Download Hybrid Therapy as an Alternative in Refractory Atrial Fibrillation

Hybrid Therapy as an Alternative in Refractory Atrial
Fibrillation: When, Why, and How?
S. SAKSENA1, N. SKADSBERG2
Introduction
Hybrid therapy has been proposed for the treatment of drug-refractory atrial fibrillation (AF). The development of hybrid therapy has been going on
over the past 10 years and has largely stemmed from the modest efficacy and
limited patient benefits seen with a variety of monotherapies in patients
with drug-refractory AF. A number of clinical studies have demonstrated
that drug-refractory AF is common and that rhy thm control is rarely
achieved with drug strategies alone. In the AFFIRM study, drug therapy
added only a modest 23% increment to the likelihood of maintaining rhythm
control in patients who were started on a rhythm control strategy [1].
Similar results were seen with amiodarone in the STAF study and in the
RACE study [2, 3]. As a result, non-pharmacological monotherapies such as
atrial pacing and catheter ablation either of focal triggers or isolation of
these foci as well as linear ablation of the atrial substrate were proposed. The
last 10 years have been spent in evaluating each of these monotherapies as a
suitable non-pharmacological alternative to drug therapy of AF for rhythm
control. In each of these instances, there has been some success, but a substantial proportion of patients has failed to respond to the monotherapy.
Focal catheter ablation of AF triggers in patients with little or no structural heart disease has been performed in the pulmonary veins [4]. Focal
ablation has had modest success; in prospective studies and recent metaanalysis this has averaged around 50–70% at most centres [5]. In a recent
worldwide survey, practitioners described somewhat higher success rates at
1Electrophysiology
Research Foundation, Warren, New Jersey; 2Robert Wood Johnson
Medical School, New Brunswick, New Jersey, USA
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S. Saksena, N. Skadsberg
centres that had larger volumes of patients, but nevertheless most centres
saw only modest success rates. Even these modest success rates were
achieved in many centres with the concomitant use of anti-arrhythmic
drugs, in a hybrid approach with the ablation procedure. In a survey of clinical practitioners, Mikelsen et al. reported a significant level of failure in the
responses from clinical practitioners [6]. In view of these outcomes and the
limited target patient population (i.e., the patients with little or no structural
heart disease), few practitioners believe that monotherapy with focal
catheter ablation can be curative in the large body of AF patients. More
recently, isolation of the pulmonary veins has been attempted [7]. While isolation procedures have been associated with lesser degrees of complications
such as pulmonary vein stenosis, efficacy rates have been variable. While certain centres report good results, the first prospective multi-centre study
reported a 60% freedom from AF at 1 year [8]. Linear ablation of the right
atrium has had low success rates, with rates of efficacy between 15% and
54% being reported, but many of these data may relate to treatment combined with anti-arrhythmic drugs [9, 10]. In a prospective clinical trial, a
partial or complete response on the basis of symptoms and intermittent
ECGs was obtained in approximately 50% of patients [10]. In this prospective study using a multi-electrode ablation catheter, anti-arrhythmic drugs
were continued, allowing hybrid therapy with right-sided ablation and antiarrhythmic medication. More importantly, linear ablation in the left atrium
has been combined with pulmonary vein isolation in many centres. Pappone
et al. reported a significantly higher success rate with this combination of an
ablative compartmentalisation approachwith trigger isolation in the left atrium, but anti-arrhythmic drugs were continued in many patients [7].
Atrial pacing as monotherapy alone has had very minimal efficacy in
patients with AF with and without bradycardia. In clinical trials involving
patients with bradycardia–tachycardia syndrome, a small reduction in the
AF burden as well as limited reduction of frequency have been reported, but
in most trials AF recurs without restoration of rhythm control in most
patients [11–14]. A major limitation of ablation studies has been patient
symptom-based reporting of AF recurrences. Recent studies show this to be
highly unreliable and vastly underestimates AF events [15].
Definition of Hybrid Therapy
In view of these less than encouraging results, hybrid therapy of AF has been
investigated by us and increasingly by other selected centres. These data will
be discussed here together with the electrophysiological basis for this
approach. The electrophysiological mechanisms of hybrid therapy efficacy
Hybrid Therapy as an Alternative in Refractory Atrial Fibrillation: When,Why, and How?
269
are currently being examined, and the results of hybrid therapy will be discussed in subsequent sections. Hybrid therapy in its broadest sense is taken
to be a combination of pharmacological and non-pharmacological therapies
using anti-arrhythmic and non-anti-arrhythmic therapies to optimise and
even individualise patient management.
Electrophysiological Mechanisms Underlying Efficacy
The electrophysiological mechanisms underlying different approaches to
hybrid therapy are, of necessity, dissimilar. Thus, individual combination of
pharmacological and non-pharmacological techniques may target specific
mechanisms to achieve efficacy for an individual patient. The combination of
anti-arrhythmic drugs and pacing, anti-arrhythmic drugs and catheter ablation, and the combination of all three approaches – drugs, pacing and ablation – need to be considered individually. There is a potential for significant
synergy between these approaches, and it seems that for each therapy more
than one anti-arrhythmic mechanism may be operative. Thus, while we can
both hypothesise synergistic mechanisms and can document efficacy of the
hybrid therapy prescription, dissecting the contribution of each of the components of hybrid therapy still remains a major challenge.
Anti-arrhythmic drugs are well known to suppress ectopic activity in the
AF, prolonged atrial refractoriness, and reduced conduction velocity. The use
of these drugs would contribute to reduce the AF burden by reducing AF
triggers, in the form of ectopic activity or atrial or atrioventricular (AV)
nodal tachycardias. Anti-arrhythmic drugs can retard intra-atrial conduction and prolonged atrial refractoriness, thus affecting the initiation of atrial
reentrant tachycardias that trigger or maintain AF. They also produce conduction block in patients, which may be important in alteration of sites of
conduction delay or interruption of a reentrant pathway. These mechanisms
could reduce the frequency with which AF events are triggered or prevent
the inscription of reentrant tachycardias at the initiation or during maintenance of AF. They can terminate AF by producing either conduction block in
reentry circuits or expanding the window or excitable gap that could be penetrated by ectopic beats or other mechanisms for spontaneous AF termination. Thus, anti-arrhythmic drug trials rarely examine the ability to terminate or interrupt tachycardias except for spontaneous cardioversion of AF,
which occurs in a proportion of patients with various forms of cardiac disease. Patients with advanced structural heart disease or heart failure are
clearly more resistant to drug therapy.
Atrial pacing can suppress atrial triggers as well as alter the depolarisation of the atrial substrate, changing its vulnerability to AF. However, many
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of these tachycardias are unaffected by atrial triggers and the AF burden is
not resolved by this mechanism. Dual-site atrial pacing and biatrial pacing
has been shown to abbreviate P wave duration and also improve the haemodynamics of left-sided AV filling. In a sub-study of the DAPPAF study, left
atrial filling of the left ventricle was improved with increased atrial jet velocity, as well as AV conduction being improved by reduction of AV conduction
intervals [13, 14, 16]. However, in the absence of anti-arrhythmic drugs dualsite atrial pacing has not shown any meaningful clinical effect on time to
symptomatic AF recurrence. The recurrence and frequency of atrial flutter
and AF is generally minimally altered by atrial pacing alone despite increasing evidence that premature beats can be reduced. In the DAPPAF study and
later in the ASPECT and ATTEST trials, atrial pacing alone did not prolong
the time to the first recurrence of symptomatic AF, and the addition of AF
termination therapies did not alter this outcome [17–19]. However, when
combined with the class I or III anti-arrhythmic drugs, overdrive dual-site
atrial pacing prolonged the time to the first symptomatic AF recurrence in
the DAPPAF study [16]. Thus, we hypothesised that the combination of dualsite atrial pacing and anti-arrhythmic drug therapies may have electrophysiological effects on both focal triggers and the atrial conduction, as well as on
the haemodynamics affecting the atrial substrate which may have favourable
anti-arrhythmic effects.
Catheter ablation can isolate triggers or ablate triggers, as well as isolate
critical areas of the atrium that may be necessary for AF. Catheter ablation
has also been performed in patients with structural heart disease or patients
with drug-refractory AF that has not responded to any other approach. [18]
Results have been reported to be favourable, but more objective endpoint
data are unavailable.
Atrial ablation can be combined with pacing to reduce the frequency of
triggers and alter the substrate to make it less vulnerable to AF maintenance.
Pacing, in particular dual-site atrial pacing, and ablation therapy (mainly
right atrial ablation) have been combined by us for the treatment of drugrefractory AF. Our recent reports included 130 patients with paroxysmal,
persistent, or permanent AF followed over 10 years, most of them having significant structural heart disease [18]. Most importantly, pacing and ablation
therapy can supplement each other. The Maze procedure can help ablate
right atrial flutters as well as compartmentalise the right atrial substrate.
Better visualisation of linear ablation by new techniques of three-dimensional mapping permits more effective compartmentalisation and flutter ablation. These compartments can be resynchronised by multi-site atrial pacing
and P-wave abbreviation is observed. Dual-site right atrial pacing when performed in this fashion not only serves to resynchronise the two atrial compartments, but also has a marked anti-arrhythmic effect by pacing on both
Hybrid Therapy as an Alternative in Refractory Atrial Fibrillation: When,Why, and How?
271
sides of a linear radiofrequency lesion, which can be extremely anti-arrhythmic with respect to reentrant tachycardias around the incised lesion. It is our
contention that these effects result in prevention of persistence of AF. This
has been demonstrated in our pilot studies with device datalogues showing
progressive elimination of persistent AF and later symptomatic paroxysmal
AF [19]. Patients are usually left with brief asymptomatic salvoes of atrial
tachycardia or AF that last a few seconds or a few minutes and have no clinical importance.
Effectiveness and Safety of Hybrid Therapy
Efficacy of Hybrid Therapy
The efficacy of hybrid therapy in a variety of patient populations has now
become evident (Tables 1, 2). In early pilot studies from our group in drugrefractory paroxysmal AF, we noted prolongation of the time to first day of
recurrence as well as restoration of rhythm control in a significant proportion of patients. Long-term data from our studies are now available and the
patient population has been expanded to include patients with persistent
and permanent AF, with and without structural heart disease, and patients in
whom heart failure was present with advanced left ventricular dysfunction
(Fig. 1). There were no differences in outcome based on coexisting brady-
Fig. 1. Clinical outcome of a consecutive series of 130 consenting patients undergoing
hybrid therapy of refractory atrial fibrillation enrolled over the period 1994-2002. Data
is censored as of December 2003. CV Free Survival cardioversion free survival, Rhythm
control maintenance of atrial paced or sinus rhythm with freedom from permanent AF
S. Saksena, N. Skadsberg
272
cardia (Fig. 2). These studies have been summarised in recent reports and
will not be described in detail here [20, 21]. A tabulation of these studies is
available in [21] and in Table 3. Pilot data have supported the use of this
approach in even refractory permanent AF populations.
Fig. 2. Stratification of rhythm control endpoint based on the coexistence of a primary
bradycardia indication for pacemaker implantation. Survival curve shows proportion of
patients remaining in atrial paced or sinus rhythm free of permanent AF over an actuarial follow-up period up to five years (X axis) using a Kaplan Meier survival analysis.
AF atrial fibrillation only, AF + Brady atrial fibrillation and a coexisting primary bradycardia
Table 1. Early clinical results with combination therapy: drug + ablation (data from [17])
Ablation
technique
Garg
RA maze
PAF
12
56 (18)
None
Stabile
Tricuspid
isthmus
PAF + CAF
24
58 (8)
None
Gerstenfeld
PVA
PAF 71
6
31 (23)
8.3 (angio)
Natale
PVA
PAF 293
10
86 (81)
11.5 (CT)
Kanagaratnam
PVI
PAF 71
29
83 (21)
36 (CT)
Natale
CUVA
PAF 30
12
80 (47)
3 (CT)
a
b
Percentage (number) of patients
Percentage of patients
Patients
Mean
follow-up
(months)
Rhythm
controla
PV stenosisb
Series
Hybrid Therapy as an Alternative in Refractory Atrial Fibrillation: When,Why, and How?
273
Table 2. Early clinical results with combination therapy: drug + device (data from [17])
Series
Device
technique
Patients
Mean
% Rhythm
follow-up control
(months)
% Complications
Metrix
Atrial ICD
186
9
84
6
Jewel AF
AV ICD
537
11 ±8
86
NA
Delfaut
Dual RA pacing
30
12
80
6
D’Allones
Biatrial pacing
86
33
64
15
ICD implantable cardioverter–defibrillator, A-V atrioventricular, RA right atrium, NA
not available
Table 3. Hybrid therapy algorithms: drug + device + ablation
Series
Method
Patients
AF type
Follow-up
(months)
Rhythm
control
Saksena
DAP + AAD
± ABL
118
Parox/Persist
1–54 (20 ± 14)
93 pts
(79%)
Prakash
DAP + AAD
+ TVI ABL
40
Parox AF
± A Flutter
5–56 (26 ± 14)
90% at
2 years
Saksena
DAP + AAD
± ABL ± CV
113
Parox (70)
1–81 (30 ± 23)
92% at
3 years
Filipecki
AP/ICD + RA
Maze AAD
25
Persist/Perm
6–49 (17 ± 10)
75% at
18 months
DAP dual RA pacing, AAD anti-arrhythmic drug, TVI tricuspid isthmus, ABL ablation, CV
cardioversion, AP atrial pacing, ICD implantable atrioventricular cardioverter-defibrillator,
Parox paroxysmal, Persist persistent, Perm permanent, pts patients
Most recently we have reported on a consecutive series of patients with
persistent and permanent AF in whom detailed biatrial and three-dimensional mapping was performed and hybrid therapy outcomes could be evaluated using electrogram-validated device datalogues. Rao et al. studied 47
patients with symptomatic persistent (n = 26) or permanent (n = 21) AF
[22–24]. They underwent ‘hybrid therapy’ and were followed for 24 ± 15
months. All patients underwent linear right atrial ablation and implantation
of a pacemaker or atrioventricular defibrillator capable of overdrive right
atrial pacing together with therapy with previously ineffective anti-arrhyth-
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S. Saksena, N. Skadsberg
mic medication. Device datalogues were used to monitor AF recurrences
(Fig. 3). Freedom from permanent AF was 97%, 90%, and 83% at 6 months
and 2 and 3 years respectively. Sixteen patients (30%) had no AF recurrence
after hybrid therapy. Thirty-one patients (66%) had a total of 55 AF recurrences (mean 1.8 per patient), usually in the first 6 months of therapy. These
generally resolved, with 39 of the 47 patients (83%) achieving long-term
rhythm control. There was a significant reduction in mean AF-related hospitalisations (from 3.5 ± 2.8 to 0.57 ± 1.1), cardioversion hospitalisations
(from 3.5 ± 2.2 to 0.38 ± 0.5 per patient), and DC cardioversions (from 3.1
± 3.9 to 0.7 ± 0.5 per patient) after hybrid therapy compared to event rates
before therapy (P < 0.05 for all; Fig. 4). The authors concluded that hybrid
therapy can establish rhythm control significantly in patients with persistent
and permanent AF refractory to drugs and cardioversion therapy. This
improvement is associated with a significant reduction in AF-related hospitalisations and need for cardioversion therapy.
Fig. 3. Device datalogs with long term electrogram storage validating rhythm control in a
cohort of patients with drug refractory persistent and permanent AF. The left panel
shows the datalog electrograms showing classification of patient rhythm at initiation of
hybrid therapy and the right panel shows the outcome after long term followup. AF
atrial fibrillation, AT atrial tachycardia; numbers show patients in each category at end
of followup
Hybrid Therapy as an Alternative in Refractory Atrial Fibrillation: When,Why, and How?
AF
hospitalisations
275
CV
hospitalisations
Fig. 4. Hospitalisations for atrial fibrillation and cardioversion before and after hybrid
therapy. AF atrial fibrillation, Cv cardioversion, Rx hybrid therapy
Mechanisms of AF and Correlation with Hybrid Therapy Outcomes
For these unique patients in the study by Rao et al., biatrial mapping and AF
mechanisms were available for analysis [22–24]. In the initial reported mapping data, we were able to demonstrate conclusively that biatrial mechanisms
for AF were present in virtually all patients. Right atrial interventions in the
form of linear ablation and dual- or single-site atrial pacing were the major
form of hybrid therapy. In most patients, no targeted ablation of left atrial
sites was undertaken. Yet over 80% of patients achieved excellent rhythm
control. These data conclusively indicate that hybrid therapy can achieve
rhythm control in refractory AF with biatrial involvement in AF.
Safety of Hybrid Therapy
Hybrid therapy has been proven safe in our long-term observational studies.
There have been no procedural deaths or strokes. Complication rates average
less than 2%. Long-term anti-coagulation has been withdrawn in over 25% of
patients with device-documented freedom from AF for 1 year. The overall
stroke incidence is 1.1% per patient year in our study population of 130
patients followed for an average of 5 years [25]. This is comparable to the
stroke risk in an age-matched study population without AF.
S. Saksena, N. Skadsberg
276
Comparison with Therapeutic Alternatives
Alternative therapy approaches include left atrial interventions such as pulmonary vein isolation or focal ablation. There is little evidence that these
offer superior rhythm control to hybrid therapy, and in fact survey data suggest much more modest efficacy [5, 6]. Long-term observational data show
maintenance of efficacy based on objective device datalogues. Such data are
still not available for left atrial interventions, with the usual endpoints used
in ablation studies being increasingly put into question by device-based data
[15]. Reports of the risks of left atrial ablation are now increasing, with
major complication rates in excess of 5% [26–28]. These include mortality,
stroke, symptomatic pulmonary stenosis, atrio-oesophageal fistula, etc.
Hybrid therapy procedural complication rates are far lower in terms of
major complications (< 2% in our experience), with no procedural deaths or
stroke in over 10 years.
Finally, hybrid therapy offers ease of use, wider applicability, and shorter
procedural times and radiation exposure than do prolonged ablation procedures. These advantages alone merit its use as a first line non-pharmacological alternative in refractory AF.
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