Does atrial fibrillation in elderly patients with chronic heart failure limit the efficacy of carvedilol? Suggestions from an observational study.
ABSTRACT No clinical investigation provided any information about a possible influence of atrial fibrillation on the response to beta-blocker therapy in elderly patients with chronic heart failure (CHF). The aim of this study was to observe carvedilol effects in a cohort of patients > 70 years of age with CHF due to left ventricular dysfunction and with chronic atrial fibrillation.
An observational, 12-month prospective clinical and echocardiographic study was carried out on 240 patients > 70 years of age with heart failure due to systolic dysfunction, 64 of whom with atrial fibrillation.
After 1 year of beta-blocker treatment, patients with atrial fibrillation and those in sinus rhythm showed similar benefits, in terms of symptomatic improvement (deltaNYHA -0.44 if atrial fibrillation vs -0.57 if sinus rhythm, p = NS), reduction of events (death + hospitalizations -38 vs -15%), recovery of cardiac function (left ventricular ejection fraction delta +8.8 vs +9.4%, p = NS; left ventricular end-diastolic volume delta -17.2 vs -12.5 ml, p = NS), and reduction in mitral regurgitation (delta -042 vs -0.57, p = NS). No difference was found between the two study groups regarding left ventricular end-diastolic volume reduction (12% in atrial fibrillation patients and 18% in sinus rhythm patients, p = NS) and prevalence of the "reverse remodeling" phenomenon (22 and 21%, respectively, p = NS).
In CHF patients > 70 years of age, beta-adrenergic blockade was shown to be equally effective in improving symptoms and left ventricular geometry and function in patients with atrial fibrillation or in sinus rhythm, without any adjunctive sign of long-term clinical deterioration.
- [show abstract] [hide abstract]
ABSTRACT: To evaluate the effects of vasodilator therapy on mortality among patients with chronic congestive heart failure, we randomly assigned 642 men with impaired cardiac function and reduced exercise tolerance who were taking digoxin and a diuretic to receive additional double-blind treatment with placebo, prazosin (20 mg per day), or the combination of hydralazine (300 mg per day) and isosorbide dinitrate (160 mg per day). Follow-up averaged 2.3 years (range, 6 months to 5.7 years). Mortality over the entire follow-up period was lower in the group that received hydralazine and isosorbide dinitrate than in the placebo group. This difference was of borderline statistical significance. For mortality by two years, a major end point specified in the protocol, the risk reduction among patients treated with both hydralazine and isosorbide dinitrate was 34 percent (P less than 0.028). The cumulative mortality rates at two years were 25.6 percent in the hydralazine--isosorbide dinitrate group and 34.3 percent in the placebo group; at three years, the mortality rate was 36.2 percent versus 46.9 percent. The mortality-risk reduction in the group treated with hydralazine and isosorbide dinitrate was 36 percent by three years. The mortality in the prazosin group was similar to that in the placebo group. Left ventricular ejection fraction (measured sequentially) rose significantly at eight weeks and at one year in the group treated with hydralazine and isosorbide dinitrate but not in the placebo or prazosin groups. Our data suggest that the addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics in patients with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality.New England Journal of Medicine 07/1986; 314(24):1547-52. · 51.66 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: To define better the efficacy of vasodilator therapy in the treatment of chronic congestive heart failure, we compared the effects of hydralazine and isosorbide dinitrate with those of enalapril in 804 men receiving digoxin and diuretic therapy for heart failure. The patients were randomly assigned in a double-blind manner to receive 20 mg of enalapril daily or 300 mg of hydralazine plus 160 mg of isosorbide dinitrate daily. The latter regimen was identical to that used with a similar patient population in the effective-treatment arm of our previous Vasodilator-Heart Failure Trial. Mortality after two years was significantly lower in the enalapril arm (18 percent) than in the hydralazine-isosorbide dinitrate arm (25 percent) (P = 0.016; reduction in mortality, 28.0 percent), and overall mortality tended to be lower (P = 0.08). The lower mortality in the enalapril arm was attributable to a reduction in the incidence of sudden death, and this beneficial effect was more prominent in patients with less severe symptoms (New York Heart Association class I or II). In contrast, body oxygen consumption at peak exercise was increased only by hydralazine-isosorbide dinitrate treatment (P less than 0.05), and left ventricular ejection fraction, which increased with both regimens during the 2 years after randomization, increased more (P less than 0.05) during the first 13 weeks in the hydralazine-isosorbide dinitrate group. The similar two-year mortality in the hydralazine-isosorbide dinitrate arms in our previous Vasodilator-Heart Failure Trial (26 percent) and in the present trial (25 percent), as compared with that in the placebo arm in the previous trial, (34 percent) and the further survival benefit with enalapril in the present trial (18 percent) strengthen the conclusion that vasodilator therapy should be included in the standard treatment for heart failure. The different effects of the two regimens (enalapril and hydralazine-isosorbide dinitrate) on mortality and physiologic end points suggest that the profile of effects might be enhanced if the regimens were used in combination.New England Journal of Medicine 09/1991; 325(5):303-10. · 51.66 Impact Factor
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ABSTRACT: Atrial fibrillation occurs frequently in patients with congestive heart failure and commonly results in clinical deterioration and hospitalization. Sinus rhythm may be maintained with antiarrhythmic drugs, but some of these drugs increase the risk of death. We studied 1518 patients with symptomatic congestive heart failure and severe left ventricular dysfunction at 34 Danish hospitals. We randomly assigned 762 patients to receive dofetilide, a novel class III antiarrhythmic agent, and 756 to receive placebo in a double-blind study. Treatment was initiated in the hospital and included three days of cardiac monitoring and dose adjustment. The primary end point was death from any cause. During a median follow-up of 18 months, 311 patients in the dofetilide group (41 percent) and 317 patients in the placebo group (42 percent) died (hazard ratio, 0.95; 95 percent confidence interval, 0.81 to 1.11). Treatment with dofetilide significantly reduced the risk of hospitalization for worsening congestive heart failure (risk ratio, 0.75; 95 percent confidence interval, 0.63 to 0.89). Dofetilide was effective in converting atrial fibrillation to sinus rhythm. After one month, 22 of 190 patients with atrial fibrillation at base line (12 percent) had sinus rhythm restored with dofetilide, as compared with only 3 of 201 patients (1 percent) given placebo. Once sinus rhythm was restored, dofetilide was significantly more effective than placebo in maintaining sinus rhythm (hazard ratio for the recurrence of atrial fibrillation, 0.35; 95 percent confidence interval, 0.22 to 0.57; P<0.001). There were 25 cases of torsade de pointes in the dofetilide group (3.3 percent) as compared with none in the placebo group. In patients with congestive heart failure and reduced left ventricular function, dofetilide was effective in converting atrial fibrillation, preventing its recurrence, and reducing the risk of hospitalization for worsening heart failure. Dofetilide had no effect on mortality.New England Journal of Medicine 09/1999; 341(12):857-65. · 51.66 Impact Factor
It is well known that beta-blockers are
useful in patients with chronic heart failure
(CHF), in that they improve left ventricular
function and reduce deaths from heart fail-
ure and hospital admissions1-4. These fa-
vorable effects have recently been observed
even in elderly CHF patients5, who are sub-
jects of a recently concluded, not yet pub-
lished, randomized trial6.
Atrial fibrillation is present in about a
quarter of CHF patients7-12and seems to be
a risk factor for significant morbidity13-16.
Retrospective analysis of the US Car-
vedilol Trial and other studies showed that
the benefits of beta-blockers seen in ran-
domized trials (improvement of left ven-
tricular ejection fraction [LVEF], physical
global assessment, symptoms and exercise
capacity, and, probably, reduction in the
combined endpoint of CHF hospitaliza-
tions and death) extend to patients with
atrial fibrillation17,18. However, the mean
age of patients involved in these studies
was 60 years, thus data on elderly CHF pa-
tients with atrial fibrillation are lacking.
The aim of this observational study was
to evaluate the effects of carvedilol therapy
on the clinical status and left ventricular re-
modeling process in a cohort of patients
> 70 years of age with CHF due to left ven-
tricular dysfunction and with chronic atrial
Two hundred and forty CHF patients
(151 males, 89 females, mean age 76 ± 5.7
years, range 70-99 years) with an echocar-
diographically measured LVEF of 29.6 ±
7.3% (range 10-39%) were consecutively
recruited by four heart failure clinics into a
© 2005 CEPI Srl
Received November 3,
2004; revision received
January 14, 2005;
accepted January 17,
Dr.ssa Cristina Opasich
Divisione di Cardiologia
Fondazione S. Maugeri
Via Ferrata, 4
Does atrial fibrillation in elderly patients
with chronic heart failure limit the efficacy
of carvedilol? Suggestions from
an observational study
Cristina Opasich, Stefania De Feo, Giovanni Cioffi*, Giovanni Pulignano**,
Donatella Del Sindaco§, Luigi Tarantini§§, Alessandra Gualco, Anna Patrignani
Department of Cardiology, S. Maugeri Foundation, Institute of Care and Scientific Research, Pavia, *Department
of Cardiology, Villa Bianca Hospital, Trento, **Department of Cardiology, San Camillo Hospital, Rome, §Department
of Cardiology, INRCA, Institute of Care and Scientific Research, Rome, §§Department of Cardiology, San Martino
Hospital, Belluno, Italy
Background. No clinical investigation provided any information about a possible influence of atri-
al fibrillation on the response to beta-blocker therapy in elderly patients with chronic heart failure
(CHF). The aim of this study was to observe carvedilol effects in a cohort of patients > 70 years of age
with CHF due to left ventricular dysfunction and with chronic atrial fibrillation.
Methods. An observational, 12-month prospective clinical and echocardiographic study was car-
ried out on 240 patients > 70 years of age with heart failure due to systolic dysfunction, 64 of whom
with atrial fibrillation.
Results.After 1 year of beta-blocker treatment, patients with atrial fibrillation and those in sinus
rhythm showed similar benefits, in terms of symptomatic improvement (?NYHA -0.44 if atrial fib-
rillation vs -0.57 if sinus rhythm, p = NS), reduction of events (death + hospitalizations -38 vs -15%),
recovery of cardiac function (left ventricular ejection fraction ? +8.8 vs +9.4%, p = NS; left ventric-
ular end-diastolic volume ? -17.2 vs -12.5 ml, p = NS), and reduction in mitral regurgitation (? -042
vs -0.57, p = NS). No difference was found between the two study groups regarding left ventricular
end-diastolic volume reduction (12% in atrial fibrillation patients and 18% in sinus rhythm patients,
p = NS) and prevalence of the “reverse remodeling” phenomenon (22 and 21%, respectively, p = NS).
Conclusions. In CHF patients > 70 years of age, beta-adrenergic blockade was shown to be equal-
ly effective in improving symptoms and left ventricular geometry and function in patients with atri-
al fibrillation or in sinus rhythm, without any adjunctive sign of long-term clinical deterioration.
(Ital Heart J 2005; 6 (4): 323-327)
12-month prospective study and their data collected in-
to a single database. Sixty-four patients had permanent
chronic atrial fibrillation (27%), 24 of whom were fe-
males. Thirty-nine out of the 64 patients were treated
with carvedilol, while 25 subjects had contraindica-
tions to such treatment. In fact, chronic obstructive pul-
monary disease limited the carvedilol prescription in 12
cases, low heart rate or blood pressure in 10 cases, and
severe peripheral arteriopathy in 3 cases.
Carvedilol was used together with angiotensin-con-
verting enzyme inhibitors or sartans, spironolactone and
digoxin (if not contraindicated) and started at a low dose
of 3.125 mg twice daily and then progressively doubled
in order to reach the target dosage of 50 mg/day or symp-
toms and signs indicative of “effective” beta-blockade
(defined as clinical stability on fixed diuretic dosage,
heart rate and systolic blood pressure comprised between
60-70 b/min and 100-120 mmHg, respectively). Four pa-
tients were intolerant to carvedilol (worsening heart fail-
ure in 2, severe bradycardia in 2). Six patients died be-
fore the completion of the follow-up period (1 on and 5
off carvedilol therapy). Thus, clinical effects of 1 year of
carvedilol therapy in elderly patients with atrial fibrilla-
tion were assessed in 34 patients and compared with
those in patients without atrial fibrillation. Clinical and
echocardiographic variables were recorded before and
after 12 months of carvedilol therapy in all survivors.
Standard transthoracic echocardiographic studies were
systematically performed by expert cardiologists at
baseline and at the end of the follow-up using a Megas
Esaote Biomedica machine (Florence, Italy) equipped
with a 2.5 to 3.5 MHz annular-array transducer. Left ven-
tricular volumes and LVEF were computed from apical
2- and 4-chamber views by the area-length method and
mitral regurgitation was diagnosed by color Doppler and
quantified using a 1-4+ grading system. Details of the re-
producibility of echocardiographic measurements de-
tected in patients with heart failure from our laboratory
have been previously reported19.
In this study we used the NYHA functional classifi-
cation as measure of the functional status, and the left
ventricular end-diastolic volume (LVEDV), LVEF
(normal if ≥50%) and the degree of mitral regurgitation
as markers of the left ventricular remodeling process.
Patients were defined as “improved” when a reduction
of at least one NYHA functional class associated with
an increase in LVEF > 10 points % were documented
from baseline to 1-year evaluation. The left ventricular
reverse remodeling phenomenon was recognized in
case LVEDV decreased > 24 ml/m2from baseline to the
end of follow-up (> 2 SD of the mean)19.
Statistical analysis. The differences in continuous
variables between groups were assessed by an analysis
of variance (ANOVA/MANOVA); post-hoc compar-
isons were analyzed by the Scheffé test. Differences in
categorical variables were tested by ?2tests. Multivari-
ate analysis was used to evaluate the independent pre-
dictors of clinical improvement and left ventricular re-
verse remodeling. Statistical significance was set at p
< 0.05 for all analyses.
The clinical characteristics of all patients and com-
parisons between patients with atrial fibrillation and in
sinus rhythm are reported in table I.
Valvular disease was more frequent among patients
with atrial fibrillation.
Contraindications to carvedilol were present in sim-
ilar percentages among patients with atrial fibrillation
(39%) and among those in sinus rhythm (31%). In the
latter group, chronic obstructive pulmonary disease
represented the main contraindication in 28, bradycar-
dia or hypotension in 15, and peripheral vascular dis-
ease (with or without diabetes) in 11 patients.
There were no differences in the tested characteris-
tics between atrial fibrillation patients treated or not by
carvedilol. The same was true for sinus rhythm pa-
tients. Moreover, apart from a slightly higher LVEF
and, obviously, their heart rhythm, atrial fibrillation pa-
tients treated with carvedilol did not differ from sinus
rhythm patients. As regards concomitant treatment, as
expected digoxin was more often prescribed in atrial
fibrillation patients. Dosages of furosemide were high-
er among patients not treated with carvedilol, especial-
ly if they had atrial fibrillation.
After 1 year of beta-blocker treatment, patients with
atrial fibrillation and those in sinus rhythm showed
similar benefits, in terms of symptomatic improvement
and recovery of cardiac function (Table II). Of note, the
dose of carvedilol was significantly higher in atrial fib-
rillation patients (perhaps because of the ventricular re-
sponse control) but the dosages of furosemide had not
been increased further. The portion of atrial fibrillation
patients who could be defined “improved” at the final
1-year evaluation was 22%. This behavior was recog-
nized in a similar percentage of counterparts with sinus
rhythm (28%, p = NS). Compared to the latter, our el-
ders with atrial fibrillation had a similar relevant de-
crease of the degree of mitral regurgitation over time
(Table II). Concordantly, no difference was found be-
tween the two study groups in terms of LVEDV reduc-
tion and prevalence of the reverse remodeling phenom-
enon (22 and 21%, respectively, p = NS).
At a multivariate analysis where atrial rhythm to-
gether with age, sex, Charlson score, systolic blood
pressure, diabetes mellitus, duration of symptoms and
etiology of CHF, basal NYHA class, LVEF, mitral re-
gurgitation and LVEDV were considered, the duration
of symptoms (< 6 months) emerged as the only inde-
pendent predictor both of clinical improvement (odds
ratio 7.3, confidence interval 19.1-2.7, p < 0.0001) and
left ventricular reverse remodeling process (odds ratio
3.3, confidence interval 8.3-1.3, p = 0.01).
Ital Heart J Vol 6 April 2005
During the follow-up of the patients with atrial fib-
rillation, 10 of those on carvedilol were rehospitalized
at least once (25%) as were 15 of those patients not re-
ceiving beta-blocker therapy (60%). The respective
numbers for sinus rhythm patients were 31 (25%) and
26 (48%). Thus, combining 1-year death and hospital-
izations, atrial fibrillation patients on carvedilol had a
lower rate of events than did patients not receiving the
beta-blocker (31 vs 69%, p = 0.003). This reduction in
event rate is even greater than that seen in the sinus
rhythm patients (41% in carvedilol-treated patients vs
56% in patients not given carvedilol, p = 0.0059).
The effectiveness of beta-blocker therapy in CHF
patients with atrial fibrillation is still controversial.
Similar degrees of clinical and LVEF improvements in
response to carvedilol were reported in patients with
atrial fibrillation in a retrospective analysis of 45 pa-
tients in Arnold’s study20as well as in the US
Carvedilol Heart Failure Trials Program17. Moreover,
in this latter trial, there was a trend (albeit not statisti-
cally significant) toward a reduction in the combined
endpoint of death and heart failure hospitalization in
the carvedilol group. However, when changes in LVEF
after carvedilol treatment were measured by Schleman
et al.21, a significant negative correlation was found
with the presence of atrial fibrillation, which also was
associated with hospitalization after initiation of
carvedilol therapy. Furthermore, conflicting results
emerged by subgroup analyses of the CIBIS II and
MERIT-HF trials regarding the effects of bisoprolol
and metoprolol in reducing the risk of death and/or hos-
pitalization in CHF patients with atrial fibrillation22-24.
No clinical investigation provided any information
about a possible influence of atrial fibrillation on the re-
sponse to beta-blocker therapy in elderly patients with
CHF. In this 1-year observational study, carvedilol was
equally effective in improving symptoms and left ven-
tricular systolic function in elderly patients with atrial
fibrillation or in sinus rhythm, without any adjunctive
sign of long-term clinical deterioration (i.e. there was
no change in the dosage of loop diuretics, and there was
a reduction in the combined endpoint of hospitaliza-
tions and death).
Considering the older age and the multiple comor-
bidities of our patients, the percentage of “clinical im-
provement” found in the subjects with atrial fibrillation
(near a quarter of survivors) has to be considered par-
ticularly high. In our analysis atrial fibrillation per se
did not influence the clinical effects of beta-blocker
therapy, which exclusively depended, instead, on the
duration of the cardiac syndrome. Similarly, the pres-
ence of atrial fibrillation in CHF elders receiving
carvedilol did not reduce the likelihood of developing
left ventricular reverse remodeling process, which was,
once again, inversely related to the duration of heart
failure symptoms. Our data confirm the analyses of
Palazzuoli et al.25and Konstam et al.26, who clearly
showed in the recent past that left ventricular reverse
C Opasich et al - Carvedilol in elderly HF patients with atrial fibrillation
Table I. Comparison between atrial fibrillation and sinus rhythm elderly patients treated and not treated with carvedilol.
Atrial fibrillation Sinus rhythmFp p post-hoc
Carvedilol No carvedilolCarvedilol No carvedilol
Comorbidity Charlson index
Heart failure duration (months)
Furosemide dosage (mg)
75.4 ± 5.7
2.1 ± 1.5
31.4 ± 6.8
2.7 ± 0.6
15.6 ± 20
78.1 ± 5.3
2.2 ± 1.3
30.8 ± 7.7
3.0 ± 0.6
20.2 ± 19
75.8 ± 5.3
2.1 ± 1.5
28.7 ± 7.3
2.7 ± 0.6
15.9 ± 20
76.2 ± 5.4
2.4 ± 1.5
29.4 ± 7.4
2.6 ± 0.6
21.6 ± 19
56 ± 64
80.8 ± 66**
37.6 ± 31
58.5 ± 785.070.002 0.04**
5 (20%) 8 (15%)
ACE = angiotensin-converting enzyme; AT-I = angiotensin I; LVEF = left ventricular ejection fraction. Only significant ?2are depict-
ed. * digoxin percentage significantly higher in atrial fibrillation patients treated (p = 0.02) and not treated (p = 0.004) with carvedilol;
** valvular etiology significantly higher in atrial fibrillation patients treated (p = 0.0001) and not treated (p = 0.0001) with carvedilol;
§ischemic etiology significantly lower (p = 0.0001) in atrial fibrillation patients not treated with carvedilol.
remodeling may take place in many elderly as well as
in younger CHF patients.
An expected finding of our observation was that pa-
tients with atrial fibrillation, who had a slightly higher
mean heart rate at baseline, required higher dosages of
carvedilol than those with sinus rhythm specifically for
the ventricular response control. It is worth noting,
however, that the reductions in heart rate and systolic
blood pressure were similar in both groups, irrespective
of the dose prescribed at the end of follow-up. Further,
unlike controlled clinical trials, only a minority of our
patients achieved the “target dose” of 50 mg daily (giv-
en in a similar percentage of atrial fibrillation and sinus
rhythm patients), and yet effects on the clinical status
and left ventricular geometry were evident, suggesting
that even low doses may be effective in elderly patients
The originality of the present study lies in the com-
bination of the two clinical variables such as age > 70
years and atrial fibrillation; its limits are that it is an ob-
servational and non-randomized study in a small sam-
ple of patients, with few clinical endpoints. Our experi-
ence suggests that the beneficial effects of carvedilol on
the clinical status and left ventricular geometry and
function are independent of cardiac rhythm even in el-
derly CHF patients with left ventricular systolic dys-
function. While waiting the results of subgroup analy-
sis of the SENIORS trial, this information may reassure
physicians who operate in the general setting that in-
cludes older patients with multiple comorbidities.
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Table II. Carvedilol effects: 1-year follow-up. Comparison between atrial fibrillation and sinus rhythm elderly patients.
75.7 ± 5.7
75.3 ± 4.9
p = 0.63, NS
Carvedilol dose (mg)
29.2 ± 16.5
22.7 ± 14.8
p = 0.03
(range 6.25 ÷ 62.5)
(range 3.125 ÷ 50)
Heart rhythm effect
2.73 ± 0.67
2.29 ± 0.76
2.64 ± 0.6
2.07 ± 0.59
31.5 ± 6.1
40.3 ± 12
28.7 ± 7.4
38.1 ± 10
94.8 ± 41.5
77.6 ± 34.2
101.8 ± 37
89.3 ± 35.8
2 ± 0.8
1.58 ± 0.7
1.75 ± 1
1.18 ± 0.99
86.4 ± 15
72.5 ± 11
75.8 ± 13
65.3 ± 9
135 ± 21
126 ± 14
132.4 ± 21
123.9 ± 20
Furosemide dosage (mg)
53.7 ± 67
50.4 ± 49
33.4 ± 28.5
28.8 ± 20
HR = heart rate; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; SBP = systolic blood pressure.
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