Almanac 2011: Cardiac Arrhythmias and Pacing. The National Society Journals Present Selected Research That has Driven Recent Advances in Clinical Cardiology◊
Department of Cardiology, National Heart Centre Singapore, Duke-NUS Graduate Medical School, Singapore, SingaporeArticle history:Available online 1 December 2011
group had symptomatic hypotension and renal dysfunction than those in the placebo group.
Although the main findings from both of these large RCTs were
negative, it should be noted that they were secondary prevention
In the past 2 years, a number of landmark clinical trials have been
studies—that is, patients already had established AF, and also had
published which further our understanding and clinical management
more advanced stages of disease (over 80% of patients in both studies
of patients with atrial fibrillation (AF). Two of the major goals in the
had a history of persistent or permanent AF), implying that the sub-
treatment of this condition include reducing progression or recur-
strate for AF was already well established in both study groups. It
rence of the arrhythmia and decreasing the risk of cardiovascular
might be argued that blockade of the renin-angiotensin system may
events, thereby improving quality of life and decreasing morbidity.
be a more effective strategy if performed earlier during the natural
Following on from a large body of evidence from preclinical studies,
history of the disease or even before AF develops (ie, primary preven-
small clinical trials and meta-analyses suggesting that blockade of the
tion), since angiotensin-converting enzyme inhibitors and ARBs may
renin-angiotensin system has beneficial effects on the pathophysiol-
prevent, but not necessarily reverse, the electrical and structural
ogy of AF,1 two large multicentre, placebo-controlled, randomised tri-
remodelling that leads to the development and progression of the
als were conducted to determine the effects of angiotensin II receptor
arrhythmia. In support of this, a smaller randomised single-centre
study of 62 patients with lone AF, with no history of hypertension or
The first of these trials, published in 2009, tested the hypothesis
heart disease, presenting to the emergency department reported that
that the ARB valsartan could reduce the recurrence of AF in patients
patients given ramipril (5 mg/day) had significantly fewer AF relapses
with underlying cardiovascular disease, diabetes or left atrial enlarge-
during a 3-year follow-up period than patients given placebo.4
ment and a history of documented AF, in addition to established
A significant new addition to the pharmacological options availa-
treatments.2 A total of 1442 patients were enrolled into the study—
ble for treating AF has been the emergence of dronedarone, a mul-
722 assigned to the valsartan group (target dose 320 mg) and 720 to
tichannel blocker with similar structural and electrophysiological
the placebo group. The investigators found that treatment with val-
properties to amiodarone with the main exception being removal of
sartan had no significant effect on AF recurrence (AF recurrence 51.4%
iodine and the addition of a methane-sulphonyl group.5 These struc-
in the valsartan group and 52.1% in the placebo group, P=.73) over a
tural changes result in decreased lipophilicity, shortened half-life (to
relatively short follow-up period of 1 year.
approximately 24 h), reduced tissue accumulation and theoretically
The second large ARB randomised controlled trial (RCT) published
fewer side effects than associated with amiodarone.
this year evaluated whether irbesartan would reduce the risk of car-
The ATHENA (A placebo-controlled, double-blind, parallel-arm
diovascular events in patients with AF.3 Patients with a history of risk
Trial to assess the efficacy of dronedarone 400 mg twice daily for the
factors for stroke and a systolic blood pressure of at least 110 mmHg
prevention of Hospitalisation or death from any cause in patiENts
were randomly assigned to receive either irbesartan (target dose of
with Atrial fibrillation/flutter) trial was a ground-breaking study pub-
300 mg once daily) or placebo. Patients for this study were already
lished in early 2009 evaluating the effect of dronedarone on cardio-
enrolled in one of two other AF trials looking at clopidogrel plus aspi-
vascular events in patients with AF.6 In this trial, 4628 patients with
rin vs aspirin alone or vs oral anticoagulants. The investigators found
AF (paroxysmal or persistent) or atrial flutter who had an additional
that irbesartan did not reduce cardiovascular events or hospitalisa-
risk factor for death (age ≥70 years, diabetes, history of stroke/tran-
tion rates for AF (total of 9016 enrolled with a mean follow-up of 4.1
sient ischaemic attack (TIA), systemic embolism, left atrial diameter
years) and that, not surprisingly, more patients in the irbesartan
≥50 mm and ejection fraction (EF) ≤40%) were randomly assigned to receive dronedarone (400 mg twice daily) or placebo. Over a mean follow-up of 21 (5) months, the investigators found that patients in
the dronedarone group had significantly lower primary outcome of
Reproduced with permission and in agreement with the authors and the editors.
first hospitalisation due to cardiovascular events or death than the
As previously published in: Heart. 2011;97:1734-43.
placebo group (734 [32%] vs 917 [39%], respectively, P<.001). Mortal-ity from cardiac arrhythmias was significantly lower in the dronedar-
*Corresponding author: Department of Cardiology, National Heart Centre
Singapore, 17 Third Hospital Avenue, Singapore 168752, Singapore.
one group, although there was no overall difference in all-cause
E-mail address: firstname.lastname@example.org
mortality. Interestingly, there was also a small but statistically signifi-
0300-8932/$ - see front matter. Published by Elsevier España, SL. on behalf of the Sociedad Española de Cardiología. R. Liew / Rev Esp Cardiol Almanac. 2011
cant reduction in acute coronary syndromes in the dronedarone
control with β blockers and/or digoxin (target heart rate <80 bpm at
group—the exact reason for this remains unclear. Patients taking
rest and <110 bpm after walking). The investigators found that resto-
dronedarone had higher rates of bradycardia, QT-prolongation, nau-
ration of sinus rhythm in patients with AF and heart failure improved
sea, diarrhoea, rash and increased serum creatinine than those receiv-
quality of life and LV function compared with a strategy of rate con-
ing placebo. There were no significant differences in rates of
trol (66% in the rhythm control group were in sinus rhythm at 1 year
thyroid- and pulmonary-related adverse events between the two
and 90% in the rate control group achieved the target heart rate). For
groups, although, as acknowledged by the investigators in their dis-
patients with AF for whom a rate control strategy has been decided
cussion, the follow-up period of 21 months might have been too short
upon, the optimal target heart rate has remained controversial. Guide-
to detect such adverse effects, which may take more than 2 years to
lines have previously recommended strict rate control, although this
develop, as is often observed with amiodarone.
was not based on clinical evidence. In an attempt to examine this
In the original ATHENA trial and also a subsequent post hoc
issue, a prospective, multicentre, randomised trial was conducted to
analysis,7 there was no evidence of harm in patients with heart failure
test the hypothesis that lenient rate control was not inferior to strict
or those with a low EF and New York Heart Association (NYHA) class
rate control in preventing cardiovascular events in patients with per-
II or III symptoms. This contrasts with results from the earlier
manent AF.17 The investigators found that of the 614 patients recruited
ANDROMEDA (ANtiarrhythmic trial with DROnedarone in Moderate
into the study, the frequencies of symptoms and adverse events were
to severe congestive heart failure Evaluating morbidity DecreAse)
similar between patients assigned to a lenient rate control strategy
study, which was terminated early owing to excess mortality in the
(resting heart rate <110 bpm) and those assigned to a strict rate con-
dronedarone group.8 The reason for this difference may be attributed
trol strategy (resting heart rate <80 bpm and heart rate during moder-
to the exclusion of patients with NYHA class IV symptoms in the ATH-
ate exercise <110 bpm). A lenient-control strategy was easier to
ENA study and the fact that the ANDROMEDA study also included
achieve as more patients in this group attained their heart rate target
patients with a recent exacerbation of heart failure. Nonetheless, in
compared with the strict-control group (97.7% vs 67%, P<.001).
view of the results from the ANDROMEDA study, the authors warned
Despite some promising results from preclinical experiments and
against use of dronedarone in patients with severe heart failure and
observational studies in humans,18-20 the potentially beneficial effects
left ventricular (LV) dysfunction. This is reflected in the latest Euro-
of polyunsaturated fatty acids (PUFA) in AF have not been confirmed
pean and American guidelines, which propose that dronedarone can
from the results of several prospective randomised trials reported
be used as a first-line pharmacological option in patients with symp-
recently. The largest and most comprehensive study to date designed
tomatic AF, including those with structural heart disease, coronary
to examine this subject was a prospective, multicentre, RCT of 663
artery disease, hypertensive heart disease and stable heart failure
patients with confirmed paroxysmal (n=542) or persistent (n=121)
with NYHA class I or II symptoms, but should not be used in patients
AF, with no substantial structural heart disease and in sinus rhythm at
with NYHA class III or IV symptoms or recently unstable heart
baseline.21 Patients were randomly assigned to take prescription PUFA
failure.9,10 A number of post hoc analyses of the ATHENA trial have
(8 g/day) or placebo for the first 7 days, followed by PUFA (4 g/day) or
been published providing further evidence for several beneficial
placebo thereafter for 24 weeks. Despite the assigned treatment being
effects of dronedarone. These include a reduction in stroke risk from
relatively well tolerated in both groups and plasma levels of eicosap-
1.8% a year to 1.2% a year,11 and favourable effects on rhythm and rate
entaenoic and docosahexaenoic acid being significantly higher in the
prescription group than in the placebo group at weeks 4 and 24, the
Another newly emerging drug that may have a role in the pharma-
investigators found no reduction in AF recurrence over 6 months
cological cardioversion of AF is the atrial-selective antiarrhythmic
between the two groups. Two smaller prospective, placebo-control-
drug vernakalant (RSD1235).13 Vernakalant is one of several new
led, randomised studies investigating the effects of PUFA in patients
agents that have been designed to target atrial-specific ion channels
after electrical cardioversion of AF22 and after cardiac surgery23 have
and in doing so, theoretically reduce or limit the risk of ventricular
failed to demonstrate a beneficial action of PUFA in decreasing the
proarrhythmia. In an open-label trial assessing the efficacy of ver-
nakalant in the cardioversion of AF, the intravenous agent was found to convert 50.9% of patients with AF (out of a total of 236) to sinus
Strategies to Decrease Thromboembolism
rhythm with a median time to conversion of 14 min among respond-ers.14 There were no episodes of ventricular arrhythmias and the drug
Important advances have been made in stroke prevention in
was relatively well tolerated, apart from 10 patients (4.2%) who had to
patients with AF over the past 2 years, which are likely to have a sig-
discontinue treatment owing to side effects (most commonly hypo-
nificant impact on future clinical management. In the RE-LY study
tension). In a more recent small randomised trial of 254 patients with
(Randomised Evaluation of Long-term anticoagulation therapY), two
recent onset AF (3-48 h duration), vernakalant (10 min infusion of 3
fixed doses (110 mg or 150 mg twice daily) of a new oral direct
mg/kg followed by a second 10 min infusion of 2 mg/kg if patient was
thrombin inhibitor, dabigatran, were compared with warfarin in over
still in AF after a 15 min observation period) was compared with
18 000 patients with AF and at least one additional risk factor for
intravenous amiodarone (5 mg/kg over 60 min followed by 50 mg
stroke.24 The investigators found that patients taking the 110 mg dose
maintenance infusion over 60 min).15 A greater number of patients
of dabigatran had similar rates of stroke and systemic embolism to
achieved the primary end point of conversion to sinus rhythm within
those receiving warfarin, but had lower rates of major haemorrhage,
90 min in the vernakalant group compared with the amiodarone
while subjects taking the 150 mg dose had lower rates of stroke and
group (60/116 [51.7%] compared with 6/116 [5.2%], P<.0001, respec-
systemic embolism, with similar rates of major haemorrhage. Results
tively). The median time of cardioversion in the patients receiving
from this study were so impressive that dabigatran has since been
vernakalant who responded was 11 min and this was associated with
incorporated into the latest European and American guidelines on AF
a higher rate of symptom relief than with amiodarone. Both drugs
as an alternative to warfarin for the prevention of stroke and systemic
were well tolerated in this study and there were no cases of ventricu-
embolism in patients with paroxysmal and permanent AF.9,25
As 80% of the active drug is excreted by the kidneys, patients with
A small randomised study of 61 patients with heart failure and
a creatinine clearance of <30 ml/min were excluded from the RE-LY
persistent AF contributed additional useful data towards the continu-
trial; dabigatran should be used with caution in patients with signifi-
ing topic of rate vs rhythm control in patients with heart failure and
cant renal impairment. The dose of dabigatran approved by the United
AF.16 Patients in this study were randomly assigned to a rhythm con-
States Food and Drug Administration in October 2010 was 150 mg
trol strategy (oral amiodarone and electrical cardioversion) or rate
twice daily in patients with non-valvular AF with a reduced dose of
R. Liew / Rev Esp Cardiol Almanac. 2011
75 mg twice daily for those with mild renal impairment (creatinine
neous left atrial appendage (LAA) closure device was compared with
clearance of 15-30 ml/min). There are no dosing recommendations
warfarin treatment in 707 patients with non-valvular AF. Study par-
for patients with a creatinine clearance <15 ml/min or those undergo-
ticipants had to have at least one risk factor for stroke (in addition to
ing dialysis. In addition to the superiority of dabigatran (150 mg twice
AF) and were assigned in a 2:1 ratio to receive the LAA-closure device
daily) over warfarin for treatment of stroke and systemic embolism,
and subsequent discontinuation of warfarin or warfarin alone (with a
another major advantage is that there is no need for international
target INR of between 2 and 3). The LAA-closure device was success-
normalisation ratio (INR) monitoring. However, disadvantages include
fully implanted in 88% of subjects assigned to the intervention group.
the lack of a specific antidote (its half-life is 12-17 h) and a slightly
After a mean follow-up of 18 (10) months, the primary efficacy event
increased risk of non-haemorrhagic side effects, including dyspepsia.
rate of stroke (ischaemic or haemorrhagic) was 3 per 100 patient-
How this promising new oral anticoagulant drug will be incorporated
years (95% confidence interval [95%CI], 1.9 to 4.5) in the intervention
into current local practices around the world will require future eval-
group and 4.9 per 100 patient-years (95%CI, 2.8 to 7.1) in the control
uation and consideration. For example, there may be little to be
group. Primary safety events were more common in the intervention
gained from switching patients already receiving warfarin and with
group than in the control group, and were mainly related to periproc-
excellent INR control to dabigatran, while patients with poor INR con-
edural complications (pericardial effusion in 4.8%, major bleeding in
trol or those who have newly started oral anticoagulation may derive
3.5% and periprocedural ischaemic stroke in 1.1%). This important
greater benefit. Local standards of care for anticoagulation control
study demonstrates that the Watchman (Atritech, Plymouth, Minne-
and follow-up may also be an important consideration, as concluded
sota, USA) LAA-closure device may provide an alternative strategy to
in a subanalysis of the RE-LY study, in which the investigators found
oral anticoagulation for the prevention of stroke in patients at high
that sites with poor INR control and greater bleeding from warfarin
risk with non-valvular AF and at high thromboembolic risk, although
may receive greater benefit from dabigatran 150 mg twice daily.26
the trade-off is an increased risk of periprocedural complications
Other substudies following on from the original RE-LY trial have
related to device implantation. As with all new interventional proce-
shown that the benefits of dabigatran are similar between patients
dures, safety of the Watchman LAA-closure device is likely to improve
who have never received a vitamin K antagonist (VKA-naive patients)
with increased operator experience and familiarity with the new
and VKA-experienced patients,27 and that dabigatran can be used as a
technology.34 Longer-term follow-up data with an earlier percutane-
safe alternative to warfarin in patients requiring cardioversion.28
ous LAA-closure device, PLAATO (Percutaneous Left Atrial Appendage
In the ACTIVE A study, the ACTIVE (Atrial Fibrillation Clopidogrel
Transcatheter Occlusion) system,35 suggest that such devices can
Trial with Irbesartan for prevention of Vascular Events) investigators
lower the annualised risk of stroke/TIA compared with the expected
evaluated whether the addition of clopidogrel to aspirin would reduce
stroke/TIA risk assessed using the CHADS score (3.8% a year and 6.6%
the risk of vascular events compared with aspirin alone in patients for
a year, respectively), although event rates still remain significant.36
whom a VKA was considered unsuitable.29 The ACTIVE W trial had previously demonstrated that the combination of aspirin and clopi-
Epidemiology and Genetics of Atrial Fibrillation
dogrel was inferior to oral anticoagulation for the prevention of vas-cular events in patients with AF at high risk of stroke.30 In the ACTIVE
Epidemiological studies have shed further light on the mecha-
A study, involving 7554 patients and a median follow-up of 3.6 years,
nisms underlying AF and identified new risk factors. Using data from
the investigators found that the combination of both antiplatelet
the Framingham Heart Study, investigators identified a prolonged PR
agents reduced the risk of major vascular events, especially stroke,
interval (>200 ms) as a predictor of incident AF, pacemaker implanta-
compared with aspirin alone but at the price of increased risk of
tion and all-cause mortality in 7575 individuals (mean age 47 years;
major haemorrhage. The clinical implications of the ACTIVE A and
54% women).37 This study contradicts the previously held belief that
ACTIVE W trials are that oral anticoagulation is better than the com-
first-degree heart block is benign38 and raises further questions about
bination of aspirin and clopidogrel in stroke prevention in patients
the mechanism by which a prolonged PR interval might increase the
with AF, but for patients for whom oral anticoagulation is unsuitable,
risk of developing AF. In another study using 4764 participants from
the combination of antiplatelet agents is better than aspirin alone,
the Framingham Heart Study, a new risk score was developed aimed
although the risk of major haemorrhage is also greater. This reinforces
at predicting an individual’s absolute risk for developing AF.39 Age,
the need for appropriate counselling and risk stratification of patients
sex, body mass index, systolic blood pressure, treatment for hyper-
when deciding upon the most suitable strategy to lower the risk of
tension, PR interval, clinically significant cardiac murmur and heart
failure were all found to be associated with AF (P<.05, except body
Another important randomised controlled clinical trial including
mass index P=.08). When incorporated in a risk score, the clinical
patients for whom a VKA was not suitable involved the use of new
model C statistic was 0.78 (95%CI, 0.76 to 0.80).
oral direct and competitive inhibitor of factor Xa, apixaban.31 The
In a subsequent study, the same investigators looked at the rela-
AVERROES (Apixaban vs acetylsalicylic acid to prevent stroke in
tion between a number of plasma biomarkers and incident AF using
patients with AF who have are unsuitable for vitamin K antagonist
the Framingham cohort and found that B-type natriuretic peptide
treatment or for whom this treatment has failed) study involved the
(BNP) was a predictor of incident AF and improved risk stratification,
random assignment of 5599 patients with AF (involving 522 centres
increasing the C statistic from 0.78 (95%CI, 0.75 to 0.81) to 0.80 (95%CI,
in 36 countries) to apixaban (5 mg twice daily) or aspirin (81-324 mg/
day).32 In that study, patients with AF were aged ≥50 years and had to
In another community-based population study of older adults
have at least one risk factor for stroke in addition to being unable to
(n=5445) who participated in the Cardiovascular Health Study (CHS),
take a VKA, either because it had already been shown to be unsuitable
N-terminal fragment of-BNP (NT-proBNP) was found to predict new-
or was deemed to be unsuitable. The investigators found that apixa-
onset AF, independently of any other previously described risk fac-
ban reduced the risk of stroke or systemic embolism without signifi-
tor.41 Similar findings have now been reported in a Finnish cohort.42
cantly increasing the risk of bleeding or intracranial haemorrhage and
The potential role of biomarkers may extend beyond predicting inci-
also reduced the risk of a first hospitalisation for a cardiovascular
dent AF—a recent study reporting that the kinetics of plasma NT-
proBNP release in patients presenting acutely with AF provides a
Recent studies in the field of new mechanical approaches to stroke
potential means of determining its time of onset and the safety of
prevention in AF include the PROTECT AF (Watchman Left Atrial
cardioversion.43 There therefore appears to be a promising role for
Appendage System for Embolic Protection in Patients with AF) study.33
new biomarkers in predicting incident AF, which may help guide cli-
In this non-inferiority study, the efficacy and safety of a new percuta-
nicians as to which individuals are most at risk of developing AF and
R. Liew / Rev Esp Cardiol Almanac. 2011
who may benefit from prophylactic treatments. Other studies looking
three patients (3%), and minor complications (arteriovenous [AV] fis-
at population data in women have reported body-mass index44 and
tula, femoral pseudoaneurysm and asymptomatic pulmonary vein
birth weight45 to be associated with incident AF. Furthermore, recent
stenosis) occurred in another three patients. The important point to
data from 34 722 participants of the Women’s Health Study provided
note from this study is that even in experienced hands with a selected
evidence that new-onset AF in initially healthy women was inde-
AF population (patients who are referred for AF ablation tend to be
pendently associated with all-cause and cardiovascular mortality.46
younger and have fewer comorbidities), there is a steady decline in
The past 2 years have seen important advances in our understand-
arrhythmia-free survival with recurrences seen up to 5 years after
ing of the genetics and heredity of AF. Following the landmark discov-
ablation, although the majority occur within the first 6-12 months.
ery using genome-wide association studies on subjects from European
An experienced German centre also recently reported their long-
and Chinese descent that two sequence variations on chromosome
term follow-up data of catheter ablation in 161 patients (75% male;
4q25 are associated with an increased risk of developing AF,47 two
age 59.8 [9.7] years) with symptomatic paroxysmal AF and normal LV
new AF susceptibility signals have been identified on the same chro-
function.58 They found that 75 patients (46.6%) were in sinus rhythm
mosome.48 A meta-analysis of four independent cohorts of European
after the initial procedure during a median follow-up period of 4.8
descent (the Framingham Heart Study, Rotterdam Study, Vanderbilt
years (0.33 to 5.5 years). A second procedure was performed in 66 and
AF Registry and German AF Network) confirmed a significant rela-
a third procedure in 12 patients. One patient had an aspiration pneu-
tionship between AF and intergenic regions on chromosome 4.49
monia that was successfully treated and two developed a sterile peri-
Interestingly, genetic variants in the chromosome 4q25 region also
cardial effusion that did not require drainage (no other procedural
appear to modulate the risk of AF recurrence after catheter ablation50
complications were noted). There was a low rate of progression to
and are associated with the development of AF after cardiac
chronic AF during the follow-up period, which was seen in only four
surgery.51,52 Whether genetic sequencing of chromosome 4q25 will
prove useful in risk stratification for the development of AF after cath-
A group from London, United Kingdom, similarly reported their
eter ablation or cardiac surgery remains to be determined—at present,
long-term results following catheter ablation for AF in 285 patients
this remains a distinct and promising possibility. In line with the
(75% male; mean age 57  years; 53% paroxysmal AF; 20% with
newly emerging genetic data on AF, studies on population-based
structural heart disease) undergoing a total of 530 procedures.59
cohorts have also provided evidence for a heredity component. Using
During a mean follow-up of 2.7 years (0.2 to 7.4 years), freedom from
data from the Framingham Heart Study, investigators found that
AF/atrial tachyarrhythmia was 86% for patients with paroxysmal AF
familial AF occurred in 1185 (26.8%) and premature familial AF
and 68% for those with persistent AF. Complications included three
occurred among 351 (7.9%) participants out of 4421 participants
strokes/TIAs. Late recurrence was three per 100 years of follow-up
(11 971 examinations) during the period 1968-2007.53 The association
after >3 years. The investigators also found that targeting complex
was not attenuated by adjustment for AF risk factors or reported AF-
fractionated atrial electrograms (CFAEs) during the ablation proce-
related genetic variants. Racial factors and ancestry also appear to be
dure improved outcome in patients with persistent AF. However, this
related to the risk of AF. Data from white and African-American sub-
was not seen in a randomised study performed by another group in
jects enrolled in the CHS and Atherosclerosis Risk in Communities
which 119 patients with persistent AF were randomised to additional
(ARIC) study suggest that European ancestry is a risk factor for inci-
CFAE ablation following pulmonary vein isolation or no additional
In summary, the reports on long-term success rates following
Catheter Ablation of Atrial Fibrillation
catheter ablation for AF demonstrate that the procedure is effective in a selected group of symptomatic patients with AF, although a significant
In a large prospective, multicentre trial involving 19 centres, the
proportion require more than one ablation procedure, there are risks of
use of catheter ablation was compared with antiarrhythmic drug
periprocedural complications and AF recurrence remains a possible
treatment.55 A total of 167 patients with paroxysmal AF for whom at
problem, even after follow-up periods as long as 5 years. It should be
least one antiarrhythmic drug had failed and who had experienced at
noted that reported outcomes from the different centres cannot be
least three AF episodes in the preceding 6 months were randomised
directly compared, since there are differences in patient population
(2:1) to undergo catheter ablation or medical treatment. After a 9
(eg, percentage of patients with paroxysmal and permanent AF, patients
month follow-up period, the investigators found that catheter abla-
with structural heart disease), techniques used (segmental pulmonary
tion resulted in a longer time to treatment failure and significantly
vein isolation vs wide area circumferential ablation), length of
improved quality-of-life scores. Major 30-day treatment-related
follow-up and methods used to detect AF recurrence.
adverse events occurred in five of 103 patients (4.9%) treated with
A number of studies have been performed to search for new non-
catheter ablation and five of 57 patients (8.8%) treated with
invasive parameters which may help to predict AF recurrence follow-
antiarrhythmic drugs. An improvement in the quality of life was also
ing catheter ablation. These factors include renal impairment,61 novel
demonstrated in a prospective follow-up study of 502 symptomatic
echo parameters such as the atrial electromechanical interval,62 atrial
subjects who underwent AF ablation.56 The improvement in quality of
fibrosis assessed with echo63 or magnetic resonance imaging (MRI)64
life was sustained at 2 years in patients with and without recurrence
of AF, although the change was greatest in patients who remained free from AF and without antiarrhythmic drug treatment. VENTRICULAR ARRHYTHMIAS AND SUDDEN CARDIAC DEATH
Several well-respected, high-volume centres have recently pub-
lished their long-term outcomes following catheter ablation for AF.
Ventricular Arrhythmias After Myocardial Infarction
The Bordeaux group reported their 5 year follow-up data on 100 patients (86% male; age 55.7 [9.6] years; 63% paroxysmal AF; 36%
To further understand the significance of the occurrence and
with structural heart disease).57 Arrhythmia-free survival rates after a
timing of ventricular arrhythmias in the context of primary
single catheter ablation procedure were 40%, 37% and 29% at 1, 2 and
percutaneous coronary intervention (PCI), a secondary analysis of the
5 years, respectively (most recurrences occurred over the first 6
APEX AMI (Assessment of PEXelizumab in Acute Myocardial
months). A total of 175 procedures were performed with a median of
Infarction) trial was undertaken.66 Of the 5745 patients with
two for each patient (51 patients underwent a second procedure and
ST-elevation myocardial infarction presenting for primary PCI (across
17 a third). There were no periprocedural deaths, although major
296 hospitals in 17 countries), ventricular tachycardia/ventricular
complications (cardiac tamponade requiring drainage) occurred in
fibrillation (VT/VF) occurred in 329 (5.7%). Clinical outcomes and
R. Liew / Rev Esp Cardiol Almanac. 2011
90-day mortality were found to be worse in those with VT/VF than in
Another important area requiring further clarification is the
those without. Furthermore, outcomes were worse if the VT/VF
optimal timing of ICD insertion among AMI survivors who are deemed
occurred late (after the end of cardiac catheterisation) rather than
to be at greatest risk of SCD. The landmark DINAMIT study
early (before the end of cardiac catheterisation). The occurrence of
(Defibrillation IN Acute Myocardial Infarction Trial), which did not
ventricular arrhythmias remained associated with a significantly
show any mortality benefit from prophylactic ICD insertion in patients
increased mortality after adjustment for potential confounders,
after AMI if the device was inserted within 40 days of the index
although whether they were causally related to a poorer prognosis or
event,79 has been used to guide current recommendations on ICD
simply a reflection of more severe heart disease is not yet clear.
insertion among AMI survivors. A recent secondary analysis of this
In the Occluded Artery Trial-Electrophysiological Mechanisms
trial confirmed the original findings that the reduction in sudden
(OAT-EP) study, PCI to open a persistently occluded infarct-related
death in ICD patients was offset by an increase in non-arrhythmic
artery after an acute myocardial infarction (AMI) phase was compared
deaths, which was greatest in those who received ICD shocks.80
with optimal medical treatment alone to determine which strategy
A postmortem study looking at 105 autopsy records of patients
reduced markers of vulnerability to ventricular arrhythmias.67 There
from the VALIANT (VALsartan In Acute myocardial infarctioN Trial)
were no significant differences in heart rate variability, time-domain
study who had died suddenly showed that recurrent myocardial
signal-averaged ECG, or T-wave variability parameters (all surrogate
infarction or cardiac rupture accounted for a high proportion of
markers of ventricular instability) between either group at 30 days
sudden death in the early period after an AMI, thereby partly
and 1 year after the AMI, which is consistent with the lack of clinical
explaining the lack of benefit of early ICD insertion on overall
benefit from PCI in stable patients after AMI with persistently
mortality.81 Arrhythmic death was more likely to occur later on (after
occluded infarct-related arteries in the main OAT study.
3 months), which is consistent with the findings of improved survival
The CARISMA (Cardiac Arrhythmias and Risk Stratification After
among ICD recipients from other major ICD trials in which the devices
Myocardial Infarction) trial was designed to investigate the incidence
were inserted at a later stage. It should be noted, however, that 20% of
and prognostic significance of arrhythmias detected by an
sudden deaths in the first month after AMI were presumed arrhythmic
implantable cardiac monitor among patients after AMI with
as there was no specific postmortem evidence of any additional
impaired LV function.68 A total of 297 patients (out of 5969 initially
abnormality that might have caused the sudden death. A significant
screened) who had had a recent AMI and had reduced LVEF (≤40%)
proportion of patients who have an AMI therefore appear to continue
received an implantable loop recorder within 11 (5) days of the AMI
to die suddenly in the early postinfarction period from cardiac
and were followed up every 3 months for an average of 1.9 (0.5)
arrhythmias. These patients are not included in current international
years. The investigators detected a clinically significant number of
guidelines for ICD insertion and remain a group for which more
bradyarrhythmias and tachyarrhythmias in these patients (28%
research is required. Another group of patients who are not covered
new-onset AF, 13% non-sustained VT, 10% high-degree AV block, 7%
by current primary prevention ICD guidelines are those with relatively
significant sinus bradycardia, 3% sinus arrest, 3% sustained VT and
preserved LVEF after an AMI. Although these patients are at lower risk
3% VF). In particular, intermittent high-degree AV block was
of SCD than those with poor LVEF, they represent a larger proportion
associated with a very high risk of cardiac death. The arrhythmogenic
substrate for ventricular arrhythmias following reperfusion therapy
Data from a multicentre Japanese study suggest that in the era of
for AMI was investigated in a study of 36 AMI survivors referred
primary PCI there is a low incidence of SCD among AMI survivors
for catheter ablation of VT (13  years after the AMI).69 Of these,
(overall mortality was 13.1% and SCD 1.2% over an average follow-up
14 patients had early reperfusion during AMI, while 22 were non-
period of 4.2 years among 4122 patients).82 The risk was highest for
reperfused. The investigators found, using detailed electroanatomical
those with poor LVEF (<30%), although the absolute number at risk
mapping, that scar size and pattern were different between VT
was greatest in those with relatively preserved LVEF (>40%).
patients with and without reperfusion during AMI, with early
The Intermediate Risk Stratification Improves Survival (IRIS) trial
reperfusion and less confluent electroanatomical scar being
published in 20 09 further tested the hypothesis that early
implantation of an ICD soon after an AMI could improve survival compared with optimal medical treatment. 83 This was a randomised,
Risk Stratification for Sudden Cardiac Death and Implantable
prospective, multicentre trial which enrolled 898 patients, 5-31 days
after their AMI, who met the following clinical criteria: LVEF ≤40% and a heart rate ≥90 bpm on the first available ECG or non-sustained VT
A continuing area of active research in ventricular arrhythmias
(≥150 bpm) during Holter monitoring. The main difference between
and sudden cardiac death (SCD) is in improved methods of risk
this study and DINAMIT was a contemporary patient population (70%
stratification and selection of appropriate implantable cardioverter
had undergone PCI and the majority were receiving optimal long-
defibrillator (ICD) recipients.70 A numb er of non-invasive
term medication) and additional non-invasive criteria to identify a
cardiovascular tests have recently been evaluated among patients
population at potentially higher risk. However, the investigators did
with an increased risk of SCD (eg, AMI survivors and patients with
not find that ICD therapy reduced overall mortality after a mean
coronary artery disease and cardiomyopathies) with promising
follow-up of 37 months. Consistent with the findings from DINAMIT,
results. These include T-wave alternans,71,72 single-photon emission
the reduced incidence of SCD among ICD recipients in the IRIS study
computed tomography myocardial perfusion imaging,73 sympathetic
was offset by an increased incidence of non-SCD.
nerve imaging with 123-iodine metaiodobenzylguanidine74 and late-gadolinium enhancement on cardiac MRI.75 In addition, plasma
Catheter Ablation of Ventricular Arrhythmias
biomarkers, such as serum collagen levels, which reflect extracellular matrix alterations that may play a part in the generation of the
The VTACH (Ventricular Tachycardia Ablation in Coronary Heart
arrhythmogenic substrate,76 may have a future role in risk
disease) study, involving 16 centres in four European countries,
stratification. Genetic markers may also be relevant, as suggested by
assessed the potential benefit of catheter ablation of VT before ICD
the observation from a combined population of 19 295 black and
implantation in patients with a history of VT, myocardial infarction
white adults from the ARIC Study and the CHS that sequence
and LVEF ≤50%.84 Patients (n=110) were randomly allocated to receive
variations in the nitric oxide synthase 1 adaptor protein (NOS1AP)
catheter ablation and an ICD or an ICD alone and followed-up for a
were associated with baseline QT interval and the risk of SCD in white
mean period of 22.5 (9) months. The investigators found that prophy-
(but not black) United States adults.77,78
lactic VT ablation before ICD implantation prolonged the time to VT
R. Liew / Rev Esp Cardiol Almanac. 2011
recurrence from 5.9 months (IQR 0.8-26.7) in the ICD only group to
ure and that there was no significant difference in mortality between
18.6 months (lower quartile 2.4 months; upper quartile could not be
the two groups (which was 3% annually). Furthermore, the study
determined) in the ablation and ICD group. Complications related to
failed to show that NYHA class I patients fulfilling the enrolment cri-
the ablation procedure occurred in two patients. This study is in
accordance with an earlier prospective randomised study of
In RAFT (Resynchronisation-defibrillation for Ambulatory heart
128 patients, which demonstrated that prophylactic catheter ablation
Failure Trial), CRT-D was compared with ICD alone in patients with
of the ventricular arrhythmogenic substrate reduced the incidence of
NYHA class II or III heart failure, LVEF ≤30%, intrinsic QRS duration
ICD therapy in patients with a history of myocardial infarction and
≥120 ms or a paced QRS duration of ≥200 ms.94 The investigators
previous ventricular arrhythmias.85 It should be noted that VT abla-
found that over a mean period of 40 months, the primary outcome
tion was performed in experienced centres in both these trials and
(all-cause mortality or heart failure hospitalisation) occurred in fewer
that there was no significant effect of catheter ablation on overall
patients in the CRT-D group (33.2% compared with 40.3% in the ICD
mortality. Whether VT ablation should routinely be performed before
group, P<.001). Unlike MADIT-CRT, RAFT demonstrated that CRT-D
ICD insertion for secondary prevention of SCD in stable patients with
significantly reduced overall mortality and cardiovascular mortality
previous myocardial infarction remains to be determined.
compared with ICD alone, although more adverse device-related
There has been an increase in the number of publications on epi-
events were also seen in the CRT-D group. Possible reasons for mor-
cardial ablation for VT over the past few years in view of the realisa-
tality benefit seen in RAFT, but not MADIT-CRT, are that RAFT included
tion that not all VTs can be successfully eliminated by an
patients with more advanced disease (and a higher proportion with
endocardial-only approach.86,87 In a retrospective study of 156 epicar-
ischaemic heart disease) and follow-up was longer and more com-
dial ablations for VT (out of a total of 913 VT ablations) in three terti-
ary centres evaluating the safety and mid-term complications of
A number of subanalyses of MADIT-CRT have since been con-
epicardial VT ablation, the risk of major acute (epicardial bleeding,
ducted to provide further information on the findings. One subanaly-
coronary stenosis) and delayed (pericardial inflammatory reaction,
sis demonstrated that women experienced significantly greater
delayed tamponade, coronary occlusion) complications related to
reductions in all-cause mortality and heart failure than men, which
epicardial access was found to be 5% and 2%, respectively.88 Therefore,
was accompanied by greater echo evidence of reverse cardiac remod-
although this technique can be effective in some cases, especially
elling.95 Another subanalysis looking specifically at the echo parame-
where endocardial ablation has failed, it is associated with significant
ters and performance between the two groups found that CRT
morbidity and should only be performed in centres experienced with
significantly improved cardiac size and performance compared with
the ICD-only strategy, which probably accounted for the outcomes
The prognostic significance of frequent premature ventricular
benefit in the CRT-D group.96 Other studies have also provided addi-
contractions (PVCs) and the effect of catheter ablation of these ectop-
tional echo evidence that CRT in mild heart failure (NYHA class I/II)
ics has received further attention recently. In a study of 239 asympto-
results in major structural and functional reverse remodelling which
matic patients with structurally normal hearts and frequent PVCs
may prevent disease progression.97,98 The PACE (Pacing to Avoid Car-
(>1000/day) from the right or LV outflow tract, a significant negative
diac Enlargement) study explored whether biventricular pacing was
correlation between PVC prevalence and δLVEF and positive correla-
better than RV apical pacing in preventing adverse cardiac remodel-
tion with δLV diastolic diameter was observed over a 5.6 (1.7)-year
ling in patients with bradycardia and normal ventricular function at
period.89 In addition to PVC burden, other factors such as longer PVC
baseline.99 In this small randomised study of 177 patients followed up
duration, presence of non-sustained VT, multiform PVCs and right
over a 12-month period, the investigators found that the mean LVEF
ventricular (RV) PVCs may be associated with a decline in LV
was significantly lower in the RV-pacing group than in the biventricu-
function.90,91 Although it is well known that catheter ablation of fre-
lar-pacing group (54.8 [9.1]% vs 62.2 %, P<.001), with an absolute
quent PVCs can improve and restore LV function in some patients, the
difference of 7.4% points. However, the beneficial effects of biven-
potential benefits of ablation in patients with normal LV function
tricular pacing on echo parameters in this group of patients were not
have been less well studied. A prospective study of 49 patients with
accompanied by any clinical benefit.
frequent PVCs and normal baseline LVEF demonstrated that catheter
Other important and continuing areas of investigation in the field
ablation can improve the subtle LV dysfunction-detected pre-ablation
of CRT include how best to select candidates who are most likely to
using speckle tracking imaging analysis.92 However, unanswered
respond to CRT and how to optimise response. Parameters that have
questions remain, including benefits of catheter ablation on hard end
recently been studied to improve patient selection include QRS mor-
points (especially mortality) and when ablation should be performed
phology in MADIT-CRT (left bundle branch block [LBBB], rather than
(degree of PVC burden, LV function, after a trial of antiarrhythmic
non-LBBB, patterns appears to be the predominant morphology—that
is, related to response),100 baseline LV radial dyssynchrony, discordant LV lead position, and myocardial scar in the region of the LV pacing
CARDIAC RESYNCHRONISATION THERAPY AND PACING
lead,101 and pre-pacing systolic dyssynchrony measured by tissue Doppler imaging velocity.102 Consistent with existing knowledge, LV
Two pivotal cardiac resynchronisation therapy (CRT) clinical trials
lead positioning has been reconfirmed to be important in MADIT-CRT
have been published in the past 2 years that potentially expand the
patients103 and patients with non-ischaemic dilated cardiomyopa-
indications for CRT in patients with heart failure to those in NYHA
thy.104 The prospective, randomised SMART-AV (SmartDelay deter-
class I and II symptoms. MADIT-CRT (Multicenter Automatic Defibril-
mined AV optimisation: a comparison with other AV delay methods
lator Implantation Trial-CRT) compared the use of ICD alone with
used in CRT) study compared three different methods of AV optimisa-
CRT-D (CRT with a defibrillator component) in patients with asymp-
tion (fixed empirical AV delay of 120 ms, echo-optimised AV delay, or
tomatic or mildly symptomatic heart failure symptoms (NYHA class I
AV optimisation with an ECG-based algorithm) in 980 patients with a
or II), LVEF ≤30% and QRS duration of ≥130 ms.93 During an average
CRT device to determine if any method was superior.105 The study
follow-up of 2.4 years, fewer patients in the CRT-D group experienced
found that neither echo- or ECG-based AV optimisation was better
the primary composite end point (all-cause mortality and heart fail-
than a fixed AV delay of 120 ms and therefore concluded that the rou-
ure) compared with the ICD group (17.2% compared with 25.3%,
tine use of AV optimisation techniques was not indicated. However,
respectively, P=.001). Although these results appear impressive at first
the data did not exclude the possibility that AV optimisation might
glance, closer examination of the data reveals that the main superior-
have a role in selected patients who do not respond to CRT with
ity of CRT-D was in reducing the rate of hospitalisation for heart fail-
R. Liew / Rev Esp Cardiol Almanac. 2011
The potentially deleterious effects of chronic RV pacing on cardiac
rs16847548 and rs10494366) were genotyped to assess the effect of
function were re-examined in 103 patients with isolated congenital AV
variant alleles on QTc and on the incidence of cardiac events.117 The
block. Long-term pacing was not found to be associated with the
investigators found that variant alleles tagged by SNPs rs4657139 and
development of heart failure or deterioration of ventricular function in
rs16847548 were associated with an average QTc prolongation of
patients who were negative for antinuclear antibody, although patients
7 ms and 8 ms, respectively, whereas rs4657139 and rs10494366 were
who tested positive for the antibody were more likely to develop heart
associated with an increased incidence of cardiac events. Furthermore,
failure.106 Pacing in hypertrophic cardiomyopathy was also recently
the rs10494366 minor allele was an independent prognostic marker
re-examined in a single-centre study, which found some evidence of
among patients with QTc <500 ms, but not in the entire cohort. These
benefit from dual chamber pacing in patients with hypertrophic
two studies demonstrate that genetic testing for variants in the NOS1AP
cardiomyopathy with NYHA III-IV symptoms, rest gradients of
and tagged SNPs may be clinically useful for risk stratification of
>50 mmHg and who were refractory to other drugs, after follow-up
patients with congenital LQTS and potentially guide the choice of
periods of up to 10 years.107 Another group of patients in whom the role
of pacing has remained controversial are those with carotid sinus
The FINGER (France, Italy, Netherlands, GERmany) registry, one of
hypersensitivity (CSH) with syncope. In a double-blind, placebo-
the largest series on patients with Brugada syndrome (BrS) so far,
controlled, crossover study, 34 patients (aged >55 years) with CSH and
involved 1029 consecutive individuals (745 men; 72%) with BrS (with
more than three unexplained falls in the preceding 6 months were
a spontaneous or drug-induced type I ECG) who were followed up for a
randomised to receive a dual-chamber pacemaker with rate-drop
median period of 31.9 months.118 The cardiac event rate per year was
response programming which was switched on or off.108 The
7.7% in patients with aborted SCD, 1.9% in patients with syncope and
investigators found that the pacing intervention had no effect on the
0.5% in asymptomatic patients. This study provides important
number of falls and concluded that the role of pacing for this group of
information that the event rate among asymptomatic patients with a
patients remains controversial. A similar conclusion was reached in a
Brugada ECG (which comprised 64% of subjects in the registry) is low.
multicentre study of 141 patients (mean age 78 years) with
In addition, symptoms and a spontaneous type 1 ECG were predictors
of arrhythmic events, whereas gender, familial history of SCD, inducibility of VTs during an EP study and the presence of an SCN5A
INHERITED ARRHYTHMOGENIC DISEASES
mutation were not predictive of arrhythmic events.
In an interesting mechanistic study of BrS, in vivo high-density
Major advances have been made in our understanding of the basic
mapping using non-contact mapping array was performed in the
mechanisms, genetics and clinical features of the inherited arrhyth-
right ventricle of 18 patients with BrS and 20 controls.119 The
mogenic diseases (IADs) over the past 2 years. Since these cannot all
investigators identified marked regional endocardial conduction
be covered in this short overview, only some of the major studies with
delay and heterogeneities in repolarisation in patients with BrS and
important implications for general cardiologists will be mentioned.
proposed that the slow-conduction zones may have a role in the
The rapid expansion in our knowledge of the genetic basis of the IADs
initiation and maintenance of ventricular arrhythmias.
and rise in commercially available clinical genetic services has
In line with these findings, an outstanding study was subsequently
brought with it an additional dimension to how we manage these
performed in which nine symptomatic patients with BrS who had
conditions. The reader is referred to a number of useful recently pub-
recurrent VF episodes underwent endocardial and epicardial mapping
lished reviews that examine these issues in more detail.110-112
of the right ventricle. Ablation at unique abnormal low voltage sites
SCD without morphological evidence of heart disease accounted for
(clustering exclusively in the anterior aspect of the RV outflow tract
23% of cases in a recent pathological study of United Kingdom athletes.113
[RVOT] epicardium) rendered VT/VF non-inducible in seven of the
Potential causes of unexplained cardiac arrest were systematically
nine patients, with no recurrence of ventricular arrhythmias in all
evaluated in a prospective study involving 63 patients in nine centres
patients over a follow-up period of 20 (6) months. Interestingly,
across Canada.114 The tests, which included cardiac MRI, signal-averaged
normalisation of the Brugada ECG pattern was seen in eight patients
ECG, exercise testing, drug challenge and selective electrophysiology (EP)
after ablation. This important proof-of-concept study lends further
testing, resulted in a specific diagnosis (IAD, early repolarisation,
support to the notion that the underlying EP mechanism in patients
coronary spasm and myocarditis) in 35 patients (56%). The remaining
with BrS is delayed depolarisation in the RVOT (specifically over the
28 patients were considered to have idiopathic VF. Subsequent genetic
anterior epicardial region) and demonstrates for the first time that
testing performed in 19 patients found evidence of causative mutations
substrate modification may be an effective strategy in patients with
in nine (47%) of these. Family screening of 64 family members of the
symptomatic BrS with recurrent VF episodes.
nine patients with causative mutations led to the discovery of mutations
Flecainide has recently emerged as a promising new treatment for
in 15 individuals (23%), who were subsequently treated. This study
catecholaminergic polymorphic ventricular tachycardia (CPVT). In a
provides evidence that targeted genetic testing may play a part in helping
mouse model of CPVT, flecainide was found to prevent arrhythmias
to diagnose genetically mediated arrhythmia syndromes, which may
by inhibiting cardiac ryanodine receptor-mediated calcium release.120
result in successful family screening.
In the same publication, flecainide also completely prevented CPVT in
An important study that investigated the presence of genetic factors
two patients who had remained highly symptomatic with conven-
or modifiers that could partly explain the phenomenon of incomplete
tional drug treatment. In a clinical study of 33 patients who had
penetrance seen in congenital long QT syndrome (LQTS) identified the
received flecainide because of exercised-induced ventricular arrhyth-
NOS1AP as one such candidate.115 This protein was chosen on the basis
mias despite conventional treatment, flecainide was found to either
of previous studies that showed an association between genetic
partially or completely reduce the arrhythmias in 76% of cases.121
variants of NOS1AP and small quantitative increases in the QT interval and an increased risk of death in a general population.77,116 In the study
CONFLICTS OF INTEREST
involving a South African LQTS population (500 subjects, 205 mutation carriers), NOS1AP variants were found to be significantly associated
with the occurrence of symptoms, clinical severity (including cardiac arrest and SCD) and a greater likelihood of having a QT interval in the
top 40% of values among all mutation carriers. In another study
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Today’s Therapist International Trade Journal - Issue 43 Nov Dec 2006 The Bowen Technique Knock on effects of pain relief The effects of sorting out one physical problem can often have other happy consequences in a person’s state of health 13 April 2006: one week later, he came for his second Bowen and well being. This was illustrated very well in the case of treatment. He rep
Conseil Municipal : Séance du 11 octobre 2012 Sous la Présidence de Monsieur Philippe CANOT, Maire. Présents : Mmes Copinne, Peltier et Roynette Mrs Arnould, Ducoudray, Hugueville, Peltier et Valsesia . Absents : Mr Robin procuration à Mr Valsesia. Mme Lesage procuration à Mr Peltier. Secrétaire de séance : Mme Copinne Jeannine. Approbation du procès-ver