Download Comment - Cardiac Arrhythmias

Comment
Cardiac arrhythmias—trials and tribulations
See Editorial page 1446
See Series pages 1498, 1509,
and 1520
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Patients with cardiac arrhythmias can be asymptom­atic,
suffer from serious symptoms and a degraded quality
of life, or present with sudden cardiac death. Although
rhythm disturbances of the heart have been recognised
and treated for centuries, the basic, translational, and
clinical aspects of the science of cardiac electrophysiology
are relatively recent.1 The therapeutic aspects of cardiac
stimulation (pace­makers), defibrillation using external
and implantable devices, and ablation have propelled
arrhythmology into an effective modern therapeutic
arena. In The Lancet, three Series papers summarise
current thinking and practice in arrhythmia care.2–4
www.thelancet.com Vol 380 October 27, 2012
Comment
www.thelancet.com Vol 380 October 27, 2012
into the need for better antiarrhythmic drugs or new
methods to achieve rhythm control.
After the Clinical Arrythmia Suppression Trial (CAST),
which had shown that antiarrhythmic drugs could also
be pro-arrhythmic,22 the pharma­ceutical industry became
wary of antiarrhythmic drug development. Successful
management of sustained ventricular arrhythmias using
implantable defibrillators relieved pressure to develop
such drugs. However, there was an unmet need for safe
antiarrhythmic agents for treatment of atrial fibrillation.
At first, agents intended primarily for prevention of
sudden death, such as dofetilide, were also investigated
for treatment of atrial fibrillation and then drugs, such
as dronedarone, were developed only for prevention of
atrial fibrillation.23 A high-risk atrial fibrillation population
was enrolled to test the hypothesis that dronedarone
would lead to a reduction in time to all cause mortality
or unexpected cardiovascular hospitalisation; compared
with placebo, dronedarone was effective.24 Its efficacy
was thought not to be entirely related to its atrial
antiarrhythmic effect and this concept was tested in a
trial of dronedarone versus placebo in a population of
patients with permanent atrial fibrillation. However,
the trial was halted early because of hazard associated
with dronedarone.25 The need for outcome trials was
established during development of dronedarone and no
antiarrhythmic is now likely to be approved for long-term
treatment of atrial fibrillation without satisfactory trials
of this type.26
Ablation of accessory pathways has almost eradi­
cated Wolff-Parkinson-White syndrome from adults
Science Photo Library
Cardiac pacemakers were initially used to prevent
syncope and sudden death in patients who were having
Adams-Stokes attacks. These simple devices were
effective and no trial was thought possible to support
their introduction into clinical practice.5 Trials of single
versus dual chamber pacemakers showed better results
with dual chamber pacing,6 and biventricular pacing,
or cardiac resynchronisation therapy, has proven effec­
tive for symptomatic heart failure with ventricular
dyssynchrony.7 Other trials showed little if any benefit
from pacing to prevent atrial tachyarrhythmia,8,9 or
eliminate syncope10 unless clearly related to bradycardia.11
Electrical defibrillation was used for termination of
atrial and ventricular fibrillation without the need for
clinical trials, but there were many reports of thera­
peutic success. When the implantable defibrillator was
developed in 198012 it was extensively used before the
need for clinical trials was mooted. Eventually small trials
of secondary prevention were conducted—the therapy
was life-saving, although expensive.13
It proved more difficult to provide convincing evi­
dence that primary prevention (device implantation
in a patient at risk of, but free from, life-threatening
ventricular arrhythmia) was clinically valuable. However,
one small trial in postinfarction patients with impaired
systolic function and inducible arrhythmia yielded a
positive result.14 This stimulated further trials in at-risk
populations, with variable results.15-18 Clinical experience
with implantable defibrillators has highlighted the
inadequacy (low positive predictive value) of traditional
and some novel risk-markers but, despite good ideas
for refining the population at potential risk, no new trial
of implantable defibrillator therapy, which would be
needed to validate the potential risk-marker, has been
established in recent years.
Patients with atrial fibrillation can be managed by
restoration and maintenance of sinus rhythm (rhythm
control) or more simply by controlling the ventricular rate
in response to ongoing atrial fibrillation (rate control).
Large trials consistently demonstrated no advantage to
rhythm control, and that this approach was associated
with more hospitalisations than rate control.19,20 Despite
the evidence against rhythm control, the implications
struggled for acceptance.21 Patients who remained in
sinus rhythm did better than those in atrial fibrillation,
but conventional antiarrhythmic drug therapy was
associated with a poor outcome. This argument devolved
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Comment
in developed countries. Similarly, ablation of the
re-entrant circuits that support paroxysmal supra­
ventricular tachy­cardias (AV-nodal re-entry and atrioventricular re-entry) has proven highly effective. In
1998, it was reported that atrial fibrillation was usually
triggered by atrial tachycardias arising from sleeves
of atrial tissue extending from the left atrium and
wrapping around the pulmonary veins.27 It was reasoned
that electrical isolation of the pulmonary veins from
the left atrium would prevent the initiation of atrial
fibrillation. Results from patients with pre­dominantly
paroxysmal atrial fibrillation and little or no underlying
heart disease have confirmed that 75% or more are
effectively treated with this therapy, at least in the
short-term.28 Longer term results (5–10 years) are now
emerging, and it is clear that there is a steady attrition
of patients remaining completely arrhythmia-free, but
the episodes are often short and asymptomatic, and
about a third of patients remain free of arrhythmia, and
more after multiple procedures.29,30
There have been many comparisons of the efficacy
and complications associated with antiarrhythmic
drug treatment and left atrial ablation/pulmonary vein
isolation. In every study, ablation has proved more
effective.28,31 Adverse procedure-related complications
dominate in early follow-up, but the complications of
antiarrhythmic drugs accumulate during longer followup. These trials have been criticised because patients
have generally failed previous treatment with one
or more antiarrhythmic drugs. However, one trial of
patients naive to previous antiarrhythmic drug therapy
reported a clear advantage to left atrial ablation.32
Follow-up in these trials has been relatively short
(one year or less), and the endpoint was recurrence of
atrial fibrillation rather than more meaningful cardio­
vascular outcomes. The atrial fibrillation endpoint
was variously defined but there is now uniform agree­
ment that 30 seconds of arrhythmia is sufficient to
count as a recurrence. This identifies the potential for
the arrythmia to develop, but its relationship to other
important clinical outcomes is unknown. At present
several trials, eg, CABANA (Catheter ABlation versus
ANtiarrhythmic drug therapy for Atrial fibrillation;
NCT00911508) and EAST (Early Atrial fibrillation
Stroke prevention Trial; NCT01288352) are exploring
the effect of ablation on endpoints such as all-cause
mortality and cardiovascular hospitalisations.
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In the future, advances are expected in the gen­
etics of sudden cardiac death and atrial fibrillation.
Pharmacogenomics related to anticoagulation and risk
of ventricular arrhythmia is likely to develop quickly.
Better risk stratification of patients at risk of lifethreatening arrhythmia is now beginning to make gains.
Ablation for arrhythmias not dependent on simple
macro re-entrant circuits—ventricular tachycardia,
ven­tricular fibrillation, and atrial fibrillation—is being
investigated now that better mapping techniques
have been dev­eloped and multiple ablation energies
are available. The search continues for antiarrhythmic
drugs for the treatment of atrial fibrillation and there
is new appetite to find drugs suitable for suppressing
ventricular arrhythmias. Implantable diagnostics began
in com­bination with pacemaker therapy several decades
ago, but stand-alone monitors are implanted that will
shortly be able to sense heart rate, arrhythmias, motion,
respiration, blood pressure, temperature, glucose,
electro­lytes, oxygen saturation, and more, all capable of
wireless transmission.
A John Camm
Department of Clinical Sciences, St George’s University of London,
London SW17 0RE, UK
[email protected]
I have served as an adviser to Sanofi, Gilead, Menarini, Cardiome, Servier,
Medronic, Merck, Bristol-Myers Squibb, and Boston Scientific.
Einthoven W. Le telecardiogramme. Arch Internat Physiol 1906; 4: 132–63.
Grace AA, Roden DM. Systems biology and cardiac arrhythmias.
Lancet 2012; 380: 1498–1508.
3 Lee G, Sanders P, Kalman JM. Catheter ablation of atrial arrhythmias: state of
the art. Lancet 2012; 380: 1509–19.
4 John RM, Tedrow UB, Koplan BA, et al. Ventricular arrhythmias and sudden
cardiac death. Lancet 2012; 380: 1520–29.
5 Camm AJ, Jones S, Gammage MD, Rowland E. Aubrey Leatham and the
introduction of cardiac pacing to the UK. Europace 2010; 12: 1356–59.
6 Healey JS, Toff WD, Lamas GA, et al. Cardiovascular outcomes with
atrial-based pacing compared with ventricular pacing: meta-analysis of
randomized trials, using individual patient data. Circulation 2006; 114: 11–17.
7 Wells G, Parkash R, Healey JS, et al. Cardiac resynchronization therapy:
a meta-analysis of randomized controlled trials. CMAJ 2011; 183: 421–29.
8 Camm AJ, Sulke N, Edvardsson N, et al. Conventional and dedicated atrial
overdrive pacing for the prevention of paroxysmal atrial fibrillation:
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9 Gold MR, Adler S, Fauchier L, et al. Impact of atrial prevention pacing on atrial
fibrillation burden: primary results of the Study of Atrial Fibrillation
Reduction (SAFARI) trial. Heart Rhythm 2009; 6: 295–301.
10 Romme JJ, Reitsma JB, Black CN, et al. Drugs and pacemakers for vasovagal,
carotid sinus and situational syncope. Cochrane Database Syst Rev 2011;
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11 Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patients with
neurally-mediated syncope and documented asystole. Third International
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12 Mirowski M, Reid PR, Mower MM, et al. Termination of malignant ventricular
arrhythmias with an implanted automatic defibrillator in human beings.
N Engl J Med 1980; 303: 322–24.
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Comment
13 Connolly SJ, Hallstrom AP, Cappato R, et al. Meta-analysis of the implantable
cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS
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14 Moss AJ, Hall WJ, Cannom DS, et al, for the Multicenter Automatic
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24 Hohnloser SH, Crijns HJ, van Eickels M, et al, for the ATHENA Investigators.
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32 Morillo C, Verma A, Kuck KH, et al. Radiofrequency ablation vs antiarrhythmic
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