particularly during exercise) [8]. As a consequence, left ventricular ejection fraction (EF), exercise capacity, and peripheral perfusion decrease, worsening signs and symptoms of heart failure and NYHA functional class.

CRT has been shown to improve left ventricular contractile function and symptoms in CHF patients by reversing intraventricular dyssynchrony, opti- mising ventricular filling, and reducing mitral regurgitation [10]. Most pub- lished studies testing biventricular pacing excluded patients with chronic AF, so that few data exist for this subset of patients [1–5]. As approximately 40% of potential candidates for biventricular pacing were in AF, controlled data vali- dating the efficacy of CRT in such patients are required in order to avoid excluding a large part of the CHF population from the benefits of this therapy.

Candidates for CRT Among AF Patients: Open Questions

We will discuss data from the literature in relation to three main subsets of patients with AF and potential indication for CRT:

1. Patients with CHF and primary indication for permanent ventricular pacing owing to spontaneous slow ventricular rate or for atrioventricular (AV) nodal ablation for control of heart rate. In this group, haemodynam- ic and observational [11–14] studies suggest an additional benefit of biventricular (or left ventricular) over right ventricular pacing.

2. Patients with advanced heart failure, AF, and chronic right ventricular apical pacing. In these patients, upgrading the pacing system to a biven- tricular one provides cardiac resynchronisation and improves ventricular performance, quality of life, and symptoms of heart failure in the same manner described in patients with sinus rhythm and interventricular conduction delay who undergo biventricular pacing [15].

3. Patients with advanced heart failure and AF candidates for CRT as sup- plemental non-pharmacological therapy in refractory heart failure. Data in this field are sparse and probably non-conclusive as few randomised studies have been conducted [16–22].

Haemodynamic Studies

Haemodynamic studies investigate the short-term changes in left ventricle

(LV) mechanics during different stimulation modalities under controlled

conditions. Patients with AF provide an optimal model for examining the

isolated effect of biventricular pacing on ventricular performance indepen- dently of any AV timing considerations. By eliminating the confounding fac- tor of AV conduction on LV haemody namics during pacing one may attribute any change during different pacing modes to a ‘pure’ effect of stim- ulation on LV function [23].

In a small series, Etienne et al. [11] assessed the acute haemodynamic effect of biventricular pacing in patients with severe heart failure and AF.

Patients with congestive heart failure and sinus rhythm served as control group. The 11 patients with AF, compared with 17 patients in sinus rhythm, exhibited comparable acute haemodynamic effects of biventricular pacing in terms of capillary wedge pressure reduction, V wave amplitude reduction, and rise in systolic blood pressure (Fig. 1). These data support the hypothe- sis that biventricular pacing may be beneficial in patients with severe cardiac failure and intraventricular conduction disease, regardless of whether the patients are in sinus rhythm or in AF.

Similar results were recently reported by Hay et al. [12] in nine patients with heart failure, low EF, chronic AF, and AV nodal block (six patients with AV node ablation). This acute haemodynamic study compared biventricular- based to right univentricular pacing (apex or outflow tracts) at 80 and 120 bpm. Biventricular pacing significantly improved both systolic (dP/dt

983

± 102 vs 810 ± 83 mmHg/s, P < 0.05) and diastolic ventricular function

Fig. 1.Acute haemodynamic effects of biventricular pacing in patients with heart failure and atrial fibrillation or sinus rhythm. SBP, systolic blood pressure; V, V wave amplitude;

CWP, capillary wedge pressure. (Data from [11])

-15 -10 -5 0 5 10

mmHg

AF SR

CW P V SBP

(isovolumetric relaxation). Similar results were obtained for both methods of heart rate pacing and were not influenced by a right ventricular pacing site.

Another recent acute haemodynamic evaluation was conducted by Simantirakis et al. [13] in 12 patients who had undergone ‘ablate and pace’

therapy with biventricular pacemaker implantation [24] for drug-refractory AF. With a conductance catheter left ventricular pressure–volume loops were analysed to evaluate LV mechanics during apical right ventricular versus left ventricular pacing (left free wall or biventricular). The results confirm the superiority of left ventricular-based pacing in terms of contractile function and left ventricular filling.

Puggioni et al. [14] tested the hypothesis that left ventricular pacing was superior to right ventricular apical pacing after AV junction ablation. An acute intrapatient echocardiographic evaluation of LV performance parame- ters (EF and mitral regurgitation) and QRS width demonstrated in 44 patients the superiority of left ventricular pacing compared with right ven- tricular pacing in improving EF (EF% 43 ± 14.2 vs 40 ± 14.9, P < 0.002) and decreasing mitral regurgitation (MR score 1.5 ± 0.7 vs 1.8 ± 0.9,

cant finding of this study was that AV ablation appeared acutely to improve EF with both pacing modalities, although left ventricular-based pacing would give an additive favourable haemodynamic effect.

In summary, published data support the hypothesis of an acute superiori- ty of biventricular versus right apical pacing in terms of LV mechanics.

Acute haemodynamic data represent the basis for verifying a possible bene- ficial clinical effect of such therapy in heart failure patients with chronic AF.

Clinical Data

Few data support the hypothesis that re-synchronising a left ventricle dys- synchronised by right pacing may produce a clinical benefit on heart failure patients with AF. Leon et al. [15] evaluated 20 patients with severe heart fail- ure, permanent AF, prior AV nodal ablation, and at least 6 months of right ventricular apical pacing. All patients underwent upgrading of the pacing system from right ventricular only to biventricular. Evaluated after a mean follow-up of 17 months, patients showed a significant reduction of NYHA functional class and number of hospitalisations and a significant improve- ment of Minnesota Quality of Life scores (Table 1). These results provide evi- dence that upgrading to biventricular pacing of patients with CHF, AF, and right ventricular apical pacing reverses asynchrony and improves ventricular performance and quality of life.

Although a robust series of haemodynamic preliminary data support a

beneficial effect of biventricular pacing on left ventricular performance, few

data are available about the long-term effect of permanent biventricular stimulation in patients with advanced heart failure, AF, and no primary indi- cation for pacing. Moreover, all the haemodynamic data were obtained in patients without severe heart dysfunction.

In a preliminary report by Leclercq et al. [16] chronic biventricular pac- ing significantly improved exercise tolerance and NYHA functional class after a mean follow-up of 14 ± 9.4 months in 15 patients with advanced CHF and AF. The results in this subset of patients closely resembled those obtained in patients with normal sinus rhythm.

The only randomised trial which tried to assess the clinical efficacy and safety of CRT in patients with chronic AF was the MUSTIC study [17], a sin- gle-blind, randomised, controlled, cross-over study enrolling 59 NYHA class III patients with left ventricular systolic dysfunction, chronic AF, slow ven- tricular rate requiring permanent ventricular pacing (63% after AV nodal ablation), and wide QRS complex (paced width > 200 ms). The primary end-point was the 6-min walked distance, while secondary end-points were peak oxygen uptake, quality of life, hospitalisations, and patients’ preferred study period in relation to the different stimulation modes. The intention-to- treat analysis showed no statistically significant difference as to either pri- mary or secondary end-points between conventional right ventricular and biventricular pacing. The statistical power of the study was, however, greatly limited by a high drop-out rate, so that only 37 patients completed the cross- over phases. An important reason for this – probably underestimated when the study was being designed – was the potential deleterious haemodynamic effect of right univentricular pacing during the (6- to 12-week) observation period. In the analysis of the 37 patients in whom therapy was effectively delivered (a pacing percentage > 75% at 24-h Holter ECG recording), a sig- nificant improvement of both 6-min walked distance and peak VO

uptake was revealed during biventricular pacing. The authors therefore concluded that, with all the methodological limitations imposed by the study design,

‘effective’ biventricular pacing seems to improve exercise tolerance in this group of patients. Long-term analysis of biventricular pacing results in AF MUSTIC patients confirmed positive and stable effects over 12 months of

Baseline Follow-up P

NYHA functional class 3.4 ± 0.5 2.4 ± 0.6 < 0.001

Hospitalisations (number) 1.9 ± 0.8 0.4 ± 0.6 < 0.001 Quality of life (Minnesota score) 78 ± 24 52 ± 23 < 0.01

follow-up in terms of quality of life [18] and echocardiographic measure- ments of left ventricular reverse remodelling [19].

A not yet published study, PAVE, a controlled, randomised study, evalu- ates biventricular pacing after AV nodal ablation in patients with AF whatev- er their left ventricular systolic function or NYHA functional class [20]. The primary end-point is exercise capacity as measured by the distance walked during the 6-min walk test. Secondary end-points are functional capacity as measured by peak VO

during cardiopulmonary exercise testing and health- related quality of life as measured by SF-36 score. One hundred and two left ventricular and 82 right ventricular randomised paced patients were evaluat- ed for 6 months. In patients with chronic AF treated with AV nodal ablation, biventricular pacing produces a statistically significant improvement in functional capacity over right ventricular pacing as measured by the 6-min walk test, peak VO

(Fig. 2) and exercise duration. Most of the benefit results from a progressive improvement of functional capacity in the biventricular group as compared to the right ventricular group. Therefore, the results of the PAVE study suggest that biventricular pacing should be the preferred mode of pacing in patients undergoing AV nodal ablation for control of chronic AF.

12,8 13 13,2 13,4 13,6 13,8 14 14,2 14,4 14,6 14,8

6 weeks 6 months

ml/kg/min

RV (n=20) BV (n=51) 1.02 ml/kg/min (p<0.01)

_ 0.09 ml/kg/min

Fig. 2.Data from the PAVE study [20]. There is a significant improvement in peak VO2

between 6 weeks and 6 months only in patients with a biventricular pacing system

Finally, two recent series reported data about long-term survival of patients with advanced heart failure and AF. The first one [21], in non-ablat- ed patients who underwent biventricular pacing, demonstrated a significant- ly lower mortality in sinus rhythm patients than in those with AF (33.3% in AF vs 13.4% in SR, follow-up 36 months, P < 0.05). By contrast, when study- ing patients with AF all subjected to AV nodal ablation and biventricular pacing, Gasparini et al. [22] found a reduction of major events in 71 AF patients as compared with the sinus rhythm group (219 patients) after a mean follow-up of 27 ± 13 months (cardiac mortality 5.5%/year in sinus rhythm vs 3.4%/year in AF patients, P = n.s.).

Conclusions

It may be said that CRT has a role in improving functional capacity over con- ventional right ventricular pacing in patients with left ventricular failure who require permanent ventricular stimulation and/or in those with an indi- cation for AV nodal ablation. As for the great majority of patients with advanced heart failure and AF without conventional indications for perma- nent cardiac pacing – a wide and progressively expanding population in the

‘border zone’ of current indications for CRT – no definite data are available.

Some promising results from ablated patients show a favourable trend in major cardiac event reduction after CRT. More controlled clinical data are required to achieve definite conclusions about the indications for CRT in heart failure patients with AF.

References

1. Gras D, Mabo P, Tang T et al (1998) Multisite pacing as a supplemental treatment of congestive heart failure: preliminary results of the Medtronic Inc. InSync Study.

Pacing Clin Electrophysiol 21:2249–2255

2. Cazeau S, Leclercq C, Lavergne T et al (2001) Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 344:873–880

3. Auricchio A, Stellbrink C, Block M et al (1999) Effect of pacing chamber and atrio- ventricular delay on acute systolic function of paced patients with congestive heart failure. Circulation 99:2993–3001

4. Abraham WT, Fisher WG, Smith AC et al (2002) Cardiac resynchronization in chro- nic heart failure. N Engl J Med 346:1845–1853

5. Bristow MR, Saxon LA, Borhmen J (2004) Cardiac resynchronization therapy with or without an implantable defibrillator in advanced heart failure. N Engl J Med 350:2140–2150

6. CIBIS II Investigators and Committees (1999) The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial. Lancet 353:9–13

7. Middelkauf HR, Stevenson WG, Stevenson LW (1991) Prognostic significance of atrial fibrillation in advanced heart failure. A study of 390 patients. Circulation 84:40–48

8. Stevenson WG, Stevenson LW, Middelkauf HR et al (1996) Improving survival for patients with atrial fibrillation and advanced heart failure. J Am Coll Cardiol 28:1458–1463

9. Crijns HJGM, Tjeerdsma G, De Kam PJ et al (2000) Prognostic value of the presen- ce and development of atrial fibrillation in patients with advanced chronic heart failure. Eur Heart J 21:1238–1245

10. Kerwin WF, Botnivick EH, O’Connell JW et al (2000) Ventricular contraction abnormalities in dilated cardiomyopathy: effect of biventricular pacing to correct interventricular dyssynchrony. J Am Coll Cardiol 35:1221–1227

11. Etienne Y, Mansourati J, Gilard M et al (1999) Evaluation of left ventricular based pacing in patients with congestive heart failure and atrial fibrillation. Am J Cardiol 83:1138–1140

12. Hay I, Melenovsky V, Barry J et al (2004) Short term effects of right-left sequential cardiac resynchronization in patients with heart failure, chronic atrial fibrillation and atrioventricular nodal block. Circulation 110:3404–3410

13. Simantirakis EN, Vardakis KE, Kochiadakis GE et al (2004) Left ventricular mecha- nics during right ventricular apical or left ventricular based pacing in patients with chronic atrial fibrillation after atrioventricular junction ablation. J Am Coll Cardiol 43:1013–1018

14. Puggioni E, Brignole M, Gammage M et al (2004) Acute comparative effect of right and left ventricular pacing in patients with permanent atrial fibrillation.

Circulation 43:234–238

15. Leon AR, Greenberg JM, Kanuru N (2002) Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation. J Am Coll Cardiol 39:1258–1263

16. Leclercq C, Victor F, Alonso C et al (2000) Comparative effects of permanent biven- tricular pacing for refractory heart failure in patients with stable sinus rhythm or chronic atrial fibrillation. Am J Cardiol 85:1154–1156

17. Leclercq C, Walker S, Linde C et al (2002) Comparative effects of permanent biven- tricular and right univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J 23:1780–1787

18. Linde C, Braunschweig F, Gadler F et al (2003) Long term improvements in quality of life by biventricular pacing in patients with chronic heart failure: results from the Multisite Stimulation In Cardiomyopathy study (MUSTIC). Am J Cardiol 91:1090–1095

19. Linde C, Leclercq C, Cazeau S et al (2002) Reverse mechanical remodeling by biven- tricular pacing in congestive heart failure: one-year results from patients in atrial fibrillation in the MUSTIC (Multisite Stimulation In Cardiomyopathy) Study. J Am Coll Cardiol 39:A95–A96

20. Doshi R for PAVE study group (2004) The Left Ventricular-Based Cardiac Stimulation Post AV Nodal Ablation Evaluation Study. Late breaking clinical trials, ACC 8 March, New Orleans, LA

21. Kawabata M, Regoli F, Fantoni C et al (2004) Outcome in patients with advanced heart failure and cardiac resynchronization therapy: a comparison between sinus rhythm and atrial fibrillation. Heart Rhythm 1:S59

22. Gasparini M, Galimberti P, Simonini S et al (2004) Long term results of cardiac resynchronization therapy in patients with permanent atrial fibrillation. Heart Rhythm 1:S59

23. Nishimura RA, Hayes DL, Holmes DR et al (1995) Mechanism of haemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization haemodynamic study. J Am Coll Cardiol 25:281–288

24. Brignole M, Menozzi C, Gianfranchi L et al (1998) Assessment of atrio-ventricular junction ablation and VVIR pacemaker versus pharmacological treatment in patients with heart failure and chronic atrial fibrillation: a randomized, controlled study. Circulation 98:953–960