European Heart JournaL (2005) 26, 712–722

doi:10.1093/eurheartj/ehi069

Clinical research

Comparative assessment of right, left, and

biventricular pacing in patients with permanent
atrial fibrillation
M. Brignole1*, M. Gammage2, E. Puggioni1, P. Alboni3, A. Raviele4,
R. Sutton5, P. Vardas6, M.G. Bongiorni7, L. Bergfeldt8, C. Menozzi9,

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 14, 2015

and G. Musso10 on behalf of the Optimal Pacing SITE (OPSITE)
Study Investigators
1
Department of Cardiology, Ospedali del Tigullio, Via don Bobbio, 16033 Lavagna, Italy
2
Department of Cardiology, University Hospital and University of Birmingham, Birmingham, UK
3
Department of Cardiology, Ospedale Civile, Cento, Italy
4
Department of Cardiology, Ospedale Umberto I, Mestre, Italy
5
Department of Cardiology, Royal Brompton Hospital, London, UK
6
Department of Cardiology, University Hospital, Heraklion, Greece
7
Department of Cardiology, Ospedale Cisanello, Pisa, Italy
8
Department of Cardiology, Karolinska University Hospital, Solna, Stockholm, Sweden
9
Department of Cardiology, Ospedale S Maria Nuova, Reggio Emilia, Italy
10
Department of Cardiology, Ospedale Civile, Imperia, Italy
Received 3 July 2004; revised 7 October 2004; accepted 28 October 2004; online publish-ahead-of-print 20 December 2004
See page 637 for the editorial comment on this article (doi:10.1093/eurheartj/ehi234)

Aims Left ventricular (LV) and biventricular (BiV) pacing are potentially superior to
KEYWORDS
Atrial fibrillation;
right ventricular (RV) apical pacing in patients undergoing atrioventricular (AV) junc-
Heart failure; tion ablation and pacing for permanent atrial fibrillation.
Bundle branch block; Methods and results Prospective randomized, single-blind, 3-month crossover com-
Catheter ablation; parison between RV and LV pacing (phase 1) and between RV and BiV pacing (phase
Resynchronization pacing 2) performed in 56 patients (70+8 years, 34 males) affected by severely symptomatic
permanent atrial fibrillation, uncontrolled ventricular rate, or heart failure. Primary
endpoints were quality of life and exercise capacity. Compared with RV pacing, the
Minnesota Living with Heart Failure Questionnaire (LHFQ) score improved by 2 and
10% with LV and BiV pacing, respectively, the effort dyspnoea item of the Specific
Symptom Scale (SSS) changed by 0 and 2%, the Karolinska score by 6 and 14%
(P , 0.05 for BiV), the New York Heart Association (NYHA) class by 5 and 11%
(P , 0.05 for BiV), the 6-min walked distance by 12 (þ4%) and 4 m (þ1%), and the
ejection fraction by 5 and 5% (P , 0.05 for both). BiV pacing but not LV pacing was
slightly better than RV pacing in the subgroup of patients with preserved systolic func-
tion and absence of native left bundle branch block. Compared with pre-ablation
measures, the Minnesota LHFQ score improved by 37, 39, and 49% during RV, LV, and
BiV pacing, respectively, the effort dyspnoea item of the SSS by 25, 25, and 39%,
the Karolinska score by 39, 42, and 54%, the NYHA class by 21, 25, and 30%, the
6-min walking distance by 35 (12%), 47 (16%), and 51 m (19%) and the ejection fraction
by 5, 10, and 10% (all differences P , 0.05).

* Corresponding author. Tel: þ39 0185 329569; fax: þ39 0185 306506.
E-mail address: mbrignole@asl4.liguria.it

& The European Society of Cardiology 2004. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Resynchronization pacing and atrial fibrillation
Conclusions Rhythm regularization achieved with AV-junction ablation improved
quality of life and exercise capacity with all modes of pacing. LV and BiV pacing
provided modest or no additional favourable effect compared with RV pacing.
Introduction
Pacing from the apex of the right ventricle is not
considered optimal since it provides a non-physiological
asynchronous contraction, resulting in a decrease in
cardiac performance;1,2 in addition, it causes an electro-
cardiographic pattern similar to left bundle branch block
(LBBB). In one study3 performed in patients with other-
wise normal hearts and intermittent LBBB, the advent
of LBBB was associated with a significant deterioration
of cardiac function of 10–20%. In patients with perma-
nent atrial fibrillation (AF) who have received atrioven-
tricular (AV) junction ablation and pacing from the right
ventricular (RV) apex, the beneficial haemodynamic
effect of regularization and slowing of heart rhythm is
thus assumed to be partly counteracted by the adverse
haemodynamic effect of a non-physiological pacing
mode.4
The Optimal Pacing Site (OPSITE) study is a prospective
randomized, single-blind cross-over comparison between
right, left (LV) or biventricular (BiV) pacing for patients
with permanent AF undergoing ablation and pacing
therapy. The study consisted of an acute and a chronic
evaluation. The results of the acute evaluation have
been published previously.5
In this report we present the results of the chronic
evaluation. The main study hypothesis was that LV
pacing and BiV pacing are better than RV pacing in
improving quality of life (QoL) and exercise capacity in
patients with permanent AF treated with ablation and
pacing therapy. Secondary objectives were the compari-
son between two pre-defined subgroups of patients
with preserved or depressed systolic function, and the
comparison of the two modes of pacing with baseline
measures in order to evaluate the effect of AV-junction
ablation on quality of life and exercise capacity.
Methods
Patient selection
The following patients were eligible for enrolment in the OPSITE
study: (i) patients with permanent AF in whom a clinical decision
had been made to undertake complete AV-junction ablation and
ventricular pacing because of drug-refractory, severely sympto-
matic, uncontrolled high ventricular rate, and (ii) patients
with permanent AF, drug-refractory heart failure, depressed LV
function, and/or LBBB in whom a clinical decision had been
made to undertake LV re-synchronization pacing.
Patient exclusion criteria were as follows: (i) New York Heart
Association (NYHA) class IV heart failure, despite optimized
therapy; (ii) severe concomitant non-cardiac disease; (iii) need
for surgical intervention; (iv) myocardial infarction within
3 months; (v) sustained ventricular tachycardia or ventricular
713
fibrillation; (vi) previously implanted pacemaker; (vii) inabilty
to obtain reliable RV and LV pacing and persistent AV block.
Two different subgroups were pre-defined for analysis:
patients with an ejection fraction .40% and absence of LBBB
pattern (group A); and patients with heart failure, i.e. those
with ejection fraction
40% and/or LBBB pattern (group B).
Pacemaker implantation and ablation were allowed at differ-
ent times but required to occur ,6 weeks apart. Right ventricu-
lar leads were positioned in the RV apex. LV leads were
positioned via the coronary sinus in a position considered most
appropriate by the implanting physician; in case of failure of
pacing through the coronary sinus, an epicardial lead was
implanted. A conventional dual-chamber rate-responsive pace-
maker was used; the atrial port of the pacemaker was connected
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to the LV lead and the ventricular port to the RV lead. The AV
interval of the pacemaker (the effective LV–RV interval) was pro-
grammed
30 ms in order to achieve (almost) simultaneous BiV
pacing or 200 ms during the LV phase in order to avoid RV
pacing but to assure a back-up RV pacing in case of LV pacing
failure. The pacemaker was programmed VVIR during the RV
phase. Lowest rate was set at 80 beats per min (b.p.m.).
Study design and randomization
The study was divided into two phases. Each phase consisted of a
3-month randomized crossover design:
Phase 1: comparison between RV and LV pacing
Phase 2: comparison between BiV and RV pacing
Following ablation and pacing therapy the patients underwent
randomization and phase 1 follow-up started immediately. Ran-
domization was computer-generated, blocked by centre, and
assignments were hidden from participants until the time of allo-
cation. Two different randomization sequences were generated
with phase 1 assignment linked to phase 2:
. RV to LV to RV to BiV
. LV to RV to BiV to RV
Moreover, two different randomization groups were generated
for subgroups A and B. Phase 2 started immediately after the
end of phase 1.
Endpoints
Primary endpoints were the evaluation of QoL and exercise
capacity performed at the end of each of the 3-month periods.
Secondary endpoints were the evaluation of the effects of
AV-junction ablation on QoL and exercise capacity and the
comparison between the two pre-defined subgroups.
Outcome measures
These were assessed at the time of enrolment and at the end of
each 3-month study period. QoL was measured by means of the
Minnesota Living with Heart Failure Questionnaire (LHFQ),6 the
Specific Symptoms Scale (SSS),4,7 the modified Karolinska
questionnaire,8 and the NYHA classification.9 Exercise capacity
was assessed by the 6-min walking test (average of two consecu-
tive tests).10
714
Statistical analysis
Endpoints could be assessed only in patients with no missing data
after completion of both crossover periods. Paired and unpaired
one-sided Student’s t-test was used for comparison of continuous
variables as appropriate. The z-test was used for intrapatient
comparison of proportions. The treatment–period interaction
(residual or carryover effect) was tested by a Student’s t-test
applied to the individual sums of the first and second period
data. A P-value ,0.05 was considered significant.
Sample size
In patients with severely symptomatic chronic AF, uncontrolled
by conventional drugs, the mean score of the Minnesota LHFQ
was 44 and decreased to 32 after AV-junction ablation and
pacing,4 the highest score of the SSS (6.5 points) was related
to effort dyspnoea and decreased to 4.5 after AV-junction abla-
tion and pacing.4 The minimum chance necessary to allow 99%
confidence that a real change of the 6-min walked distance
has occurred is 10% of the average performance, using the
averaged results of two consecutive tests at baseline.10 Based
on these results, a 20% reduction of the Minnesota LHFQ and of
the effort dyspnoea item of the SSS, and a 10% increase in the
6-min walked distance were pre-determined as the minimum
requirements for superiority of LV-based pacing over RV pacing
of sufficient clinical relevance. The sample size able to provide
90% power to show an intrapatient difference, with a probability
of 95%, was 40 patients.
Figure 1 Patient flow. SD, sudden death; CHF, congestive heart failure.
M. Brignole et al.
Results
Participant flow and follow-up
Fifty-six patients underwent successful pacemaker
implantation and AV-junction ablation and were random-
ized between July 2001 and January 2003 (Figure 1 ).
Their clinical characteristics are shown in Table 1. RV
leads were positioned in the RV apex in all patients. LV
leads were positioned via the coronary sinus in the mid-
posterolateral site in 51 patients and in the anterior
site in three patients. In two patients, who had failed
the coronary sinus approach, the lead was implanted
in an epicardial mid-posterolateral position through a
limited thoracotomy.
Six patients died during the year of the study, account-
ing for an 11% mortality rate; of these, three died sud-
denly and three from heart failure. During phase 2 of
the study, six other patients dropped out because of a
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progressive deterioration in their general condition,
mostly due to worsening heart failure. Thus, overall, 12
patients (21%) had severe clinical events during the
study period, six during RV pacing and six during LV/BiV
pacing. Finally, three patients refused to complete the
follow-up. In two patients, AV conduction resumed
after a few days and a second ablation procedure was
rapidly performed, which achieved persistent AV block;
in one patient a transient increase in LV pacing threshold
occurred during phase 1. These patients were included in
Resynchronization pacing and atrial fibrillation 715

the analysis. Pharmacological therapy remained stable
from baseline and during the crossover phases (Table 2 ).
Phase 1
Fifty-two patients completed phase 1. QRS duration was
173 + 29 ms with RV pacing and 175 + 28 ms with LV
pacing.
Compared with RV pacing, the improvement with LV
was modest and only echocardiographic variables
showed statistically significant changes (Table 3 ). Con-
versely, a great improvement was observed from baseline
to both RV and LV modes for all variables. For example,
the Minnesota LHFQ improved by only 2% from RV to LV
pacing and 37 and 39% from baseline to RV and LV
pacing, respectively. LV pacing led to no improvement
in effort dyspnoea score of the SSS from RV to LV
pacing, whereas the improvement from baseline to RV
and LV pacing was 25%. The Karolinska score improved
by 6% from RV to LV pacing, and 39 and 42% from baseline
to RV and LV pacing, respectively. The NYHA class
improved by 5% from RV to LV pacing, and 21 and 25%
from baseline to RV and LV pacing, respectively. The
6-min walked distance increased by 12 m (4%) from RV
to LV pacing, and 35 (12%) and 47 m (16%) from baseline
to RV and LV pacing, respectively.
Compared with RV, ejection fraction significantly
improved by 5% and mitral regurgitation score decreased
by 18% with LV pacing (Table 3 ).
At the end of phase 1, 23 (44%) patients preferred LV
pacing, 16 (31%) RV pacing, and 13 (25%) had no prefe-
rence (P ¼ 0.04).
Phase 2
Forty-one patients completed both phase 1 and 2. In

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phase 2, QRS duration was 170 + 29 ms with RV pacing
and 156 + 29 ms with BiV pacing (P ¼ 0.001).
Table 1 Patients’ characteristics at enrolment Compared with RV pacing, BiV pacing showed a signifi-
cant improvement in Karolinska questionnaire and NYHA
Number of patients 56
Age, years 70 + 8
class but not in the other measures of QoL. In absolute
Gender, males 34 (61) terms, however, the improvement was modest and much
Duration of atrial fibrillation, years 6.6 + 4.2 less than that observed from baseline to RV and BiV
Number of hospitalizations per patient 3.4 + 2.2 pacing for all variables (Table 4). For example, the Minne-
NYHA functional class 2.5 + 0.5 sota LHFQ improved by 10% from RV to BiV pacing, and 43
Minnesota LHFQ, score 47 + 18 and 49% from baseline to RV and BiV pacing, respectively.
Six-minute walking test, m 294 + 100 The effort dyspnoea score of the SSS improved by 2%
Standard electrocardiogram: from RV to BiV pacing, and 38 and 39% from baseline to
Mean heart rate, b.p.m. 99 + 24 RV and BiV pacing. The Karolinska score improved by 14%
LBBB 28 (50)
from RV to BiV pacing, and 47 and 54% from baseline to
Holter monitoring:
Minimum heart rate, b.p.m. 66 + 30
RV and BiV pacing. The NYHA class improved by 11% from
Mean heart rate, b.p.m. 88 + 20 RV to BiV pacing, and 22 and 30% from baseline to RV and
Maximum heart rate, b.p.m. 141 + 38 BiV pacing. The 6-min walked distance increased by 4 m
Standard echocardiogram: (1%) from RV to BiV pacing, and 53 (18%) and 57 m (19%)
mean ejection fraction 38 + 14 from baseline to RV and BiV pacing. Conversely, the
Associated structural heart disease palpitation score of the SSS worsened significantly with
Coronary artery disease 17 (30) both LV and BiV pacing.
Others 39 (70) Compared with RV, ejection fraction significantly
Data are mean (standard deviation) or number (%).
improved by 5% and mitral regurgitation score decreased
by 25% with BiV pacing (Table 4 ).

Table 2 Concomitant pharmacological therapy throughout the study

Drug Baseline, n ¼ 52 (%) Randomization, n ¼ 52 (%) Phase 1, n ¼ 52 (%) Phase 2, n ¼ 41 (%)

RV LV RV BiV

Digoxin 38 (73) 32 (61) 34 (65) 32 (62) 24 (59) 24 (59)

Diuretics 41 (79) 41 (79) 42 (81) 42 (81) 33 (80) 34 (83)
Nitrates 10 (19) 9 (17) 10 (19) 10 (19) 11 (27) 11 (27)
ACE-inhibitors 38 (73) 40 (77) 36 (69) 36 (69) 31 (76) 28 (68)
Beta-blockers 28 (54) 27 (52) 27 (52) 25 (48) 20 (49) 19 (46)
Calcium-antagonists 11 (21) 7 (13) 7 (13) 6 (12) 4 (10) 3 (7)
Aspirin 4 (8) 4 (8) 3 (6) 4 (8) 3 (7) 5 (12)
Warfarin 44 (85) 48 (92) 50 (96) 48 (92) 38 (93) 35 (85)
Amiodarone 5 (10) 3 (6) 3 (6) 1 (2) 1 (2) 1 (2)
Others 15 (29) 12 (23) 16 (31) 13 (25) 6 (15) 6 (15)

ACE, angiotensin-converting enzyme.

 716
Table 3 Baseline and phase 1 results in the 52 patients who completed the phase 1 period

Baseline Phase 1 RV1 vs. baseline LV vs. baseline

RV1 LV Difference (95% CI) P Difference (95% CI) P Difference (95% CI) P

LHFQ, score (range 1–105) 46.7 + 17.7 29.4 + 19.9 28.7 + 18.9 20.7 (24.7; þ 3.2) 0.36 217.3 (211.7;222.9) 0.001 218.0 (212.5; 2 23.5) 0.001
SSS score (range 1–10)
Palpitations 5.7 + 3.0 1.5 + 2.2 1.7 + 2.1 þ0.2 (20.3; þ 0.7) 0.31 24.2 (25.3;23.1) 0.001 24.0 (25.1;22.9) 0.001
Effort dyspnoea 6.4 + 2.7 4.8 + 2.8 4.8 + 2.9 0 (20.8; þ 0.8) 0.50 21.6 (22.6;20.6) 0.001 21.6 (22.8;20.4) 0.001
Rest dyspnoea 2.8 + 3.2 1.4 + 2.2 1.3 + 1.8 20.1 (20.7; þ 0.5) 0.29 21.4 (22.2;20.6) 0.001 21.5 (22.3;20.7) 0.001
Effort intolerance 6.4 + 2.5 4.6 + 3.1 4.6 + 2.8 0 (20.7;þ0.7) 0.41 21.8 (22.7;20.9) 0.001 21.8 (22.7;20.9) 0.001
Easy fatigue 2.7 + 2.5 1.8 + 2.4 1.8 + 2.2 0 (20.7; þ 0.7) 0.48 20.9 (21.7;20.1) 0.01 20.9 (21.7; 2 0.1) 0.004
Chest discomfort 1.9 + 2.7 0.6 + 1.6 0.9 + 1.9 þ0.3 (20.3; þ 0.9) 0.14 21.6 (22.4;20.9) 0.001 21.0 (21.7;20.3) 0.01
Karolinska, score (range 0–16) 8.0 + 2.9 4.9 + 3.4 4.6 + 3.4 20.3 (21.1; þ 0.5) 0.25 23.1 (23.9;22.5) 0.001 23.4 (24.2;22.6) 0.001
NYHA class (range 1–4) 2.4 + 0.6 1.9 + 0.8 1.8 + 0.8 20.1 (20.3; þ 0.1) 0.10 20.5 (20.7;20.3) 0.001 20.6 (20.8;20.4) 0.001
Six-minute walked distance, m (average of 2) 291 + 105 326 + 124 338 + 127 þ12 (þ37; 2 13) 0.13 þ35 (þ65;þ5) 0.01 þ47 (þ75;þ26) 0.003
Echocardiographic measures
Ejection fraction, % 39 + 14 41 + 15 43 + 15 þ2 (0; þ 4) 0.04 þ2 (21;þ5) 0.04 þ4 (þ2;þ6) 0.001
LVEDD, mm 56 + 9 57 + 10 56 + 9 21 (22;0) 0.06 þ1 (0;þ2) 0.09 0 (21;þ1) 0.26
LVESD, mm 44 + 10 43 + 11 42 + 12 21 (22;0) 0.02 21 (23;þ1) 0.32 22 (0; þ 4) 0.04
Mitral regurgitation, score (range 1–4) 1.7 + 0.7 1.7 + 0.9 1.4 + 0.7 20.3 (20.5; 2 0.1) 0.001 0 (20.2;þ0.2) 0.15 20.3 (20.5;20.1) 0.001

LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter.

Table 4 Baseline and phase 2 results in the 41 patients who completed the study period
Baseline Phase 2 RV2 vs. baseline BiV vs. baseline

RV2 BiV Difference (95% CI) P Difference (95% CI) P Difference (95% CI) P

LHFQ, score range 1–105) 46.7 + 18.5 26.7 + 20.3 24.0 + 19.1 22.7 (26.4;þ1.0) 0.08 220 (226.4;213.6) 0.001 222.7 (227.8;217.6) 0.001
SSS score (range 1–10)
Palpitations 5.5 + 3.1 1.0 + 1.6 1.8 + 2.8 þ0.8 (0;þ1.6) 0.04 24.5 (25.7;23.3) 0.001 23.7 (25.1;22.3) 0.001
Effort dyspnoea 6.4 + 2.6 4.0 + 2.9 3.9 + 2.8 20.1 (21.1;þ0.9) 0.44 22.6 (23.8;21.4) 0.001 22.5 (23.8;21.2) 0.001
Rest dyspnoea 2.7 + 3.3 1.2 + 2.0 1.1 + 2.1 20.1 (21.0;þ0.8) 0.45 21.5 (22.4;20.6) 0.001 21.6 (22.5;20.7) 0.001
Effort intolerance 5.9 + 2.4 3.3 + 2.8 3.9 + 3.3 þ0.6 (20.4;þ1.6) 0.12 22.6 (23.6;21.6) 0.001 22.0 (23.220.8) 0.001
Easy fatigue 2.3 + 2.7 1.4 + 2.1 1.4 + 2.4 0 (20.5;þ0.5) 0.38 21.0 (21.8;20.2) 0.001 20.9 (21.5;20.3) 0.004
Chest discomfort 2.0 + 2.7 0.8 + 1.9 1.1 + 2.1 þ0.3 (20.5;þ1.1) 0.27 21.3 (22.3;20.3) 0.001 20.9 (21.8;20) 0.01
Karolinska, score (range 0–16) 7.9 + 2.9 4.2 + 3.1 3.6 + 2.8 20.6 (21.2;0) 0.03 23.9 (24.8;23.0) 0.001 24.3 (25.2;24.4) 0.001
NYHA class (range 1–4) 2.3 + 0.6 1.8 + 0.7 1.6 + 0.7 20.2 (20.4;0) 0.03 20.5 (20.7;20.3) 0.01 20.7 (20.9;20.5) 0.02
Six-minute walked distance, m (average of 2) 293 + 108 346 + 138 350 + 116 þ4 (þ16;28) 0.27 þ53 (þ81;þ28) 0.01 þ57 (þ92;þ22) 0.001

M. Brignole et al.
Echocardiographic measures
Ejection fraction, % 41 + 12 43 + 11 45 + 13 þ2 (0;þ4) 0.02 þ2 (21;þ5) 0.16 þ4 (þ7;þ1) 0.004
LVEDD, mm 54 + 7 56 + 8 55 + 8 21 (22.5;þ0.5) 0.25 þ2 (þ1;þ3) 0.10 þ1 (0;þ2) 0.17
LVESD, mm 42 + 8 41 + 9 40 + 10 21 (22;0) 0.01 21 (23;þ1) 0.29 22 (0;þ4) 0.02
Mitral regurgitation, score (range 1–4) 1.6 + 0.7 1.6 + 0.7 1.2 + 0.4 20.4 (20.6;20.3) 0.001 0 (20.2;þ0.2) 0.53 20.4 (20.6;20.2) 0.001

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Resynchronization pacing and atrial fibrillation
Figures 2, 3, and 4 evaluate the effect of the two
sequences of randomization and the treatment–period
interaction (residual or carryover effect) of the Minne-
sota LHFQ, the 6-min walked distance, and the ejection
fraction. No statistical difference was observed except
from baseline.
The intrapatient comparison of the differences RV–LV
and RV–BiV performed on the 41 patients showed no
significant difference in any variable (Table 5).
At the end of phase 2, 25 (61%) patients preferred BiV
pacing, 8 (20%) RV pacing, and 8 (20%) had no preference
(P ¼ 0.001).
Subgroup analysis
Among the patients who completed phase 1, 19 belonged
to group A and 33 to group B (25 of group B had
LBBB) (Table 6 ). The ejection fraction was 53+8
and 31 + 10%, and the QRS width was 100 + 12 and
144 + 28 ms, respectively, in groups A and B. The
effects of LV vs. RV pacing were not statistically different
in the two groups.
Among the patients who completed phase 2, 17
belonged to group A and 24 to group B (18 of group B
had LBBB) (Table 7 ). There was a trend towards a
better outcome with BiV pacing in group A as suggested
by the significantly higher improvement in easy fatigue
score, NYHA class, 6-min walked distance, ejection frac-
tion, and of the Minnesota LHFQ and Karolinska score,
although the latter is not significant.
Discussion
Primary endpoints were QoL and exercise capacity.
Although we observed a modest significant improvement
in a few measures, especially with BiV pacing, in general
we were unable to show a definite superiority of LV-based
pacing over RV pacing. In absolute terms, the improve-
ment was modest for any variable and inferior to the
minimal level of clinical efficacy with the exception of
a few parameters with BiV pacing in the subgroup of
patients with preserved systolic function and narrow
QRS. The study was powered to show a minimum
benefit of clinical relevance, defined as an improvement
Figure 2 Effect of the two sequences of randomization and the treatment–period interaction (residual or carryover effect) on the Minnesota LHFQ.
717
of 20% of QoL scores and 10% of the 6-min walked
distance; these values were chosen based on the results
of previous trials (see Methods). The changes resulting
from the present study were far lower. Even if some
improvement of minor degree may still be present, its
clinical utility seems modest. For example, the
maximum possible improvement of the Minnesota LHFQ,
corresponding to the upper 95% of the confidence inter-
val, was 4.7 points, of a total of 105, for LV vs. RV
pacing and 6.4 points for BiV pacing and the maximum
improvement of the 6-min walked distance was 37 and
16 m, respectively. The same reasoning applies to the
other outcome measures.
The situation is almost certainly one in which some
patients are showing marked clinical benefit, balanced
by other patients with very little benefit. In Table 8 we
have reported the percentage of patients who showed a
benefit from one mode with respect to the other of suffi-
cient entity to be clinically relevant. Up to a quarter of
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patients were better with RV pacing than with LV or BiV
pacing. Only a quarter or less of the patients had
a relevant objective benefit from LV or BiV pacing. Thus
a heterogeneity effect of resynchronization therapy is
present in patients with AF.
In contrast, the improvement in QoL observed with the
rhythm regularization obtained with AV-junction ablation
and RV pacing was much more impressive, being in
general from 3 to 10 times higher than that obtained
from RV to LV or BiV pacing. For example, the effect of
ablation and RV pacing on the Minnesota LHFQ deter-
mined an improvement of 37–43% whereas the additive
effect of LV or BiV pacing was only a further 2–10%.
Admittedly, the evaluation of AV-junction ablation was
not controlled and a part of the total benefit was not
due to ablation alone. A previous study has evaluated
that a placebo effect of pacing may account for 9–40%
of the total improvement of NYHA class and of the
SSS;7 in another study4 the control arm treated with
pharmacological therapy had an improvement of 7% in
the NYHA class and of 16% in the Minnesota LHFQ.
The improvement in QoL measures with LV and BiV
pacing is consistent with that of the ejection fraction
at the end of each 3-month crossover phase in this
study—which was 5 and 5%—and that observed during
the acute study performed immediately after
718
Figure 3 Effect of the two sequences of randomization and the treatment–period interaction (residual or carryover effect) on the 6-min walked distance.
Figure 4 Effect of the two sequences of randomization and the treatment–period interaction (residual or carryover effect) on the ejection fraction.
AV-junction ablation, which was 6%.5 An improvement of
ejection fraction was also observed by Leclercq et al. 11
and by Leon et al. 12 The improvement of ejection frac-
tion was due to a reduction of both end-diastolic and
end-systolic diameters (Tables 3 and 4 ) and suggests a
beneficial influence of resynchronization pacing on the
heart. It is possible that the duration of the present
study is too short to show functional benefit over the
benefit of rate control (as experienced in the ROVA
trial13) and that a longer observation period could allow
the potential benefit of resynchronization therapy to
become more manifest.
Only a few other studies have evaluated the effect of
LV-based pacing on QoL of the patients with AF and none
have evaluated its effect on mortality. In the AF arm of
the only other randomized clinical study, the MUSTIC
trial,14 performed on 39 evaluable patients, the
intention-to-treat analysis did not show any statistically
significant difference in either primary or secondary
endpoints and efficacy analysis showed only slight
significant difference in a few endpoints between BiV and
RV pacing.
It seems likely that the main reason for the modest
effect of LV-based pacing in patients with AF is that it is
additive to the powerful beneficial effect of rhythm regu-
larization and slowing achieved with AV-junction ablation
M. Brignole et al.
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per se, which reduces the amount of the potential
additional benefits obtainable through LV or BiV pacing,
at least over the time frame of this study. The beneficial
effect of ablation and RV pacing is well known from both
haemodynamic5,15–18 and clinical studies.4,7,19–21
This situation does not occur in patients in sinus rhythm
undergoing resynchronization therapy.
Comparison with patients in sinus rhythm
The effect of resynchronization therapy in patients in
sinus rhythm seems to be different from the effect in
those in AF. There is increasing evidence for the favour-
able effect of cardiac resynchronization pacing in
patients with heart failure and intraventricular con-
duction delay who are in sinus rhythm.22–25 In the sinus
rhythm arm of the single-blind, crossover MUSTIC
trial,22 the Minnesota LHFQ improved by 13 points (32%)
and the 6-min walked distance improved by 73 m (23%)
with BiV pacing compared with no pacing. Auricchio
et al.,23 in a single-blind crossover study, showed
an improvement in the Minnesota LHFQ by eight
points (29%), of 6-min walked distance by 47 m
(12%) with LV pacing vs. no pacing. In the single-blind,
parallel-controlled, randomized MIRACLE trial,24 the
Minnesota LHFQ score improved by nine points and
Resynchronization pacing and atrial fibrillation 719

Table 5 Phase 1 and phase 2 results in the 41 patients who completed the study period

Phase 1 Phase 2 Diff. phase 1 vs.

diff. phase 2

RV1 LV P RV2 BiV P P

LHFQ, score (range 1–105) 29.1 + 19.3 27.0 + 17.8 0.16 26.7 + 20.3 24.0 + 19.1 0.08 0.47
SSS score (range 1–10)
Palpitations 1.3 + 2.1 1.8 + 2.2 0.04 1.0 + 1.6 1.8 + 2.8 0.04 0.33
Effort dyspnoea 4.8 + 2.9 4.8 + 3.0 0.48 4.0 + 2.9 3.9 + 2.8 0.44 0.46
Rest dyspnoea 1.5 + 2.1 1.3 + 2.1 0.32 1.2 + 2.0 1.1 + 2.1 0.45 0.36
Effort intolerance 4.3 + 3.0 4.4 + 2.8 0.39 3.3 + 2.8 3.9 + 3.3 0.12 0.29
Easy fatigue 1.7 + 2.3 1.6 + 2.3 0.41 1.4 + 2.1 1.4 + 2.4 0.38 0.34
Chest discomfort 0.7 + 1.8 1.0 + 1.9 0.21 0.8 + 1.9 1.1 + 2.1 0.27 0.44
Karolinska, score (range 0–16) 4.6 + 3.3 4.5 + 3.2 0.38 4.2 + 3.1 3.6 + 2.8 0.03 0.11
NYHA class (range 1–4) 1.8 + 0.8 1.6 + 0.6 0.03 1.8 + 0.7 1.6 + 0.7 0.03 0.35
Six-minute walked distance, 340 + 133 348 + 135 0.30 346 + 138 350 + 116 0.27 0.22
m (average of 2)
Echocardiographic measures

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Ejection fraction, % 43 + 15 46 + 14 0.03 43 + 11 45 + 13 0.02 0.40
LVEDD, mm 56 + 8 55 + 7 0.05 56 + 8 55 + 8 0.25 0.29
LVEDS, mm 42 + 10 40 + 9 0.01 41 + 9 40 + 10 0.01 0.19
Mitral regurgitation, 1.7 + 0.8 1.3 + 0.6 0.001 1.6 + 0.7 1.2 + 0.4 0.001 0.42
score (range 1–4)

Table 6 Subgroup analysis, phase 1: comparison between group A and group B patients

Group A (n ¼ 19) Group B (n ¼ 33) Diff. Gr. A vs.

diff. Gr. B

RV1 LV P RV1 LV P P

LHFQ, score (range 1–105) 24.3 + 18.0 24.5 + 14.1 0.47 32.4 + 20.5 31.1 + 21.0 0.32 0.49
SSS score (range 0–10)
Palpitations 0.8 + 1.2 1.4 + 1.8 0.09 1.9 + 2.5 1.8 + 2.3 0.40 0.13
Effort dyspnoea 4.0 + 2.4 3.9 + 2.6 0.47 5.2 + 2.9 5.2 + 3.1 0.47 0.46
Rest dyspnoea 1.0 + 1.9 0.5 + 0.9 0.16 1.7 + 2.4 1.7 + 2.1 0.47 0.19
Effort intolerance 4.0 + 2.4 3.9 + 1.9 0.43 4.8 + 3.4 5.1 + 3.1 0.34 0.35
Easy fatigue 1.8 + 2.4 1.2 + 2.1 0.11 1.8 + 2.4 2.1 + 2.3 0.27 0.11
Chest discomfort 0.3 + 0.6 0.4 + 0.6 0.37 0.8 + 2.0 1.2 + 2.2 0.15 0.26
Karolinska, score (range 0–16) 4.4 + 3.1 3.2 + 1.9 0.05 5.2 + 3.6 5.4 + 3.9 0.80 0.07
NYHA class (range 1–4) 1.4 + 0.5 1.4 + 0.5 0.50 2.2 + 0.9 1.9 + 0.8 0.08 0.13
Six-minute walked distance, 331 + 102 324 + 100 0.33 322 + 137 348 + 143 0.05 0.07
m (average of 2)
Echocardiographic measures
Ejection fraction, % 53 + 11 54 + 10 0.12 35 + 13 37 + 13 0.09 0.41
LVEDD, mm 51 + 6 50 + 5 0.12 61 + 10 60 + 9 0.14 0.42
LVEDS, mm 37 + 8 34 + 6 0.002 47 + 11 46 + 12 0.28 0.06
Mitral regurgitation, 1.8 + 0.9 1.3 + 0.6 0.02 1.7 + 0.8 1.4 + 0.8 0.03 0.11
score (range 1–4)

the 6-min walked distance by 29 m in paced vs. not paced
patients. In the double-blind, parallel-controlled
MIRACLE ICD trial,25 the Minnesota LHFQ improved by a
median of 6.5 points, NYHA class by 1.0 point, treadmill
exercise duration by 66 s whereas the 6-min walked dis-
tance increased by only 2 m.
Apart from the specific effect of AV-junction ablation,
there are other differences between patients in
sinus rhythm and in AF that could explain different
clinical results. In sinus rhythm patients, the optimal
resynchronization occurs with the fusion of intrinsic RV
activation and paced LV activation, which is dependent
on AV synchronization.26 Clearly, after ablating the
AV-junction, intrinsic rhythm is not conducted and thus
fusion is not possible. Typically, patients enrolled in sinus
rhythm have very low ejection fraction values and wide
QRS complexes. In our study the mean ejection fraction
was 38 + 14% and only half had LBBB. Despite the fact
720 M. Brignole et al.

Table 7 Subgroup analysis, phase 2: comparison between group A and group B patients

Group A (n ¼ 17) Group B (n ¼ 24) Diff. Gr. A vs.

diff. Gr. B

RV2 BiV P RV2 BiV P P

LHFQ, score (range 1–105) 24.7 + 18.4 19.0 + 19.1 0.04 28.4 + 21.7 27.3 + 18.9 0.39 0.11
Specific symptom scale,
score (range 0–10)
Palpitations 0.6 + 1.4 1.3 + 2.6 0.18 1.3 + 1.7 2.1 + 2.9 0.08 0.47
Effort dyspnoea 3.1 + 2.2 2.9 + 2.5 0.42 4.5 + 3.2 4.5 + 2.8 0.50 0.31
Rest dyspnoea 0.5 + 1.3 0.4 + 0.7 0.31 1.6 + 2.3 1.6 + 2.6 0.44 0.21
Effort intolerance 3.4 + 2.5 3.6 + 3.2 0.38 3.3 + 3.1 4.0 + 3.0 0.10 0.06
Easy fatigue 1.3 + 2.0 0.6 + 1.0 0.07 1.4 + 2.2 1.9 + 2.8 0.06 0.02
Chest discomfort 0.1 + 0.3 0.5 + 1.3 0.13 1.2 + 2.4 1.4 + 2.5 0.24 0.45
Karolinska, score (range 0–16) 3.3 + 2.2 2.1 + 1.6 0.03 4.9 + 3.5 4.9 + 3.0 0.24 0.09
NYHA class (range 1–4) 1.5 + 0.6 1.3 + 0.5 0.05 1.9 + 0.8 1.8 + 0.8 0.20 0.28
Six-min walked distance, 332 + 106 361 + 109 0.03 367 + 154 352 + 125 0.30 0.05
m (average of 2)

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Echocardiographic measures
Ejection fraction, % 49 + 8 53 + 9 0.001 39 + 10 39 + 13 0.38 0.02
LVEDD, mm 52 + 6 51 + 6 0.11 58 + 8 58 + 7 0.45 0.29
LVEDS, mm 37 + 7 34 + 7 0.001 45 + 9 43 + 10 0.15 0.18
Mitral regurgitation, 1.7 + 0.9 1.3 + 0.6 00.02 1.5 + 0.6 1.1 + 0.3 00.002 0.36
score (range 1–4)

Table 8 Analysis of heterogeneity: interpatient variability

Differences between mode of pacing Phase 1 (n ¼ 52) Phase 2 (n ¼ 41)

RV1 better LV better P RV2 better BiV better P

LHFQ, difference 10 points, % pts 12 (23) 10 (19) 0.52 5 (12) 5 (12) 1.00
SSS
Palpitations, difference 2 points 8 (16) 6 (12) 0.38 6 (15) 2 (5) 0.07
Effort dyspnoea, difference 2 points 10 (20) 13 (25) 0.37 7 (17) 10 (24) 0.21
Rest dyspnoea, difference 2 points 6 (12) 5 (10) 0.60 2 (5) 3 (7) 0.67
Effort intolerance, difference 2 points 7 (14) 8 (16) 0.78 7 (17) 7 (17) 0.99
Easy fatigue, difference 2 points 7 (14) 6 (12) 0.61 2 (5) 3 (7) 0.67
Chest discomfort, difference 2 points 3 (6) 2 (4) 0.78 4 (10) 3 (7) 0.80
Karolinska, difference 2 points 13 (25) 12 (23) 0.75 4 (10) 11 (27) 0.004
NYHA, difference 1 class 5 (10) 11 (21) 0.007 4 (10) 9 (22) 0.04
Six-minute walked distance, difference 50 m 5 (12) 13 (25) 0.004 5 (12) 6 (15) 0.74

Data are number (%).

that the mean LV ejection fraction was only moderately
diminished, we observed a high mortality of 11% during
the 1-year follow-up. In the MIRACLE trial,24 patients in
sinus rhythm had a mortality of 6.1% at 6 months with
an ejection fraction of about 22%.
Subgroup analysis
The clinical results were similar or even better, with BiV
pacing, in the patients with preserved systolic function
and no LBBB than in the other subgroup. This finding is
original and confirms the haemodynamic effect seen in
the acute study.5 In contrast, in sinus rhythm patients,
a benefit was seen in patients with QRS duration
.150 ms but not in those with a QRS duration of
120–150 ms.23 However, this finding needs to be verified
in a larger population.
Comparison between LV and BiV pacing
Theoretically, in the absence of fusion between intrinsic
RV activation and paced LV activation, pre-excitation of
the left ventricle alone may create delayed activation
of the septum and right ventricle, which might worsen
ventricular pump function, analogous to the deficits gen-
erated by RV-only pacing. In the present study, BiV pacing
resulted in a greater shortening of the QRS duration,
possibly indicating better ventricular synchronization.
As a result, BiV pacing may be more effective than LV
pacing in AF patients. The study was, however, not
designed for this comparison. A comparison between
Resynchronization pacing and atrial fibrillation
phases 1 and 2 cannot be performed because of the
different populations due to several drop-outs in phase
2. Among the patients who completed both phases of
the study, we were unable to find any statistical differ-
ence between LV and BiV pacing except for an advantage
of BiV but not for LV pacing in subgroup A patients
(Table 7 ). Finally, the study is probably underpowered
to show small differences between the two modes of
pacing. Thus, we believe that it is prudent not to draw
any conclusion in this respect.
Study power
Although the study population was small, it is unlikely
that even with a larger population we would have
observed clinically important favourable results on
the primary endpoints of the study. The improvement
in QoL was lower than expected (see Sample size
section). For example, the increase in the 6-min walked
distance was 4% (95% CI 24% to þ10%) in phase 1 and
1% (95% CI 25% to þ7%) in phase 2; the decrease in the
LHFQ score was 22% (95% CI þ11% to 216%) in phase 1
and 210% (95% CI þ4% to –24%) in phase 2.
Limitations
Selection bias might have been introduced into the com-
parison of BiV and RV. Fifteen patients dropped out from
the study before the termination of phase 2. The study
population included for the comparison between RV and
BiV in the second phase depends on the outcome of
the first phase and is therefore not necessarily the
population of interest. Even if not significant, some
treatment–period interaction could have been present.
On the other hand, the similarity of measures between
the two RV periods (one in phase 1 and the other in
phase 2) suggests stability of clinical condition. There-
fore, the clinical significance of the study remains, i.e.
BiV pacing provided modest additive clinical benefit to
that already achieved with AV-junction ablation and BiV
pacing benefits are not very different from those
obtained with LV pacing alone.
Conclusions and perspectives
Rhythm regularization achieved with AV-junction ablation
improved QoL and exercise capacity with all modes of
pacing. LV and BiV pacing provided modest or no
additional favourable effect compared with RV pacing
during the 3-month observation period. Results are het-
erogeneous due to a large interpatient variability,
suggesting the need for different methods of patient stra-
tification. The favourable effect of BiV pacing in the sub-
group of patients with preserved systolic function and
narrow QRS is interesting but needs further validation.
A longer observation period could have enhanced the
adverse haemodynamic effect of non-physiological RV
pacing, thus allowing the potential benefit of LV-based
pacing therapy to become manifest. However, the study
confirms that ventricular rate control and RV pacing is a
very effective and attractive therapy for patients with
721
permanent AF and refractory heart failure.4,13 LV or BiV
pacing cannot be recommended as a first line treatment
for all patients with AF and should probably be restricted
and delayed being offered to patients who have no
benefit from RV pacing alone or have deterioration in
their clinical condition late after ablation. Delayed BiV
upgrading was very effective in a prospective uncon-
trolled study.12 Alternatively, if the predictive value of
tissue-Doppler echocardiography or other imaging tech-
niques is also confirmed in patients with AF as it has
been in sinus rhythm,27 these techniques could help
provide a better stratification at the time of ablation
and pacing therapy.
Appendix
Study organization: The OPSITE study is independent
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from industry. It is officially endorsed by the Working
Group on Pacing of the European Society of Cardiology.
The Steering Committee designed the study protocol
as described in this document. All data were collected
and processed by the Study Co-ordinating Centre in
Lavagna. The Steering Committee was supported by
a limited grant from Vitatron, The Netherlands, and
St Jude Medical, Italy. Both companies agreed not to
interfere with the scientific issues of the study.
Steering committee: M. Brignole (co-chair), M. Gammage
(co-chair), P. Alboni, A. Raviele, R. Sutton, P. Vardas.
Executive committee: M. Brignole, M. Gammage.
Data and statistical analysis: M. Brignole, M. Gammage,
E. Puggioni.
Participating centres and investigators (number of
patients in brackets): Ospedali del Tigullio, Lavagna
(17): Puggioni E, Lupi G, Brignole M; Ospedale S Chiara,
Pisa (8): Soldati E, Bongiorni MG; Karolinska Hospital,
Stockholm (7): Gadler F, Bergfeldt L; University Hospital,
Eraklion (6): Simantirakis EN, Vardas P; Ospedale S Maria
Nuova, Reggio Emilia (6): Tomasi C, Menozzi C; Ospedale
Civile, Imperia (3): Mureddu R, Leoncini M, Musso G; Ospe-
dale Umberto I, Mestre (3): Corrado A, Gasparini G,
Raviele A; Queen Elizabeth Hospital, Birmingham (3):
Gammage M; Ospedale Civile, Cento (2): Scarfò S, Alboni
P; Ospedale S Pietro Igneo, Fucecchio (1): Del Rosso A.
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