prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan...

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Congestive Heart Failure

Prevention of atrial fibrillation in patients with

symptomatic chronic heart failure by candesartan

in the Candesartan in Heart failure: Assessment of

Reduction in Mortality and morbidity

(CHARM) programAnique Ducharme, MD, MSc,a Karl Swedberg, MD,b Marc A. Pfeffer, MD, PhD,c Alain Cohen-Solal, MD, PhD,d

Christopher B. Granger, MD,e Aldo P. Maggioni, MD,f Eric L. Michelson, MD,g John J.V. McMurray, MD,h

Lars Olsson, MD,b Jean L. Rouleau, MD,a James B. Young, MD,i Bertil Olofsson,j Margareta Puu,j and

Salim Yusuf MD, DPhilk on behalf of the CHARM Investigators Montreal and Hamilton, Canada; Goteborg, and

Molndal, Sweden; Boston, MA; Clichy, France; Durham, NC; Florence, Italy; Wilmington, DE; Glasgow, UK; and

Cleveland, OH

Background Atrial fibrillation (AF) is frequent in patients with chronic heart failure (CHF). Experimental and small

patient studies have demonstrated that blocking the renin-angiotensin-aldosterone system may prevent AF. In the CHARM

program, the effects of the angiotensin receptor blocker candesartan on cardiovascular mortality and morbidity were

evaluated in a broad spectrum of patients with symptomatic CHF. CHARM provided the opportunity to prospectively

determine the effect of candesartan on the incidence of new AF in this CHF population.

Methods 7601 patients with symptomatic CHF and reduced or preserved left ventricular systolic function were

randomized to candesartan (target dose 32 mg once daily, mean dose 24 mg) or placebo in the 3 component trials of

CHARM. The major outcomes were cardiovascular death or CHF hospitalization and all-cause mortality. The incidence

of new AF was a prespecified secondary outcome. Median follow-up was 37.7 months. A conditional logistic regression

model for stratified data was used.

Results 6379 patients (83.9%) did not have AF on their baseline electrocardiogram. Of these, 392 (6.15%) developed

AF during follow-up, 177 (5.55%) in the candesartan group and 215 (6.74%) in the placebo group (odds ratio 0.812, 95%CI

0.662-0.998, P = .048). After adjustment for baseline covariates, the odds ratio was 0.802 (95% CI 0.650-0.990, P =

.039). There was no heterogeneity of the effects of candesartan in preventing AF between the 3 component trials ( P = .57).

Conclusions Treatment with the angiotensin receptor blocker candesartan reduced the incidence of AF in a large,

broadly-based, population of patients with symptomatic CHF. (Am Heart J 2006;0:1-7.)

Atrial fibrillation (AF) is common in patients with

chronic heart failure (CHF), and its prevalence increases

with the severity of the disease, reaching up to 40% in

advanced stages.1,2 The development of AF, with an

ensuing decline in cardiac function, may also cause

hemodynamic and symptomatic deterioration leading to

a reduction in exercise capacity, as well as deterioration

of functional class.3 This, in turn, may lead to hospital

admission, other morbidity (eg, stroke), and, possibly, to

increased mortality. Whether AF is an independent

predictor of an increased risk of death is, however,

controversial with some studies4 -6 supporting this

conclusion, but others show no independent effect.7,8

Irrespective of its effect on death, the development of

AF is clearly undesirable in CHF, and treatments that

may prevent it are conceptually attractive in CHF.9

Experimental CHF induced by rapid ventricular pacing

is associated with electrical and structural atrial remod-

From the aMontreal Heart Institute, Montreal, Canada, bSahlgrenska University Hospital/

Ostra, Goteborg, Sweden, cBrigham & Women’s Hospital, Boston, MA, dCardiologie,

Hopital Beaujon, Clichy, France, eDuke University Medical Center, Durham, NC,fANMCO Research Center, Florence, Italy, gAstraZeneca LP, Wilmington, DE, hCardiol-

ogy, Western Infirmary, Glasgow, UK, iMedicine, Cleveland Clinic Foundation,

Cleveland, OH, jAstraZeneca, Molndal, Sweden, and kCardiology, McMaster University,

Hamilton, Canada.

Submitted March 7, 2005; accepted June 21, 2005.

The CHARM program was sponsored by AstraZeneca, Molndal, Sweden.

Reprint requests: Anique Ducharme, MD, MSc, Montreal Heart Institute, 5000 Belanger

Street East, HIT 1C8 Montreal, Quebec, Canada.

E-mail: [email protected]

0002-8703/$ - see front matter

n 2006, Mosby, Inc. All rights reserved.

doi:10.1016/j.ahj.2005.06.036

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eling, including dilation, contractile dysfunction, and

fibrosis.10,11 These changes, which lead to increased

susceptibility to AF, may be attenuated by treatment

with angiotensin-converting enzyme (ACE) inhibi-

tors.12,13 Recently, treatment with agents interfering

with the renin-angiotensin-aldosterone system (RAAS)

has also been shown to reduce the incidence of AF in

several different patient groups, including after myocar-

dial infarction (MI),14 in left ventricular systolic dys-

function,15 in symptomatic heart failure (HF) and

reduced left ventricular ejection fraction (LVEF),16 and

in hypertension with left ventricular hypertrophy

(LVH).17 The angiotensin receptor blocker (ARB),

irbesartan, has also been reported to prevent recurrence

of AF after electrical cardioversion.18

The CHARM program evaluated the effects of the ARB

candesartan on cardiovascular (CV) mortality and mor-

bidity and on total mortality in a broad spectrum of

patients with symptomatic CHF. The present report

describes a prespecified secondary analysis of the effect

of candesartan on the incidence of new AF in the

overall CHARM program. This modernly managed

international cohort included patients with reduced

as well as preserved LVEF.

MethodsStudy populationThe design and main results of the CHARM program have

been previously described in detail.19,20 Briefly, 7601 patients

(7599 with data) with symptomatic CHF in New York Heart

Association (NYHA) classes II to IV were randomized to

candesartan (target dose 32 mg once daily, mean dose 24 mg)

or placebo. Patients were enrolled into 1 of the 3 component

trials based on LVEF and treatment with an ACE inhibitor.

CHARM-Alternative21 included patients with LVEF V0.40 not

treated with ACE inhibitors because of prior intolerance.

CHARM-Added22 included patients with LVEF V0.40 treated

with an ACE inhibitor. CHARM-Preserved23 enrolled patients

with LVEF N0.40 and allowed ACE inhibitor treatment in

patients meeting specific eligibility criteria. Major exclusion

criteria included serum creatinine z265 Amol/L, potassium

z5.5 mmol/L, and symptomatic hypotension. The primary

outcome of each component trial was CV death or admission to

hospital with worsening CHF, and the primary outcome of the

overall program was all-cause mortality. Follow-up visits were

scheduled at weeks 2, 4, and 6 months; month 6 after

randomization; and every 4 months thereafter until the end of

the study. At the end of the study, we assessed whether a

diagnosis of new AF had been made during the median follow-

up of 37.7 months from randomization. A specific case report

form about AF was used at the final or closing visit, asking

whether the patient had developed AF/flutter after randomi-

zation (yes or no) while blinded to treatment allocation. In the

attached instructions for the investigator, it was specified,

bMark dNoT if the patient had AF on the visit 1 ECG or if the

patient had a diagnosis of AF/flutter before randomization.Q

If the answer was byes,Q questions regarding the description of

the episode followed, including whether an electrocardiogram

Table I. Baseline characteristics of patients developing AFduring the course of CHARM

AF duringstudy

(n = 392)

No AF duringstudy

(n = 5987) P

Demographic characteristicsAge (means [SD]) 67.2 (10.2) 65.3 (11.1) .0003Men/women 75.0%/25.0% 67.7%/32.3% .0003European origin 360 (91.8%) 5368 (89.7%)

Black 17 (4.4%) 270 (4.5%)Other 15 (3.8%) 349 (5.8%0 .246

Heart disease risk factorsNYHA class

II 147 (37.5%) 2780 (46.4%)III 232 (59.2%) 3072 (51.3%) .002IV 13 (3.3%) 135 (2.3%)

LVEF (%) (mean [SD]) 0.35 (0.14) 0.39 (0.15)b30 145 (37.0%) 1643 (27.4%)30-39 118 (30.1%) 1743 (29.1%) b.000140-49 62 (15.8%) 1060 (17.7%)z50 67 (17.1%) 1541 (25.7%)

Heart rate (beat/min)(means [SD])

72.04 (12.1) 72.2 (12.6) .769

Blood Pressure (mm Hg [SD])Systolic 130.26 (20.5) 131.1 (19.2) .442Diastolic 76.0 (10.8) 76.6 (10.7) .279

Body mass index(kg/m2) (means [SD])

28.428 (5.6) 28.245 (5.4) .534

LVH on ECG 71 (18.1%) 908 (15.2%) .117Medical History

Hospitalization for CHF 288 (73.5%) 4156 (69.4%) .077Myocardial infarction 234 (59.7%) 3326 (55.6%) .110Angina pectoris 242 (61.7%) 3579 (59.8%) .444Stroke 21 (5%) 516 (8.6%) .024Hypertension 203 (51.8% 3294 (55.0%) .213Diabetes mellitus 130 (33.2%) 1719 (28.7%) .060Coronary arterybypass grafting

7 (24.7%) 1477 (24.7%) .974

Percutaneous coronaryrevascularization

61 (15.6%) 1064 (17.8%) .266

Implanted cardioverterdefibrillator

14 (3.6%) 149 (2.5%) .188

Pacemaker implanted 23 (5.9%) 478 (8.0%) .131Cancer 23 (5.9%) 395 (6.6%) .572Current smoker 48 (12.2% 916 (15.3%) .102

Medical TreatmentACE inhibitors 175 (44.6%) 2447 (40.9%) .142h-Blockers 213 (54.4%) 3397 (56.7%) .352Spironolactone 67 (17.1%) 935 (15.6%) .437Digitalis glycoside 159 (40.6%) 2216 (37.0%) .159Calcium-channel blockers 73 (18.6%) 1235 (20.6%) .341Other vasodilators 168 (42.9%) 2425 (40.5%) .358Oral anticoagulant 91 (23.2%) 1368 (22.8%) .878Antiarrhythmic agents 34 (8.7%) 705 (11.8%) .069Amiodarone 25 (6.4%) 601 (10.0%) .018Aspirin 237 (60.5%) 3682 (61.5%) .682Other antiplatelet agent 17 (4.3%) 308 (5.1%) .481Lipid-lowering drug 153 (39.0%) 2673 (44.6%) .030Previous ARB/ACE use 86 (11.7%)/

337 (46.0%)64 (10.8%)/

4895 (81.8%).550/.036

Serum laboratory valuesCreatinine (mmol/L) 108 (40.4) 103 (56.1) .204Potassium (mmol/L) 4.4 (0.5) 4.4 (0.4) .614Chloride (mmol/L) 102.4 (3.7) 102.6 (3.8) .635Urea nitrogen (mmol/L) 9.4 (5.1) 8.3 (4.3) .026

American Heart Journal

Month Year2 Ducharme et al

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(ECG) documented it, whether it was symptomatic, whether

it was paroxysmal or persistent, and whether it required

treatment (and the types of therapy given [bMark all that

apply Q]). Baseline characteristics, past medical history, and

drug therapy at the time of randomization were obtained from

the main CHARM database. Patients with a history of AF or

flutter but who were in sinus rhythm on the baseline ECG were

included in the primary analysis. A secondary analysis was

done that excluded patients with either AF/flutter on the

baseline ECG or a history of AF/flutter even if in sinus rhythm

on the baseline ECG.

Statistical analysisAll randomized patients without AF at enrollment were

included (intention to treat), and P values were 2-sided. A

P value b.05 was considered statistically significant. We

estimated the odds ratios (ORs) and 95% CIs comparing treat-

ments, stratified by trial, with a conditional logistic regression

model. In addition, we used a conditional logistical regression

model with treatment and other prospectively defined cova-

riates (Table I) to adjust the odds ratio for these prespecified

baseline factors, which might alter CV prognosis and develop-

ment of AF. The 33 covariates are the same that were used in the

CHARM overall manuscript. These include Patients’ character-

istics (age, sex, ethnic origin [European, black, or other]); Heart-

disease risk factors (NYHA class, LVEF [%], heart rate, blood

pressure [systolic, diastolic, and mean], and body mass index

[kg/m2]); Heart failure cause (ischemic, idiopathic, or hyper-

tensive); Past Medical history (hospital admission for CHF, MI,

current angina pectoris, stroke, diabetes mellitus, hypertension,

AF, pacemaker, current smoker, revascularization [percutane-

ous coronary intervention or coronary artery bypass graft],

implantable cardioverter-defibrillator, or cancer); and Medical

treatment (ACE inhibitor, diuretic, h-blocker, spironolactone,

digoxin/digitalis glycoside, calcium antagonist, other vasodila-

tors, oral anticoagulant, antiarrhythmic agent, aspirin, other

antiplatelet agent, and lipid-lowering drug). For the secondary

analysis that excluded patients with sinus rhythm on the

baseline ECG but had a positive medical history of AF/flutter,

a conditional logistic regression model was used with 32 cova-

riates because medical history of AF/flutter was not included.

For the covariate-adjusted analysis of the 2 trials of patients with

low LVEF, the additional variable of bACE inhibitor useQ at

baseline was not included because this was already accounted

for in the bby study Q variable.

A test for heterogeneity was used to assess possible

interactions between treatment benefits on AF across the

3 component trials. All analyses were performed using SAS

version 9.1 (SAS Institute Inc, Cary, NC).

ResultsAmong the 7601 randomized patients (7599 with

data), 1148 (15.1%) had AF reported on the baseline

ECG and were excluded from the primary analysis.

In 5 patients no data were available on AF at baseline

and in 67 patients no data were available on the new

development of AF. This evaluation focuses on 6379

(83.9%) patients without AF on the baseline ECG, 3191

randomized to candesartan, and 3188 to placebo. The

secondary analysis also excluded an additional 970

patients with a history of AF, although they were in sinus

rhythm on their baseline ECG. This latter cohort

included 2700 patients randomized to candesartan and

2709 to placebo in the overall program, and 1654 and

1660 patients, respectively, in the 2 low LVEF trials.

Baseline characteristics and development of AFA total of 392 patients (6.15%) were reported to have

experienced z1 episodes of AF during follow-up. The

Table II. Atrial Fibrillation episodes: characteristics in the2 groups

Placebo(n = 215)

Candesartan(n = 177)

All(n = 392)

Characteristics of AFSymptomatic 134 (62.6%) 103 (58.5%) 237 (60.5%)

Unknown 35 (16.4%) 18 (10.2%) 53 (13.5%)Documented on ECG 190 (88.4%) 158 (89.3%) 348 (88.8%)

Unknown 13 (6.1%) 10 (5.6%) 23 (5.9%)Paroxysmal 127 (59.1%) 109 (61.6%) 236 (61.0%)Persistent 97 (45.1%) 83 (47.2%) 180 (45.8%)

Treatment givenElectrical cardioversion 42 (19.5%) 40 (22.7%) 82 (20.9%)Antiarrhythmic therapy 101 (47.0%) 90 (50.9%) 191 (48.7%)Heart rate lowering drug 80 (37.2%) 59 (33.3%) 139 (35.5%)Anticoagulation therapy 117 (54.4%) 87 (49.2%) 204 (52.0%)Antiplatelet therapy 36 (16.7%) 18 (10.2%) 54 (13.8%)

Note: categories (paroxysmal, persistent, treatment given) are not mutually exclusive.

Figure 1

Number of patients who developed AF during the course of the studyby treatment group: candesartan (white box) or placebo (black box).6379 patients (83.9%) did not have AF on the baseline ECG. Ofthese, 392 patients (6.15%) developed AF during follow-up, 177(5.55%) in the candesartan group and 215 (6.74%) in the placebogroup (OR 0.812, 95% CI 0.662-0.998, P = .048). After adjustmentfor the prespecified baseline covariates, the OR was 0.802 (95% CI0.650-0.990, P = .039).


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baseline characteristics of the study population

divided between those who developed AF during the

course of the study and those who did not are presented

in Table I. The patients who developed AF during the

course of the CHARM program were older and, more

often, male and diabetic. They also had more severe

CHF, as depicted by a lower LVEF and higher NYHA

functional class, despite similar blood pressure. In the

No-AF group, more patients were treated with antiar-

rhythmic therapy, including amiodarone.

A summary of the episodes is provided in Table II. Most

the episodes were paroxysmal, symptomatic, and re-

quired treatment; 90% were documented on an ECG. The

preferred strategy of treatment in this cohort was rhythm

control and more than two thirds of the patients received

either antiarrhythmic drugs or electrical cardioversion.

Factors associated with AF developmentOf the 392 patients, 6.15% reported to have experi-

enced =1 episodes of AF during follow-up; 177 (5.55%)

were in the candesartan group and 215 (6.74%) in the

placebo group (OR 0.812, 95% CI 0.662-0.998, P = .048)

(Figure 1). The reduction in the incidence of AF with

candesartan treatment remained significant after condi-

tional logistic regression analysis including 33 covariates

with an adjusted OR of 0.802 (95% CI 0.650-0.990,

P = .039). There was no heterogeneity of the effect of

candesartan in preventing AF between the 3 component

trials (P = .57, Figure 2). The reduction in new

development of AF was also significant for the pooled

population of patients with low LVEF in the CHARM-

Alternative and CHARM-Added trials, the patients most

typical of previous HF outcome trials (OR 0.779, 95% CI

0.608-0.997, P = .047) (Figure 2), and remained

significant after the adjusted analysis with 31 covariates

(OR 0.770, 95% CI 0.598-0.990, P = .041). The reduction

in the risk of AF among patients in the candesartan

group was also consistent across subgroups, including

NYHA class, use of antiarrhythmic agents, ACE inhib-

itors, and h-blockers (Figure 3). The reduction in AF

risk was also confirmed by the secondary analysis of the

more select cohort of patients (n = 5409) with sinus

rhythm on the baseline ECG and no medical history of

AF. In this cohort, the OR was 0.814 (95% CI 0.662-

1.001, P = .051), with an adjusted OR of 0.802, (95% CI

0.650-0.989, P = .040). For the 2 low LVEF trials, the

reduction in AF risk in the corresponding cohort of

3314 patients was also confirmed. In this cohort, the OR

was 0.778 (95% CI 0.606-0.997, P = .048), with an

adjusted OR of 0.764 (95% CI 0.593-0.985, P = .038).

DiscussionWe have shown that, compared with placebo, treat-

ment with candesartan, added to contemporary therapy

(which in most patients included an ACE inhibitor and

Figure 2

The effect of candesartan on the incidence of AF in the 3 component trials: The beneficial effect of candesartan in preventing AF was comparableacross the wide spectrum of patients with CHF because no heterogeneity was found (P = .57). For CHARM-Alternative, 69 patients (8.0%) patientsdeveloped AF in the placebo group compared with 49 (5.6%) in the candesartan group. For CHARM-Added, these numbers were, respectively,84 (7.9%) and 72 (6.8%), whereas they were 62 (4.9%) and 56 (4.4%) for the CHARM-Preserved group. The OR was, respectively, 0.686,0.856, and 0.894. For the 2 low LVEF trials (Alternative and Added pooled), the OR was 0.779, and the OR was 0.812 for the Overall programof 3 trials.



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a h-blocker), reduces the risk of developing AF in

patients with symptomatic CHF, regardless of LVEF. Our

findings extend the previously described beneficial

effects of blocking the RAAS system in patients with CHF

for the prevention of AF. This study is, to our knowledge,

the first to demonstrate a reduction in the incidence of

AF with an ARB in such a wide spectrum of patients with

symptomatic CHF, including those with preserved as

well as reduced left ventricular systolic function, many of

whom were treated with an ACE inhibitor.

Previously, Pedersen et al showed that, compared with

placebo, the ACE inhibitor trandolapril reduced the

occurrence of AF in patients with acute MI and left

ventricular systolic dysfunction.14 Those patients were

quite different from the ones studied in CHARM where

patients with chronic symptomatic HF and a broad range

of LVEF were included.24 Another relatively small post

hoc study from a single center participating in the

SOLVD showed that, compared with placebo, enalapril

reduced the development of AF in patients with reduced

LVEF.15 This retrospective finding, however, is derived

from a trial that was started almost 20 years ago and

which no longer reflects the modern treatment of CHF,

for example, only 20% were treated with a h-blocker. In

fact, a dramatic improvement in the management of CHF

has occurred in the last decade, including the introduc-

tion of h-blockers25-28 and aldosterone receptor block-

ers29,30 and better-organized outpatient and community

care. These changes in clinical practice, along with the

small number of patients studied at this single SOLVD

center, might explain the absolute difference in effect

on AF observed between CHARM and SOLVD. In Val-

HeFT, the ARB valsartan (compared with placebo)

reduced the incidence of AF by 35% in patients with

depressed systolic function CHF on top of background

ACE inhibitor treatment.16 Patients with preserved left

ventricular systolic function were not included in either

SOLVD or Val HeFT, and the proportion of patients

treated with a h-blocker, a treatment also known to

reduce AF,31 was also relatively low in both studies (35%

in Val-HeFT); whereas in CHARM, 55% of patients were

receiving a h-blocker at baseline and approximately two-

thirds by the end of the trials.20 Thus, despite modern

drug therapy, candesartan led to a significant reduction

in AF development. The risk of AF was also significantly

reduced by 22% in the low LVEF population in CHARM,

a population more typical of previous HF outcome trials.

However, no statistical heterogeneity of effect among

the 3 component trials was found. The patients in

CHARM-Preserved, with CHF and preserved LVEF, had

some similarities to those in the LIFE study,32 which

included patients with hypertension and electrocardio-

graphic signs of LVH. In that study, losartan reduced the

incidence of AF, compared with atenolol.17 Collectively,

these studies show that treatment of patients with overt

CV disease experienced reduction in the incidence of

subsequent AF with either an ACE inhibitor or ARB.

CHARM extends these findings by showing that the

benefit of candesartan is also incremental to that of an

ACE inhibitor and a h-blocker.

The mechanisms by which blockade of the RAAS

exerts its protective effect against AF development in

CHF remain unclear. One possibility is by inhibition of

the neurohormonal activation occurring in CHF. The

Figure 3

The effect of candesartan on the incidence of AF after randomization according to baseline medications and functional capacity. Odds ratio, pointestimate, and 95% CI are shown. ACE-I, angiotensin converting enzyme inhibitor; NYHA, New York Heart Association functional class.



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RAAS is widely involved in the progression of CHF and

could facilitate AF development. Angiotensin II, by

causing cardiac fibroblast proliferation and reduction of

collagenase activity, is an important promoter of

fibrosis.33 - 35 In addition, a hemodynamic effect cannot

be excluded and candesartan’s beneficial effect can be

at least partly through after load reduction. In patients

with CHF, neurohormonal activation, left ventricular

remodeling, elevated left atrial pressure, and atrial

fibrosis probably interact to provide a substrate for AF,

which can be, at least partially, reversed by an ARB

or ACE inhibitor, with further benefit evident using

the combination.

However, a direct antiarrhythmic effect of an ARB or

an ACE inhibitor on AF development cannot be

excluded because angiotensin II can participate directly

in the atrial electrical remodeling process, even in

the absence of CHF. For example, the reduction in the

atrial refractory period, which was observed experi-

mentally during rapid atrial pacing, was prevented with

RAAS blockade,36 as was the duration of AF.37 Moreover,

when the ARB irbesartan was given (in combination

with amiodarone) to patients with persistent AF 3 weeks

before electrical cardioversion, recurrence of AF was

reduced.18 Most of the benefit of the ARB occurred

during the first 2 months of treatment, suggesting a role

of angiotensin II blockade on the atrial electrical

remodeling process early after cardioversion. Similar

results were obtained with enalapril.38

Clinical implicationsAtrial fibrillation is common in patients with CHF and

is associated with increased morbidity and mortality.

Atrial fibrillation also increases the risk of thromboem-

bolism.39 The prevention of AF with the ARB candesar-

tan may thus reduce symptoms and improve the

prognosis of patients with CHF, together with the

avoidance of additional potential risk associated with the

use of antiarrhythmic agents and anticoagulation or

procedures for AF ablation.

Limitations of the studyAlthough this study was a prespecified analysis of

CHARM, the ECGs were reported locally by investigators

and not by a core laboratory, and systematic surveillance

for AF was not performed. Thus, we might have under-

estimated the true incidence of AF in this CHF population

because a substantial proportion of episodes of AF are

asymptomatic. In addition, the information was retrieved

only at the end of the study, leaving the possibility that

episodes of AF may have been missed. Furthermore,

regarding the use of heart rate–lowering drugs, anti-

coagulation, and antiplatelet therapy, we cannot discri-

minate whether the patients were on these drugs

because they were in AF at baseline or as a component of

HF therapy, irrespective of being in AF. Moreover, some

of these drugs as well as antiarrhythmic agents (including

amiodarone) may have been used by some patients

because of previous AF, although they were in sinus

rhythm at baseline. Lastly, more patients in the No-AF

group were on statins at baseline, a treatment that seems

to protect against AF in an experimental model.40

ConclusionsThe CHARM program provides evidence that angio-

tensin II receptor blockade with candesartan reduces

the risk of developing AF in patients with symptomatic

HF, regardless of the presence of left ventricular systolic

dysfunction and despite extensive background therapy

including ACE inhibitors and h-blockers.

References1. Carson PE, Johnson GR, Dunkman WB, et al. The influence of atrial

fibrillation on prognosis in mild to moderate heart failure. TheV-HeFT Studies. The V-HeFT VA Cooperative Studies Group.Circulation 1993;87:VI102 -10.

2. Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic signif-icance of atrial fibrillation in advanced heart failure. A study of390 patients. Circulation 1991;84:40 -8.

3. Pozzoli M, Cioffi G, Traversi E, et al. Predictors of primary atrialfibrillation and concomitant clinical and hemodynamic changesin patients with chronic heart failure: a prospective study in344 patients with baseline sinus rhythm. J Am Coll Cardiol1998;32:197 -204.

4. Dries DL, Exner DV, Gersh BJ, et al. Atrial fibrillation is associatedwith an increased risk for mortality and heart failure progressionin patients with asymptomatic and symptomatic left ventricularsystolic dysfunction: a retrospective analysis of the SOLVD trials.Studies of Left Ventricular Dysfunction. J Am Coll Cardiol1998;32:695 -703.

5. Stevenson WG, Stevenson LW, Middlekauff HR, et al. Improvingsurvival for patients with advanced heart failure: a study of737 consecutive patients. J Am Coll Cardiol 1995;26:1417-23.

6. Mathew J, Hunsberger S, Fleg J, et al. Incidence, predictive factors,and prognostic significance of supraventricular tachyarrhythmiasin congestive heart failure. Chest 2000;118:914 -22.

7. Crijns HJ, Tjeerdsma G, de Kam PJ, et al. Prognostic value of thepresence and development of atrial fibrillation in patients withadvanced chronic heart failure. Eur Heart J 2000;21:1238 -45.

8. Stevenson WG, Stevenson LW, Middlekauff HR, et al. Improvingsurvival for patients with atrial fibrillation and advanced heartfailure. J Am Coll Cardiol 1996;28:1458 -63.

9. Hsu LF, Jais P, Sanders P, et al. Catheter ablation for atrialfibrillation in congestive heart failure. N Engl J Med2004;351:2373 -83.

10. Li D, Fareh S, Leung TK, et al. Promotion of atrial fibrillation byheart failure in dogs: atrial remodeling of a different sort.Circulation 1999;100:87 -95.

11. Shi Y, Ducharme A, Li D, et al. Remodeling of atrial dimensions andemptying function in canine models of atrial fibrillation. CardiovascRes 2001;52:217 -25.

12. Li D, Shinagawa K, Pang L, et al. Effects of angiotensin-convertingenzyme inhibition on the development of the atrial fibrillationsubstrate in dogs with ventricular tachypacing-induced congestiveheart failure. Circulation 2001;104:2608 -14.



ARTICLE IN PRESS

13. Shi Y, Li D, Tardif JC, et al. Enalapril effects on atrial remodelingand atrial fibrillation in experimental congestive heart failure.Cardiovasc Res 2002;54:456 -61.

14. Pedersen OD, Bagger H, Kober L, et al. Trandolapril reducesthe incidence of atrial fibrillation after acute myocardial infarctionin patients with left ventricular dysfunction. Circulation1999;100:376 -80.

15. Vermes E, Tardif JC, Bourassa MG, et al. Enalapril decreases theincidence of atrial fibrillation in patients with left ventriculardysfunction: insight from the Studies Of Left Ventricular Dysfunction(SOLVD) trials. Circulation 2003;107:2926 -31.

16. Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces theincidence of atrial fibrillation in patients with heart failure: resultsfrom the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J2005;149:1 -10.

17. Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptorblockade reduces new-onset atrial fibrillation and subsequentstroke compared to atenolol: the Losartan Intervention For End PointReduction in Hypertension (LIFE) study. J Am Coll Cardiol2005;45:712 -9.

18. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan tomaintain sinus rhythm in patients with long-lasting persistent atrialfibrillation: a prospective and randomized study. Circulation2002;106:331 -6.

19. McMurray J, Ostergren J, Pfeffer M, et al. Clinical features andcontemporary management of patients with low and preservedejection fraction heart failure: baseline characteristics of patients inthe Candesartan in Heart failure—Assessment of Reduction inMortality and morbidity (CHARM) programme. Eur J Heart Fail2003;5:261 -70.

20. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartanon mortality and morbidity in patients with chronic heart failure:the CHARM-Overall programme. Lancet 2003;362:759 -66.

21. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartanin patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772 -6.

22. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartanin patients with chronic heart failure and reduced left-ventricularsystolic function taking angiotensin-converting-enzyme inhibitors:the CHARM-Added trial. Lancet 2003;362:767 -71.

23. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan inpatients with chronic heart failure and preserved left-ventricularejection fraction: the CHARM-Preserved trial. Lancet2003;362:777 -81.

24. St John SM, Pfeffer MA, Plappert T, et al. Quantitative two-dimensional echocardiographic measurements are major predictorsof adverse cardiovascular events after acute myocardial infarction.The protective effects of captopril. Circulation 1994;89:68 -75.

25. Lechat P, The CIBIS II Investigators. The Cardiac InsufficiencyBisoprolol Study II (CIBIS-II): a randomised trial. Lancet1999;353:9 -13.

26. Fagenberg B, The MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Inter-vention Trial in Congestive Heart Failure (MERIT-HF). Lancet1999;353:2001 -7.

27. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol onmorbidity and mortality in patients with chronic heart failure. USCarvedilol Heart Failure Study Group. N Engl J Med1996;334:1349 -55.

28. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survivalin severe chronic heart failure. N Engl J Med 2001;344:1651 -8.

29. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactoneon morbidity and mortality in patients with severe heart failure.Randomized Aldactone Evaluation Study Investigators. N Engl JMed 1999;341:709 -17.

30. Pitt B, Williams G, Remme W, et al. The EPHESUS trial:eplerenone in patients with heart failure due to systolic dysfunctioncomplicating acute myocardial infarction. Eplerenone Post-AMIHeart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther2001;15:79 -87.

31. Gheorghiade M, Lukas MA. Role of carvedilol in atrial fibrillation:insights from clinical trials. Am J Cardiol 2004;93:53B-7B.

32. Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity andmortality in patients with diabetes in the Losartan Intervention ForEndpoint reduction in hypertension study (LIFE): a randomised trialagainst atenolol. Lancet 2002;359:1004-10.

33. Zou Y, Komuro I, Yamazaki T, et al. Cell type–specific angiotensinII–evoked signal transduction pathways: critical roles of Gbeta-gamma subunit, Src family, and Ras in cardiac fibroblasts. Circ Res1998;82:337 -45.

34. Pages G, Lenormand P, L’Allemain G, et al. Mitogen-activatedprotein kinases p42mapk and p44mapk are required for fibroblastproliferation. Proc Natl Acad Sci U S A 1993;90:8319-23.

35. Brilla CG, Zhou G, Matsubara L, et al. Collagen metabolism incultured adult rat cardiac fibroblasts: response to angiotensin IIand aldosterone. J Mol Cell Cardiol 1994;26:809 -20.

36. Nakashima H, Kumagai K, Urata H, et al. Angiotensin II antagonistprevents electrical remodeling in atrial fibrillation. Circulation2000;101:2612 -7.

37. Kumagai K, Nakashima H, Urata H, et al. Effects of angiotensin IItype 1 receptor antagonist on electrical and structural remodelingin atrial fibrillation. J Am Coll Cardiol 2003;41:2197-204.

38. Ueng KC, Tsai TP, Yu WC, et al. Use of enalapril to facilitate sinusrhythm maintenance after external cardioversion of long-standingpersistent atrial fibrillation. Results of a prospective and controlledstudy. Eur Heart J 2003;24:2090-8.

39. Lamassa M, Di Carlo A, Pracucci G, et al. Characteristics, outcome,and care of stroke associated with atrial fibrillation in Europe:data from a multicenter multinational hospital-based registry (TheEuropean Community Stroke Project). Stroke 2001;32:392 -8.

40. Shiroshita-Takeshita A, Schram G, Lavoie J, et al. Effect ofsimvastatin and antioxidant vitamins on atrial fibrillationpromotion by atrial-tachycardia remodeling in dogs. Circulation2004;110:2313 -9.



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