Archives of Gerontology and Geriatrics
29 (1999) 275 – 282
www.elsevier.com/locate/archger

Carvedilol in elderly patients with chronic heart
failure, a 12 weeks randomized, placebo
controlled open trial
Riccardo Leonetti Luparini *, Valdisa Celli,
Gianfranco Piccirillo, Virgilio Guidi, Mauro Cacciafesta,
Vincenzo Marigliano
Institute of I Clinica Medica, Policlinico Umberto I, Uni6ersity ‘La Sapienza’, Viale del Policlinico,
155 -00161 Rome, Italy
Received 17 May 1999; received in revised form 1 September 1999; accepted 2 September 1999

Abstract
The encouraging results of recent multicenter clinical trials conducted in the US on the
effect of carvedilol therapy in patients with chronic heart failure, prompted us to verify its
tolerability in a group of elderly patients. For the open, randomized, placebo-controlled
study, we selected 40 patients (28 men and 12 women, mean age 76.8 9 5.9 years) with mild,
moderate or severe chronic heart failure. Exclusion criteria included dementia, chronic
hepatitis, renal failure, severe vascular disease and respiratory failure. All patients were
receiving treatment with digitalis, furosemide and ACE inhibitors. The study lasted 12 weeks.
During the first week, all subjects received oral placebo or carvedilol, at a dose of 6.25 mg
twice daily. The twice daily dose was then increased to 12.5 mg during weeks 2 – 4 and to 25
mg from weeks 5–12. At 0, after the 2 weeks of run-in, 4 and 12 weeks patients underwent
assessment of systolic and diastolic blood pressure, heart rate, left ventricular ejection
fraction, cognitive status and functional ability. Our findings indicate that elderly patients
with congestive heart failure tolerate carvedilol therapy well. Carvedilol slightly improves
heart function without altering functional or cognitive ability. A larger-scale trial in geriatric
patients is now required to determine whether this treatment will reduce serious morbidity or
mortality from heart failure. © 1999 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Heart failure; b-adrenergic blockade; Elderly subjects

* Corresponding author. Tel.: +39-6-49972355; fax: + 39-6-4456316.
0167-4943/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 1 6 7 - 4 9 4 3 ( 9 9 ) 0 0 0 4 0 - 0

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1. Introduction
Since the 1970s i-adrenergic-receptor blockers have been used in the treatment
of congestive heart failure (CHF) to antagonize the cardiotoxic effects of adrenergic
activation (Waagstein et al., 1974, 1975; Swedberg et al., 1979). The results have
nevertheless been skeptically viewed, partly because they came from uncontrolled
studies with small sample sizes, but primarily because they went against the current
opinion that sympathetic nervous system activation sustained the failing heart.
A recent clinical multicenter trial program conducted in the US provided
evidence that carvedilol, a nonselective i-adrenergic antagonist that also blocks
a1-receptors, reduces mortality by 65% in patients with dilated cardiomyopathy or
ischemic heart disease (Cohn et al., 1996; Packer et al., 1996). The patients studied
had New York Heart Association (NHYA) (The Criteria Committee of the New
York Heart Association, 1964) class II–IV heart failure, left ventricular ejection
fractions 535% and had received treatment with diuretics, digitalis and angiotensin-converting-enzyme (ACE) inhibitors. Carvedilol was given at an initial
dose of 3.125 mg twice daily, then progressively increased to a maximum of 25 mg
twice daily for 6 – 12 months. The primary end-point of death was prospectively
defined and results from all centers were evaluated by an independent data and
safety monitoring board. Considering the marked and highly significant reduction
in mortality with carvedilol therapy, the Data and Safety Monitoring Board
recommended suspending the program. In all study centers, carvedilol therapy
increased the left ventricular ejection fraction (Metra et al., 1994; Australia–New
Zealand Heart Failure Research Collaborative Group, 1995; Olsen et al., 1995),
reduced end-systolic and end-diastolic left ventricular volume (Australia–New
Zealand Heart Failure Research Collaborative Group, 1997; Doughty et al., 1997)
and improved the patients’ NYHA class (Olsen et al., 1995; Packer et al., 1996).
Most published data on carvedilol therapy refer to adults, but little information
is available on its use in elderly persons (Cohn et al., 1997). This prompted us to
find out how elderly patients with CHF tolerated carvedilol therapy.
In this 12-week study we evaluated, using an open randomized, placebo controlled, parallel design, the effect of short-term carvedilol administration on clinical
symptom and cognitive and functional ability in a group of elderly patients with
CHF without severe cerebrovascular disorders or dementia.

2. Patients and methods
The primary objective of the present study was to assess the short-term safety
and tolerability of carvedilol in elderly patients with chronic heart failure. These
patients were not affected by cerebrovascular disorders or dementia, events that
lead to a loss of self-sufficiency and furthermore, they do not allow a correct
evaluation of the clinical and instrumental data obtained.
This was a 3-month prospective randomized, open, placebo-controlled trial. The
trial consisted in two phases. The first was a 2-week baseline period in which the

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277

cardiac and noncardiac medications were adjusted and the second was the 12-week
open placebo controlled treatment phase. Patients were randomized to receive
carvedilol or placebo.
Patients aged 65 years or over were considered eligible for the study if they had
symptomatic heart failure NYHA II–IV (The Criteria Committee of the New York
Heart Association, 1964) caused by ischemic or idiophatic cardiomiopathy and
transthoracic echocardiography ejection fraction B 35%. Criteria for exclusion
were atrioventricular block grade II or III, unless equipped with a permanent
pacemaker, sustained ventricular extrasystole, uncontrolled hypertension, bradycardia, dementia, chronic hepatitis, renal failure (creatinine \ 2.5 mg/dl), severe
vascular disorders and severe respiratory insufficiency.
Among patients admitted to our geriatric clinic from January to November 1998,
we selected 40 elderly patients (28 men and 12 women, mean age 76.89 5.9 years,
range: 68 – 87) with NYHA class II–IV heart failure. Thirty patients had heart
failure due to ischemic and ten due to nonischemic causes. None of the patients
were candidates for coronary revascularization procedures. All patients were receiving therapy with digitalis, furosemide and ACE-inhibitors, 30 patients were receiving antiplatelet and ten anticoagulant drugs. Cardiac and noncardiac drugs were
adjusted during the first 2 weeks of observation in our geriatric clinic. Digitalis
doses ranged from 0.125 to 0.250 mg per day; furosemide from 25 to 75 mg per
day; and ACE-inhibitors from 5 to 20 mg per day. Seven patients were receiving
oral hypoglycemic drugs for non-insulin-dependent diabetes mellitus. In five patients, verapamil or diltiazem for chronic atrial fibrillation were suspended when
carvedilol therapy began; in the three patients of the placebo group that were using
calcium antagonist, the medication was maintained. The study lasted 12 weeks. At
0, 4 and 12 weeks of carvedilol or placebo therapy, all patients underwent
assessment including clinical, functional, cognitive and laboratory indexes. Clinical
assessments included measurement of the ejection fraction by transthoracic
echocardiography, determination of arterial blood pressures and heart rate, and an
electrocardiogram. Cognitive function was assessed by the Mini Mental State
Examination (MMSE) (Folstein et al., 1975) evaluating six fields: temporospatial
orientation; fixation memory, attention span, short-term memory, language, praxis
and constructional ability. The score ranges from 0 to 30: 0–20 denoted highly
probable; 21 – 26 borderline; and 27–30 improbable cognitive impairment. Basic
functional ability was assessed with an Activities of Daily Living (ADL) (Katz et
al., 1970) scale including six functions: ability to feed oneself, dress, have a bath,
walk, go to bed and continence. Activity scores ranges from 0 to 6: 0 (totally
dependent) and 6 (fully self-sufficient). An Instrumental Activities of Daily Living
(IADL) (Lawton and Brody, 1969) scale was used to assess patients’ ability to use
the telephone, go shopping, prepare food, do the housework, use public transport,
manage money and if necessary pharmacologic therapy. Scores range from 0 to 8:
0 (totally dependent) and 8 (fully self-sufficient). Laboratory profiles obtained
included routine blood chemistry, tests for glucose and lipid metabolism and kidney
and liver function.

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During the first week of the study, patients remained in hospital for daily
measurement of heart rate and arterial blood pressures and received 6.25 mg
carvedilol orally twice daily or placebo. From weeks 2 to 4, the initial dose was
increased to 12.5 mg twice daily; and from week 5 onwards to 25 mg twice daily
until the 12-week study ended. All subjects gave their written informed consent to
the study and the study procedures were approved by the hospital ethical
committee.

2.1. Statistical analysis
Results are expressed as mean value 9 S.D. Repeated measures of analysis of
variance were used for comparison between changes before and after therapy in the
placebo and carvedilol groups. The Student’s t-test for paired samples with a
Bonferroni correction for multiple comparisons was used to evaluate, within each
group, data obtained before and after drug administration. A t-test for independent
samples was used to compare changes in the carvedilol treated versus group with
placebo. Differences were considered significant at PB 0.05.

3. Results
Forty subjects were enrolled in the study, ten with idiopathic dilated cardiomyopathy and 30 with ischemic cardiomyopathy. All 40 patients were randomized to
receive carvedilol (n =20) or placebo (n= 20). Of the patients assigned to receive
carvedilol, six had heart failure caused by idiopathic dilated cardiomyopathy and
14 had ischemic cardiomyopathy. In the placebo group, four patients had idiopathic dilated cardiomyopathy and 16 had ischemic cardiomyopathy.
Clinical characteristics of the patients randomized to receive placebo or
carvedilol were not significantly different (Table 1).
Three patients did not complete the protocol. In the carvedilol group, one patient
with ischemic cardiomyopathy withdrew because of significantly worsening heart
failure, the second patient with ischemic cardiomyopathy withdrew for the presence
of hypotension, bradycardia, vertigo and astenia, after reaching a dosage of 12.5
mg twice a day. In the placebo group, one patient with clinically stable ischemic
cardiomyopathy did not return at the programmed medical control. Consequently,
the analysis comprised data from 37 patients at 4 and 12 weeks (18 receiving
carvedilol, 19 placebo).
Changes of the variables studied in the two group and the statistical analysis are
showed in Table 2.
In the carvedilol group, the assessment of cardiovascular variables (blood pressure, heart rate and ejection fraction) showed that systolic blood pressure decreased
significantly after carvedilol therapy. Diastolic blood pressure also decreased significantly. The heart rate also showed a statistically significant reduction after
carvedilol therapy. Left ventricular ejection fraction showed no significant increase
at 4 weeks and a significant increase at 12 weeks.

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279

Assessment of cardiovascular variables showed no significant changes, at 4 and
12 weeks in the placebo group.
Cognitive function scores assessed with the MMSE remained statistically unchanged throughout the study, in both groups. The ADL also remained statistically
unchanged as did the IADL.
In the three patients with non insulin-dependent diabetes mellitus, carvedilol
therapy did not alter the metabolic index hence their concomitant diabetic therapy
needed no adjustment, in the same manner as the placebo group.

4. Discussion
The conclusions obtained by the ‘US Carvedilol Heart Failure Study Group’
(Cohn et al., 1997) indicate that carvedilol is able to slow the progression of heart
disease, thus reducing CHF-related mortality and the risk of sudden death. Among
the over 1000 patients enrolled in the study, the mean age was : 58 years. The age
datum led geriatric clinics to temper their enthusiasm for carvedilol therapy and
take a more cautionary approach. In our geriatric clinic, we routinely see elderly
patients who have drug-induced diseases and adverse effects not generally seen in
younger age groups. In aging persons, the clinical presentation is often complicated
and worsened by multiple coexisting diseases. These may cause heart disease to
follow an atypical course; they also necessitate the use of multidrug therapy
frequently leading to adverse drug interactions and additive effects.
Table 1
Clinical characteristics of 40 study patientsa
Placebo (n = 20)

Carvedilol (n =20)

Age (years)
Sex (M/F)

76.40 95.11
14/6

77.05 95.67
15/5

NYHA functional class
II
III
IV

5
12
3

4
14
2

Previous MI

16

14

Medications
ACE inhibitor
Diuretic drug
Digoxin
Nitrates
Calcium-antagonist

19
20
18
8
3

18
20
15
7
5

Data are presented as mean value 9S.D. or number or percent of patients. Between-group
comparison of clinical characteristics were not significant. NYHA, New York Heart Association; MI,
myocardial infarction; ACE, angiotensin-converting enzyme.
a

4 Weeks

12 Weeks

P value*

Baseline vs. 4 weeks

Baseline vs. 12 weeks

4 weeks vs. 12 weeks

Systolic BP (mmHg)
Placebo
130.59 9 11.16
Carvedilol
128.75 9 11.03

131.18 910.97 132.94 911.05 ns
123.75 97.85** 119.38 98.34*** B0.005

ns
B0.01

ns
B0.005

ns
B0.01

Diastolic BP (mmHg)
Placebo
77.65 9 8.50
Carvedilol
77.81 98.19

77.94 97.30
72.50 97.96**

78.53 96.56
ns
70.63 97.04**** B0.05

ns
ns

ns
B0.05

ns
ns

Heart rate (beats/min)
Placebo
81.35 9 11.61
Carvedilol
81.75 9 10.38

77.12 97.50
71.88 9 7.57

78.59 97.10
ns
66.75 96.49*** B0.001

ns
B0.05

ns
B0.001

ns
B0.001

LV EF (%)
Placebo
Carvedilol

28.76 9 4.38
28.13 9 4.76

29.82 94.13
30.75 9 3.77

29.29 9 3.93
ns
33.69 9 4.21**** B0.005

ns
ns

ns
B0.005

ns
0.01

MMSE
Placebo
Carvedilol

25.20 92.98
25.00 93.06

24.94 92.79
24.88 92.68

25.29 92.44
25.25 92.82

ns
ns

Ns
ns

ns
ns

ns
ns

ADL
Placebo
Carvedilol

4.90 9 0.85
5.00 9 0.86

5.00 91.06
5.13 91.09

4.88 91.05
4.94 91.00

Ns
Ns

ns
ns

ns
ns

ns
ns

IADL
Placebo
Carvedilol

5.45 9 1.50
5.609 1.50

5.65 9 1.27
5.25 91.44

5.18 9 1.29
5.50 91.37

Ns
Ns

ns
ns

ns
ns

ns
ns

* Repeated measure analysis of variance (ANOVA). Paired t-test was used to evaluate, within each group data obtained at baseline, 4 and 12 weeks.
** PB0.05.
*** PB0.001.
**** PB0.005 carvedilol versus placebo by independent samples t-test.

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Baseline

280

Table 2
Blood pressure, heart rate, ejection fraction (LV EF), mini mental state examination (MMSE), activities of daily living (ADL), instrumental activities of
daily living (IADL) at baseline and 4 and 12 weeks

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281

Our group of elderly patients with congestive heart failure uncomplicated by
other disorders and without severe cognitive deficits, selected for this 12-week
study, tolerated carvedilol therapy well.
The analysis of our results shows that two patients treated with carvedilol
dropped out because of adverse effects. One because of the worsening of the cardiac
function and the other for the presence of hypotension, vertigo and bradycardia.
The other patients treated demonstrated a slight increase in the ejection fraction
without modification of cognitive and functional abilities.
In the placebo group, we did not see any significant change in ejection fraction.
Cognitive and functional abilities were stable in both therapy and placebo groups.
In our elderly patients with CHF, carvedilol therapy did not significantly change
the symptoms of heart failure. These findings could be due to short-term observation or to the reduction of functional reserve in elderly patients.
Further studies are also needed to determine the optimal dosage of carvedilol and
the long-term effect of the drug on morbidity, mortality and quality of life in elderly
patients.
In conclusion our results agree with the previous studies so far conducted on
non-geriatric patients. Carvedilol therapy did not affect our patients’ cognitive and
functional abilities. Our study suggests that in conjunction with conventional
therapy, carvedilol improves the heart function in elderly patients with heart failure
without worsening their cognitive and functional abilities. Lastly, none of our
patients’ metabolic indexes was altered during carvedilol therapy, in particular
those for glucose and lipid metabolism.

References
Australia–New Zealand Heart Failure Research Collaborative Group, 1995. Effects of carvedilol, a
vasodilator-b-blocker, in patients with congestive heart failure due to ischaemic heart disease.
Circulation 92, 212–218.
Australia–New Zealand Heart Failure Research Collaborative Group, 1997. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease.
Lancet 349, 375–380.
Cohn, J.N., Fowler, M.B., Bristow, M.A., Colucci, W.S., Gilbert, E.M., Kinal, V., Krueger, S.K.,
LeJemtel, T., Narahara, K.A., Packer, M., 1996. Effect of carvedilol in severe heart failure. J. Am.
Coll. Cardiol. 26, 169A.
Cohn, J.N., Fowler, M.B., Bristow, M.R., Colucci, W.S., Gilbert, E.M., Kinhal, V., Krueger, S.K.,
Lejemtel, T., Narahara, K.A., Packer, M., Young, S.T., Holcslaw, T.L., Lukas, M.A., 1997. Safety
and efficacy of carvedilol in severe heart failure. The U.S. Carvedilol Heart Failure Study Group. J.
Card. Fail. 3, 173–179.
Doughty, R.N., Whalley, G.A., Gahble, G., MacMahon, S., Sharpe, N., 1997. Left ventricular
remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. J.
Am. Coll. Cardiol. 29, 1060–1066.
Folstein, M.F., Folstein, S.E., Mc Hugh, P.R., 1975. Mini-mental state. A practical method for grading
the cognitive state of patients for the clinician. J. Psychiatry Res. 3, 189 – 198.
Katz, S., Downs, T.D., Cash, H.R., Grotz, R.C., 1970. Progress in development of the index of ADL.
Gerontologist 1, 20–30.

282

R. Leonetti Luparini et al. / Arch. Gerontol. Geriatr. 29 (1999) 275–282

Lawton, M.P., Brody, E.M., 1969. Assessment of older people: self-maintaining and instrumental
activities of daily living. Gerontologist 3, 179 – 186.
Metra, M., Nardi, M., Giubbini, R., Dei Cas, L., 1994. Effects of short- and long-term carvedilol
administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions
in patients with idopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 24, 1678 – 1687.
Olsen, S.L., Gilbert, E.M., Renlund, D.G., Taylor, D.O., Yanowitz, F.D., 1995. Carvedilol improves left
ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J. Am.
Coll. Cardiol. 25, 1225–1231.
Packer, M., Bristow, M.R., Cohn, J.N., Colucci, W.S., Fowler, M.B., Gilbert, E.M., Shusterman, N.H.,
1996. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N.
Engl. J. Med. 334, 1349–1355.
Swedberg, K., Hjalmarson, A., Waagstein, F., Wallentin, I., 1979. Prolongation of survival in congestive
cardiomyopathy by b-receptor blockade. Lancet 1, 1374 – 1376.
The Criteria Committee of the New York Heart Association, 1964. Diseases of the Heart and Blood
Vessels: Nomenclature and Criteria for Diagnosis, 6th ed. New York Heart Association/Little,
Brown and Co, New York.
Waagstein, F., Hjalmarson, A., Wasis, H.S., 1974. Apex cardiogram and systolic time intervals in acute
myocardial infarction and effect of pratolol. Br. Heart. J. 36, 1109.
Waagstein, F., Hjalmarson, A., Varnauskas, E., Wallentin, I., 1975. Effect of chronic b-adrenergic
receptor blockade in congestive cardiomyopathy. Br. Heart. J. 37, 1022 – 1036.

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