Ignacio Fernández Lozano, Jorge
Toquero, José Antonio Fernández Díaz, Bogdan Ionescu,
Vanesa Moñivas, Pilar Ortiz, Beatriz Fuertes, Luis Alonso Pulpón.
Clínica Puerta de Hierro, Madrid.
Address for correspondence: Ignacio Fernández
Lozano, C/ Julio Palacios 20. 1º D., Madrid 28029. Email:
ifernandezl@sego.es
Introduction
Atrial fibrillation
(AF) is the most frequent sustained cardiac arrhythmia in clinical practice
and, although its importance has been underestimated even in recent years,
we are now becoming aware of its clinical transcendence
1,2,3. The
classical treatment is pharmacological, but its efficacy is limited and
it does have side effects
4,5.
Therefore, in recent years, there has been an increasing interest in other
types of non-pharmacological treatments
6,7.
Physiologic
cardiac pacing has proven to be more effective than VVI mode pacing to prevent
the occurrence of AF during the follow-up of patients who have had a permanent
pacemaker implanted
8,9,10. There are currently different lines of
research that use different atrial pacing techniques to prevent and treat
episodes of paroxysmal atrial fibrillation
11,12. Techniques of multi-site pacing in the
right atrium or both atria, new atrial pacing sites, prevention algorithms
for paroxysmal atrial fibrillation episodes, and even high-frequency atrial
tachyarrhythmia termination algorithms have all been proposed. In this article,
we will try to synthesize the grounds for and findings of the different lines
of research currently being developed.
Pacing Activation Mechanisms
The occurrence
of atrial fibrillation in a patient depends on the interaction of three
factors: substratum, triggers and modulating factors. The substratum is
the usually sick atrial myocardium with areas of fibrosis that result
in heterogeneous refractoriness that facilitates the appearance of functional
reentry areas. Shortening the refractory periods that take place in atrial
myocardium as a result of electrical remodeling favors the perpetuation
of AF
13. The triggers are the
atrial extra-systoles or episodes of atrial tachycardia or flutter that
in many cases precede episodes of AF
14.
The modulating factors such as sympathicotonia or circulating catecholamines
facilitate the occurrence and sustainability of AF.
Atrial pacing can prevent the development of AF through
several mechanisms. It can prevent dispersion of the atrial refractory periods
associated with bradycardia. This effect can be particularly beneficial
in cases of vagotonic AF
15,16.
New approaches of interatrial septal, Bachmann or simultaneous dual-site
pacing have demonstrated an enhanced speed of conduction of the electric
pulse through the atrium. This higher speed of conduction is reflected in
a shorter duration of the P wave of the superficial electrocardiogram
17,18,19
and can help to prevent AF.
Atrial pacing at frequencies higher than the basal
frequency can prevent the occurrence of AE by overdrive suppression, or
at least significantly decrease their number. It can also decrease the post-AE
pauses that result in high dispersion in the refractory periods. In addition,
it can suppress the increased automatism that is responsible for focal
AF
20.
The new techniques of multi-site pacing can improve
the hemodynamics of sick atria, and this hemodynamic improvement can in
itself prevent episodes of AF
21.
Finally, the episodes of high-frequency atrial tachycardia that often precede
the occurrence of AF can, on occasions, be terminated with atrial pacing
22.
Patients with Permanent Pacing Indication
In 1994, Andersen
and Cols
23 published the results
of the first randomized trial that compared physiologic pacing with VVI
mode. It included 225 patients with sinus node dysfunction and narrow QRS
and an average age of 76 years who were randomized to receive an AAI versus
VVI pacemaker. The long-term follow-up of these patients was published in
1997
8; the outcome, after 5.5 years
of follow-up, was a lower rate of AF, a lower cardiovascular mortality and
a significant reduction in overall mortality in patients randomized to the
AAI modality. Subsequent publications of this same population showed a lower
number of cases of progression to heart failure, improved echocardiographic
parameters
24 and fewer thromboembolism
events
25.
In 1998, the
results of the PASE (“Pacemaker Selection in the Elderly”) study were published
26. This study randomized 407 patients over
65 years of age and with bradycardia to receive a DDDR versus VVIR pacemaker.
After an average follow-up of 2.5 years, the quality of life endpoint significantly
improved in both groups (p<0.001) compared to the baseline situation,
but no significant differences were detected between the two groups except
for a slight difference in favor of using the DDDR pacemaker in patients
with SND. No differences were found in number of deaths, ACVA or admissions
for heart failure. However, a lower incidence of AF in the DDDR randomized
group was demonstrated. The results of the study were partially clouded
because a very high rate of crossover (26%) from the VVIR to DDDR group was
recorded due to pacemaker syndrome during follow-up. This may have undervalued
the benefit of DDDR pacing in this type of patient.
That same year,
Mattioli published the results of a prospective study that analyzed the
incidence of atrial fibrillation as a function of the pacing modality
27. It included 210 patients, 110 with SND and
100 with AV block, who received a physiologic PM (AAI, DDD, DDDR or VDD) versus
a ventricular PM (VVI or VVIR). Patients with a background of atrial fibrillation
were excluded, and the incidence of AF was 10% during the first year, 23%
after 3 years and 31% after 5 years. The patients randomized to a physiologic
PM had a lower risk of developing AF during follow-up, and the greatest benefits
were for patients with SND.
The CTOPP (Canadian
Trial of Physiologic Pacing)
28
randomized 2568 patients with pacemaker indication, 1474 to ventricular
pacing (VVI or VVIR) and 1094 to physiologic pacing (AAI, AAIR, DDD or DDDR).
After an average follow-up of 3 years, no significant differences were found
in the combined endpoint of cardiovascular mortality and ACVA between both
groups. However, the annual incidence of atrial fibrillation was 5.3% in
the physiologic pacing group versus 6.6% in the ventricular pacing group.
A relative risk reduction of 18% was statistically significant (p=0.05).
A subsequent analysis of this same study published in 2001
29 demonstrated that physiologic pacing was
very beneficial for the patients most dependent on pacemakers. Thus, those
patients with an intrinsic cardiac frequency of less than 60 bpm during the
first follow-up had a lower rate of cardiovascular death or ACVA and a lower
total mortality (p<0.001).
The MOST trial,
published in 2002, randomizes 2010 patients with SND to receive a VVIR versus
DDDR pacemaker
30. After completing
an average follow-up of 2.7 years, the primary endpoint of ACVA or total
mortality occurred in 22.2% of the patients, and no significant differences
were observed between the two groups (p=0.32). However, a lower incidence
of AF was observed in the DDDR randomized group (p=0.008). The occurrence
of permanent AF was 26.7% in the VVIR group versus 15.2% in the DDDR group
(p=0.001).
The preliminary
findings of the UK-PACE trial
31
were reported during the 2003 Congress of the American College of Cardiology.
This trial randomizes 2000 patients with AV block to a DDDR versus VVIR
pacemaker, and no differences are found in total or cardiac mortality between
the two groups.
In all, almost
7000 patients have been included in randomized trials, and there is indisputable
proof of a lower incidence of atrial fibrillation and less progression to
chronic AF when a physiologic pacemaker is used in patients with permanent
pacing indication.
Patients Without Associated Bradycardia
In 1999, the
results of PA
3 32
were published. This study assesses the efficacy of atrial pacing in patients
with paroxysmal atrial fibrillation and without permanent pacing indication.
In order to be included, the patients had to have had at least three episodes
of paroxysmal AF during the preceding year in spite of having received correct
antiarrhythmic treatment. A dual-chamber pacemaker was implanted in 97
patients, and they were randomized to DDIR programming at 70 bpm or DDI
at 30 bpm. The primary endpoint was the time up to the first recurrence of
an atrial tachycardia lasting more than 5 minutes. The counters of the device,
which did not have intracavity electrographs, were used for this purpose.
This endpoint did not differ significantly in the two groups.
Subsequently, AV node ablation was performed in 67
patients, randomizing the DDDR PM at 70 bpm minimum frequency or VDD PM
at 60 bpm
33. There were also
no differences detected in the recurrence of AF in this second phase.
This study has some methodological limitations, the
main one being a high rate – 25% – of group crossover from the DDI mode
at 30 bpm to the DDIR mode at 70 bpm. In addition, the DDIR programming only
achieved 67% atrial pacing, and other studies have demonstrated that the
higher the percentage of pacing, the greater is the efficacy in preventing
AF. Finally, the primary endpoint is based on analysis of the PM counters,
without electrographs that confirm the recurrence of the arrhythmia.
In spite of
all this, an analysis of the results of PA
3
puts in doubt the efficacy of atrial pacing in preventing episodes of AF
in patients with associated bradycardia.
Pacing at Special Sites
A) Biatrial Pacing
The association
between disorders of intra- and inter-atrial conduction and the occurrence
of AF episodes has been known for some years
34.
Techniques of simultaneous pacing in both atria
35
have been proposed to correct this. This technique uses an electrode located
inside the coronary sinus and another in the right atrium; both are jointly
connected to the atrial port by a Y-connector. Some second-generation PMs
have algorithms that resynchronize both atria in case an event sensed in
the opposite atrium occurs
36.
The French
group directed by Dr. Daubert publishes the experience of a single center
over a period of 9 years
37.
It demonstrates a reduction of the P wave from 187 to 106 msec with biatrial
pacing. After an average follow-up of 34 months, a third of the patients
is free of arrhythmias, a third presents paroxysmal episodes but with maintenance
of sinus rhythm, and the remaining third has permanent atrial fibrillation.
This technique
has also been effectively used to prevent episodes of AF after heart surgery
38, 39,40.
However, the technique is limited by the need for 2 electrodes, the high
rate of displacement of the coronary sinus electrode and the use of Y-connectors.
B) Dual-Site Right Atrial Pacing
In this technique,
an electrode is implanted in the right appendage and another in the coronary
sinus ostium. This succeeds in reducing the conduction time and achieves
a more homogeneous atrial activation, thus eliminating the displacement problems
of electrodes placed inside the coronary sinus.
Early publications
19 demonstrated a beneficial effect of dual-site
pacing versus single-site pacing or no pacing. In a prospective randomized
study that includes 118 patients, dual-site pacing only demonstrates a tendency
for longer times without arrhythmias. In the subgroup of patients that
continues under antiarrhythmic treatment, dual-site pacing from the right
atrium significantly reduces the number of atrial arrhythmia episodes.
C) Pacing at Special Sites
The atrial
pacing site is of utmost importance to the total conduction time. To try
to achieve the potential beneficial effects of dual-site pacing, different
pacing sites in the right atrium have been proposed, specifically Bachmann's
bundle
18 and the coronary sinus
ostium
42. In a randomized study,
Padeletti analyzes the effects of pacing in 46 patients with a history
of AF. During the pacing phase in the right appendage, the number of symptomatic
AF episodes was reduced from 6 to 2 a month, whereas with interatrial septum
pacing the number was reduced from 5 to 0.2 a month. In another study
44, septal pacing resulted in a subjective 68%
improvement of symptomatic episodes and an objective 60% reduction of the
incidence of AF.
The results
with Bachmann's bundle pacing are promising
45.
The electrode is easily positioned by using a simple fluoroscopic reference,
and this position is associated with a marked reduction in the P wave duration.
In a prospective study that included 120 patients, pacing from Bachmann's
bundle reduced the incidence of progression to permanent AF (45 versus 75%,
p<0.05) after an average follow-up of one year.
In short, both
techniques have proved to be somewhat useful, although in trials with short
follow-up periods and with a small number of patients. Of the two positions,
Bachmann's bundle offers the advantage of causing fewer problems in ventricular
signal detection. The far field can be significant in this group of patients;
it limits the utility of mode exchange algorithms and introduces incorrect
information in the pacemaker event counters.
Prevention Algorithms
Different atrial
pacing algorithms have been developed, all designed for atrial overdrive
pacing and prevention of AF episodes. Basically they can be divided into
four types
46: atrial overdrive
pacing algorithms (
Figure 1), response to atrial extrasystoles (to
prevent short-long sequences), response to sinus rhythm recovery, and post-exercise
relative bradycardia sequence prevention algorithms. The most commonly used
algorithm is intended to stimulate the atrium just above the sinus frequency
to achieve unified atrial refractory periods. The higher the atrial pacing
percentage, the greater the effectiveness. However, excessively high frequencies
are perceived by the patient as a disagreeable sensation. Therefore, the
objective is to achieve a high percentage of atrial pacing without excessively
increasing the patient's frequency.
Figure 1: Example of atrial overdrive pacing
algorithms.
DAO continuously monitors the atrial channel for intrinsic
atrial events. When two P-waves are sensed within 16 cardiac cycles, the
atrial pacing rate is increased. The P waves do not need to be consecutive.
Following the delivery of the programmed number of DAO pacing cycles, pacing
cycle length is extended or increased to facilitate the search for intrinsic
atrial activity. Once atrial activity is sensed and meets the above criteria,
the algorithm will automatically calculate and provide an incremental A
pacing rate just above the patients own circadian rhythm.
The efficacy
of an atrial overdrive pacing algorithm has been analyzed in the ADOPT-A
trial
47. A total of 288 patients
with sinus node dysfunction and a background of paroxysmal or persistent
AF received a DDDR pacemaker with a lower frequency programmed at 70 bpm.
In a parallel design, the patients were randomized to activate or not activate
the overdrive pacing algorithm. After a 6-month follow-up, it was confirmed
that activation of the algorithm caused an increase in the pacing percentage
of 92.9% versus 67.9% (p<0.001). The atrial fibrillation percentage
dropped 25% with the algorithm activated (2.5% vs 1.87%, p=0.005). The
number of rehospitalizations or the need for cardioversion did not differ
between the two groups.
The AFT (AF
Therapy) Trial included 372 patients with paroxysmal AF, with or without
permanent pacing indication, in a complex protocol divided into 4 phases
48. The first phase of the study was a monitoring
phase intended to obtain information on the way AF begins in this population.
The second phase compares the efficacy of conventional pacing. During the
third phase of the study, the efficacy of four combined pacing algorithms
is analyzed and compared to conventional DDDR pacing at 70 bpm. Unfortunately,
it has only been possible to analyze data from 97 patients because information
was lost during follow-up and because of detection of ventricular activity
in the atrial channel. The prevention algorithms achieved a 34% reduction
of the AF rate (p<0.05). A subsequent subanalysis of this study
49 showed how conventional pacing was very effective
in patients with AF and bradycardia, whereas the algorithms tended to be
more useful for those patients with prior AF and without bradycardia..
The ASPECT
trial (Atrial Septal Pacing Efficacy Clinical Trial) included 298 patients
who were randomized to receive the atrial electrode in the septum or another
position in the right atrium. After one month, those patients with recurrence
of AF were randomized to conventional pacing or algorithms activated during
a 3-month phase. At the end of this phase, the PM of the opposite group was
reprogrammed. The PM counters did not show evidence of any significant differences
with activation of the algorithms, nor were any objective differences based
on the electrode position found, except that the symptomatic episodes were
less frequent in those patients who had an electrode implanted in the interatrial
septum.
PREVENT Register
Atrial fibrillation
is a complex arrhythmia. Phase 1 of the AFT study
48 demonstrated that there are multiple mechanisms
of AF initiation that differ in different patients. Nowadays, modern PMs
have numerous diagnostic functions that help to characterize the way AF begins
in a specific patient. In addition, the prevention algorithms generally
vary, and it may be that not all of them are beneficial in all patients.
The prospective studies have a strict protocol that makes it difficult to
optimize programming for a specific patient. Therefore, to study the efficacy
of the AF prevention algorithms in the real world by using all the advantages
of a PM in a particular patient, we have designed the Prevent Register
51.
The Prevent-AF
Register is prospective, non-randomized and multicentric. It includes candidate
patients for permanent pacing due to sinus node dysfunction (type I or
IIa indication of the AHA-ACC)
52
with or without prior paroxysmal atrial fibrillation.
Four preventive
pacing algorithms are incorporated: Pace Conditioning
TM,
Post-PAC Response
TM, PAC Suppression
TM,
Post-Exercise Response
TM. The Pace Conditioning
detects the patient's basal frequency and increases the pacemaker pacing
frequency to increase the percentage of paced beats, in an attempt to maintain
patients slightly above their basal frequency. The PAC Suppression is activated
if atrial extrasystoles are detected, increasing the basal pacing frequency
in an attempt to suppress them. The Post-PAC Response prevents the compensatory
pause after an atrial extrasystole by eliminating the short-long sequences.
The Post-Exercise Rate Control prevents abrupt frequency drops after episodes
of physical exercise. The Register was implemented in 14 centers in Spain.
A total of 68 patients (33 men, 35 women) were included from April 2000 to
April 2001. The average age was 72±12 years and the pacing indication
was sinus node dysfunction in all cases. A total of 53 patients (78%) had
had documented paroxysmal AF episodes prior to implant.
The recurrence
of at least one episode of paroxysmal atrial fibrillation was documented
in a total of 32 patients during the monitoring phase, and at least one
subsequent phase of preventive pacing was completed. The preventive algorithms
were programmed on an individualized basis, based on information from the
AF episode commencement mode.
The average
atrial arrhythmic burden was reduced in the total group (32 patients) from
0.94 to 0.3 hours a day (Wilcoxon test: p=0.034) (
Figure 2). In relative
values, the average atrial arrhythmic burden dropped from 3.9% to 1.3%, i.e.
a 67% reduction. The mean atrial pacing percentage rose from 72% to 78%,
i.e. an increase of only 13%.
Figure 2. Change in AF Burden during follow up. Median AF
burden reduced from 12% to 3%.
The Register
results confirm the usefulness of latest-generation pacemakers both for
diagnosing episodes of paroxysmal atrial fibrillation and for preventing
them by means of pacing algorithms. The diagnostic functions of the pacemaker
provided relevant information on the occurrence and development of atrial
fibrillation in each patient. In this way, the most suitable algorithms for
preventing AF were programmed on an individualized basis.
Atrial Tachycardia Termination Algorithms
Many episodes
of AF begin preceded by a rapid, relatively regular atrial tachycardia.
Some of these atrial tachycardias can be eliminated by overdrive pacing in
a way similar to overdrive pacing and termination of other tachycardias by
reentry. To end atrial tachycardias, algorithms similar to those used in
implantable defribillators have been employed, and specific algorithms have
been designed to act in the atrium as 50 Hz bursts (
Figure 3).
Figure 3: Overdrive pacing algorithms.
These therapies
have been tested in 537 patients possessing a DAI with atrial therapies
53. After an average follow-up of 11.4 months,
the overall efficacy of the algorithms was 48%, with 59% in cases of atrial
tachycardia and 30% in those cases classified as AF. The efficacy depends
on the arrhythmia cycle length, and it is lower the faster the atrial tachycardia.
The main limitation of this and similar work is that we know that many episodes
of AF and atrial tachycardia are self-limited and brief, and therefore the
quantification of efficacy may be clearly overestimated.
In the ATTEST
study
54, the efficacy of atrial
overdrive pacing in 368 patients possessing a pacemaker was evaluated. The
overdrive pacing algorithms terminated 54% of the episodes, although the
reduced percentage of atrial arrhythmias was not statistically significant:
from 42 hours a month to 1.3 hours a month (p=0.2).
Conclusions
As we have
seen in this review of the state-of-the-art, several parallel lines of
research have been developed in recent years to treat patients with AF,
either associated or not with bradycardia. The situation may seem confusing,
and even more so if we consider some limitations of this work.
The first limitation
is that in each study, we are analyzing something different that has not
been studied previously. The data that we have from classical prevalence
studies
1,2,3
are based on records, either with ECG or by Holter, of AF episodes, most of
them symptomatic. In most of the mentioned studies, the presence or absence
of AF is analyzed according to records of the pacemaker itself. This has two
limitations. The first is that, as the devices and detection criteria are
different, the data from a study may not be comparable to data from other
studies. The second is that, as most AF episodes are asymptomatic, we are
overestimating the incidence and it is not easy to extrapolate the data
from these studies, which use symptomatic episodes as diagnostic or efficacy
criteria.
Another limitation
is that atrial fibrillation is a complex, dynamic arrhythmia. For reasons
of protocol, the programming of devices in most of the trials has been based
on a rigid, inflexible protocol.
55.
Perhaps if there had been a little more freedom on adapting the algorithms
to each patient, the degree of efficacy of the algorithms would have been
higher. In addition, we are increasingly more aware of the adverse effect
of VD apex pacing on the hemodynamics of these patients
55.
This effect at least partially explains the high incidence of atrial arrhythmias
in patients with a permanent PM that was not accounted for in some studies.
Perhaps in the future, with new algorithms tending to reduce VD pacing to
the necessary minimum and with the expansion of resynchronization techniques,
the approaches for treating atrial arrhythmias may yield greater benefits.
Finally, the
follow-up of these studies has been very short. In Andersen's classical
study
8, the AAI pacemaker did
not yield benefits until after 5 years of follow-up; however, the data we
have on these new techniques are limited to 6-month or one-year follow-ups.
We need a longer follow-up to be able to accurately evaluate the efficacy
of these devices..
From the data
presented to date, we can conclude that the benefits obtained by implanting
two electrodes, either in the right atrium or in both atria, are insignificant
and probably do not justify the increased complexity of the implant. These
techniques should be limited to research protocols, to try to identify the
type of patient that would benefit the most.
The prevention
algorithms are sound and barely raise the PM price, although their utility
is limited. Nowadays, they could be used for different categories of patients:
1)Patients with PM indication and documented AF episodes.
2)Patients with a background of AF who develop secondary symptomatic
bradycardia to medication.
3)Patients with paroxysmal atrial arrhythmias not suppressible by ablation
and drug-refractory techniques for whom AV node ablation is considered as
a therapeutic measure.
For the time
being, the results of pacing do not justify its therapeutic use in patients
with atrial fibrillation or atrial arrhythmias without associated bradycardia.
One unanswered question is the optimum site of atrial pacing. Current data
suggest a rather inconsistent benefit with septal pacing, whether it be
from the coronary sinus ostium or Bachmann's bundle. But we still have very
few data. Trials with more patients and longer follow-up periods are needed
to change the current standard of implanting the atrial electrode in the
appendage.
Abbreviations:
Atrial Fibrillation: AF
Atrial Extra-systoles: AE
Sinus Node Dysfunction SND
Pacemaker: PM
Pacemaker Selection in the Elderly: PASE
Canadian Trial of Physiologic Pacing: CTOPP
Mode Selection Trial: MOST
United Kingdom Pacing and Cardiovascular Events Trial: UK-PACE
Atrial Pacing Periablation for Prevention of Paroxysmal Atrial Fibrillation:
PA
3
Atrial Fibrillation Therapy Study: AFT
Atrial Septal Pacing Efficacy Clinical Trial: ASPECT
Atrial Therapy Efficacy and Safety Trial: ATTEST
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