Controversial and Emerging Indication for CRT: Atrial Fibrillation

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Atrial Fibrillation

M. BRIGNOLE¹, P. JAÏS²

Introduction

Randomised trials have shown that in patients affected by atrial fibrillation (AF) the ‘rhythm control strategy,’ which uses medication to maintain sinus rhythm, increases the rate of hospitalisation, with no improvement in mortality and no or little symptomatic benefit, as compared with the ‘rate control strategy.’ However, both pharmacological strategies give, respectively, largely incomplete rhythm or rate control. Indeed, maintaining sinus rhythm with the use of anti-arrhythmic drugs is challenging, owing to the limited efficacy and potentially deleterious effects of the drugs [1–4]. However, the control of heart rate achievable with pharmacologic therapy is also imperfect and, in many patients, difficult to achieve. Moreover, acute studies have shown that during AF irregular RR intervals are associated with a negative haemody- namic effect, which is independent of heart rate [5], and that this effect is reversed by regularisation of the rhythm [6].

Curative catheter ablation has been established as an effective therapeu- tic option for treating atrial fibrillation that is resistant to pharmacologic rhythm control, with successful long-term maintenance of sinus rhythm without the need for anti-arrhythmic drugs [7, 8]. AV junction ablation and pacing therapy offer theoretically perfect control of heart rate; consequent- ly, the expected results are superior to those observed with drug therapy [9, 10]. Catheter ablation is easier for rate control than for rhythm control.

Creating heart block and implanting a permanent pacemaker provide regularisation of the ventricular rate, and the use of biventricular pacemakers

1Centro Aritmologico, Dipartimento di Cardiologia, Ospedali del Tigullio, Lavagna (Genua), Italy;²Hôpital Cardiologique du Haut-Lévêque and Université Victor Segalen, Bordeaux II, Bordeaux-Pessac, France

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may prevent the adverse effect of right ventricular pacing on left ventricular function [11].

Thus, both non-pharmacological strategies seem to be able to provide better (potentially optimal) rate and rhythm control than pharmacological therapies. Two recently published studies, one using AV junction ablation [10] and the other using curative left atrial catheter ablation [8] have shown a great improvement in quality of life, exercise capacity, and cardiac performance compared with the pre-ablation evaluation.

The present study compares the effect of optimal rate control (RATE) obtained with AV junction ablation and bi-ventricular pacing with optimal rhythm control (RHYTHM) obtained with catheter ablation using the populations of the above studies [8, 10].

Methods

The results of two recently published studies, one using AV junction ablation (RATE) [10] and the other using curative left atrial catheter ablation (RHYTHM) [8] have been compared. There were 56 and 58 patients, respectively, with persistent or permanent AF (with the exception of 9% of patients of the RHYTHM study who had a paroxysmal form), which was severely symptomatic and refractory to pharmacological therapy. The two populations had similar baseline characteristics except that the RATE patients were older (70 ± 8 vs 56 ± 10 years) and 50% of them had left-bundle-branch block (LBBB) (Table 1); minor differences were also present regarding gender, NYHA functional class, and left ventricular end diastolic diameter.

There were also some differences in pharmacological therapy at enrolment (Table 2). The RATE study was a prospective randomised, single-blind, 3- month cross-over comparison between right ventricular (RV) and left ventricular (LV) pacing (months 0–6) and between RV and biventricular (BiV) pacing (months 7–12); total follow-up lasted 12 months. RYHTHM was a case-control parallel study. For the purpose of the present comparison, only the 58 patients belonging to the congestive heart failure arm were considered; total follow-up lasted 12 ± 7 months. For a comprehensive description of the study protocol, inclusion and exclusion criteria, and outcome measures, refer to the original publications [8, 10].

Procedural success rate and complications as well as clinical events that occurred during the study period were compared between the two studies.

Symptoms, quality of life, exercise capacity, and echocardiographic LV function measures were compared between the 41 patients of the RATE group who completed the BiV pacing phase (i.e. at month 9 or 12) and the 34 patients of the RHYTHM group who were seen at 1-year follow-up. Symptom

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Table 1.Patients’ characteristics at enrolment. LV left ventricle, NYHA New York Heart Association classification, LVEDD left ventricular end diastolic diameter, LVESD left ventricular end systolic diameter

Rate control Rhythm control P value

group group

Number of patients 56 58

Age, years 70 ± 8 56 ± 10 0.001

Gender, males 34 (61%) 51 (88%) 0.001

Duration of atrial fibrillation, years 6.6±4.2 6.7±3.7 0.9

Persistent/permanent AF 56 (100%) 53 (91%) 0.03

Bundle-branch block 28 (50%) 0 (0%) 0.001

Holter monitoring: (on 53 patients)

Mean heart rate, bpm 88 ± 20 89 ± 11 0.7

Maximum heart rate, bpm 142 ± 41 154 ± 30 0.1

Inadequate heart rate^a 34 (61%) 29 (50%) 0.2

Associated structural heart disease

Coronary artery disease 17 (30%) 12 (21%) 0.2

Others 39 (70%) 46 (79%) 0.2

NYHA functional class 2.5 ± 0.5 2.3 ± 0.5 0.04

Standard echocardiogram:

LV ejection fraction, % 38 ± 14 35 ± 7 0.2

LV ejection fraction < 40% 33 (59%) 38 (66%) 0.3

LVEDD, mm 56 ± 9 60 ± 8 0.01

LVESD, mm 44 ± 10 46 ± 9 0.3

aInadequate ventricular rate control was defined as a mean ventricular rate < 80 bpm without exercise during Holter monitoring before the procedures

Table 2.Concomitant pharmacological therapy at enrolment

Drug Rate control Rhythm control P value

group n = 56 group n = 58

Digoxin 40 (71%) 17 (29%) 0.001

Diuretics 44 (79%) 32 (55%) 0.01

Nitrates 12 (21%) NA

Ace-inhibitors/AT-II blockers 40 (71%) 42 (72%) 0.4

Beta-blockers 29 (52%) 56 (97%) 0.001

Calcium-antagonists 11 (20%) 16 (28%) 0.2

Aspirin 4 (7%) 10 (17%) 0.09

Warfarin 47 (85%) 58 (100%) 0.001

Amiodarone 7 (12%) 41 (71%) 0.001

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and the Specific Symptom Scale in the RATE study and the 36-item Short Form of the Medical Outcome Study and the Symptom Checklist question- naires in the RHYTHM study were used to measure symptoms and quality of life. Exercise capacity was evaluated by the 6-min walked distance in the RATE study and by exercise time and capacity in the RHYTHM study.

The comparison between the two study populations was made by unpaired t test for continuous variables and by Fisher’s exact test for propor- tions. To make the measures of the two studies comparable, the intrapatient comparison that had been performed in the original study between enrolment and follow-up was reported as percentage of change. The respective percentages were then compared between the two study populations.

Results

A stable rate or rhythm control was achieved in 98% of RATE patients and in 78% of RHYTHM patients (P = 0.001). At least one procedure was necessary in 11% and 50% of patients, respectively (P = 0.001) (Table 3). Two RHYTHM patients who had heart failure symptoms after failed ablation received successful AV junction ablation and AV pacing. Severe peri-procedural complications occurred in 0% and 3% of patients (difference not significant). During a follow-up of 12 months (Table 4), compared with pre- ablation measures, NYHA class improved by 30% in RATE patients and by 39% in RHYTHM patients (difference not significant). In the RATE study, the Minnesota Living with Heart Failure Questionnaire score improved by 49%, the Specific Symptom Scale total score by 53%, and the Karolinska score by 54%. In the RHYTHM study, the Physical and the Mental summary scores of the 36-item Short Form of the Medical Outcome Study questionnaire increased by 53% and 40%, respectively, and the frequency and severity scores of the Symptom Checklist questionnaire increased by 45% and 57%, respectively (all differences not significant compared with RATE quality of life measures). In the RATE study, the 6-min walked distance increased by 19%; in the RHYTHM study, exercise time increased by 9.4% and exercise capacity by 17% (difference not significant). Congestive heart failure recurred during the follow-up in 11% of RATE and in 5% of RHYTHM patients (difference not significant). The RHYTHM patients had significantly greater improvement in LV function (+60% vs +10%, P = 0.001), reduction of LV diastolic diameters (-10% vs +2%, P = 0.001), and LV systolic diame- ters (-17% vs -5%, P = 0.001). There were six deaths in the RATE study and one in the RHYTHM study (P = 0.05). The mean age of the six patients who died in the RATE study was 75±4 years; five of those patients (83%) had LBBB.

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Discussion

This is the first attempt to compare two recent, non-pharmacological, innov- ative therapies that are not yet fully established. Although the methodologi- cal limitations of this kind of comparison are obvious, nevertheless to our knowledge no prospective randomised trial has yet been designed for this purpose, and many years of follow-up will probably be necessary before such a study can be concluded. Therefore, our results provide the background to perform a proper randomised controlled trial.

Nonetheless, the results should be interpreted with caution, taking in account the following considerations:

1. Non-pharmacological rate and rhythm control strategies are very effective in improving quality of life and exercise capacity during 1 year of follow-up. While NYHA class was used in both studies, quality of life and exercise capacity were evaluated by different outcome measures. Thus, Table 3.Procedures and outcome. CS coronary sinus

Rate control P Rhythm control

group value group

Undergoing initial 56 58 Performing initial

procedure procedure

Failures: no CS pacing (2), 6 (11%) 0.001 29 (50%) Failure:

no stable AV block (3), AF persistence

threshold increase (1):

Stable rate control 55 (98%) 0.001 45 (78%) Stable sinus rhythm

after correction after repeated ablation

(5 with drugs Severe complications 0 (0%) 0.3 2 (3%) Severe complications:

tamponade (1), stroke (1)

Length of 12 12 ± 7 Length of follow-up,

follow-up, months months

Clinical events Clinical events during

during follow-up follow-up

Death (sudden 3, 6 (11%) 0.05 1 (1%) Death

heart failure 3)*

Congestive heart failure 6 (11%) 0.2 3 (5%) Congestive heart failure

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Table 4.Improvement ofquality oflife,exercise capacity and left ventricular function during the follow-up compared with baseline evaluation. NYHANew York Hear Associaton classification,LHFQMinnesota Living with Heart Failure questionnaire,SSSSpecific Symptom Scale,SF 3636- item Short Form ofthe Medical Outcome Study questionnaire,SCLSymptom Checklist *Intrapatient comparison with baseline valves NYHA,P= 1.0;LHFQ vs SF36 physical:P=0.9;LHFQ vs SF36 mental:P=0.6;Karolinska vs SF36physical:P= 0.9;Karolinska vs SF36mental:P =0.3;SSS vs SCL frequency:P=0.6;SSS vs SCL severity:P=0.9;6-min walked distance vs exercise time:P=0.4,6-min walked distance vs exercise capacity:P=0.9;EF,P=0.001;LVEDD,P=0.001;LVESD,P=0.001 Rate control group (BIV pacing) (n = 41 patients)

Rhythm control group (n = 34 patients) Outcome measureaAbsolute improvement vs baselineImprovement vs baseline (%)P value*Outcome measureAbsolute improvement vs baselineImprovemen t vs baseline(%)P value* NYHA-0.7 ± 0.6 points out of 4300.02NYHA -0.9 ± 0.5 points out of 4390.001 Minnesota LHFQ-23 ± 16 points out of 105490.001SF 36 (physical)+24 ± 21 points out of 100530.001 Karolinska questionnaire-4.3 ± 2.6 points out of 16540.001SF 36 (mental)+21 ± 19 points out of 100400.001 SSS total-12 ± 11 points out of 60530.001SCL (frequency)-13 ± 9 points out of 64450.001 SCL (severity)-10 ± 8 points out of 64570.001 6-minute walked distance

From 293 ± 108 to 350 ± 116 m (+57 m)190.001Exercise time from 11 ± 4 to 14 ± 5 min9.40.001 Maximal exercise capacityfrom 123 ± 44 to 144 ± 55 Watts170.001 LV ejection fraction+4 ± 9 points100.004LV ejection fraction+21 ± 13 points600.001 LVEDD+1 ± 6 mm-20.2LVEDD-6 ± 6 mm100.03 LVESD-2 ± 6 mm50.02LVESD-8 ± 7 mm170.001

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the results could be compared only indirectly, by comparing the percent variations from baseline to the end of the follow-up. However, they were very similar in terms of improvement in quality of life and exercise capacity. It is likely that the greater improvement of cardiac performance obtained with the rhythm control therapy was counterbalanced by the lower procedural success rate of this therapy and by the potentially deleterious effects of antiarrhythmic drugs, which were continued in some patients.

2. Advanced age and the presence of LBBB are independently associated with poorer survival in population-based studies of patients with heart failure [12, 13]. In one study [12], patients ≥ 75 years the age of those who died in the RATE study had an odds ratio of 4.2 (CI 3.5–5.1) to die after 1 year compared to the odds ratio of 1.6 (CI 1.3–1.9) of patients age 50–64 years as which affected five of the six patients who died in the RATE study had a odds ratio of1.9 (CI 1.4–2.3) to die after 1 year compared to those without LBBB. Thus, it seems that the great difference in age and the presence of LBBB can explain sufficiently the observed difference in mortality between the two studies. The 1-year mortality rate of our population was 11%, which is very similar to that of the large series of patients affected by AF and mild-to-moderate heart failure enrolled in the V-HeFT II study [14]. In some population-based studies, mortality at 1 year was higher, ranging from 8% up to 60% [12, 13, 15]. The large disparity between patient-fatality rates observed in the RHYTHM study and the rates reported in population-based studies is due clearly to some selection criteria of the patients, making mortality rates difficult to compare.

Perspectives

What scenario is likely in the next few years? Both strategies will probably become established in clinical practice, and many patients with drug-refractory symptomatic AF will benefit from one or the other therapy. The advan- tage of a curative approach that maintains sinus rhythm should be weighed against the lower success rate, the need to perform a second procedure in many patients, and the potential for severe complications. The choice of one or the other therapy may well depend on the individual characteristics of the patients. For example, younger patients with narrow QRS and absence of LV dyssynchrony could first undergo an attempt of curative left atrial catheter ablation. Conversely, older patients with wide QRS and LV dyssynchrony will probably benefit more from resynchronisation therapy. Since the risk of arrhythmic sudden death remains a major issue, an ICD back-up should be considered in those patients with severely depressed systolic function.

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