ORIGINAL CONTRIBUTION
Effects of Initiating Carvedilol in Patients
With Severe Chronic Heart Failure
Results From the COPERNICUS Study
Henry Krum, MB, BS, PhD
Ellen B. Roecker, PhD
Paul Mohacsi, MD
Jean L. Rouleau, MD
Michal Tendera, MD
Andrew J. S. Coats, MD
Hugo A. Katus, MD
Michael B. Fowler, MD
Milton Packer, MD
for the Carvedilol Prospective
Randomized Cumulative Survival
(COPERNICUS) Study Group
B
ETA-BLOCKERS PROLONG LIFE
and reduce the risk of disease
progression in patients with
chronic heart failure,1-6 but they
remain underutilized in clinical prac-
tice despite their established benefits.7
In part, this underutilization is related
to physician concerns that initiation of
treatment with a ␤-blocker is difficult and
requires special expertise.8 Patients who
start taking a ␤-blocker may experi-
ence decreases in blood pressure as well
as retention of sodium,9,10 which can
cause symptomatic hypotension and/or
worsening heart failure during the first
4 to 8 weeks of therapy.9-14 Further-
more, many physicians have assumed
that the beneficial effects of ␤-blockers
are delayed9,15 so that a favorable effect
of treatment on symptoms, hospitaliza-
tions, or death may not become appar-
ent for many months.2-4,16 Concerns that
See also pp 730 and 754.
712 JAMA, February 12, 2003—Vol 289, No. 6 (Reprinted)
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Context ␤-Blockers remain underused despite their established utility for improving
outcome in heart failure. Concerns that initiation of treatment produces few imme-
diate benefits and may have important risks may be deterring widespread use.
Objective To evaluate the early effects of the ␤-blocker carvedilol in patients with
severe heart failure.
Design, Setting, and Patients Randomized, double-blind, placebo-controlled trial
conducted from October 28, 1997, to March 20, 2000, at 334 hospital centers in 21
countries among 2289 patients with symptoms of heart failure at rest or with minimal
exertion who were clinically euvolemic and had a left ventricular ejection fraction of
less than 25%.
Intervention Patients were randomly assigned to receive carvedilol, with start dos-
age of at 3.125 mg twice daily with uptitration to a target dosage of 25 mg twice daily
(n=1156), or placebo (n=1133), in addition to their usual medications for heart failure.
Main Outcome Measures Death, hospitalization, or permanent withdrawal from
study drug, as well as adverse events during the first 8 weeks of treatment.
Results The carvedilol group experienced no increase in cardiovascular risk but instead
had fewer patients who died (19 vs 25; hazard ratio [HR], 0.75; 95% confidence interval
[CI], 0.41-1.35); who died or were hospitalized (134 vs 153; HR, 0.85; 95% CI, 0.67-
1.07); or who died, were hospitalized, or were permanently withdrawn from treatment
(162 vs 188; HR, 0.83; 95% CI, 0.68-1.03). These effects were similar in direction and
magnitude to those observed during the entire study, and were apparent particularly in
the 624 patients with recent or recurrent decompensation or a very depressed left ven-
tricular ejection fraction. Differences in favor of carvedilol became apparent as early as
14 to 21 days following initiation of treatment. Worsening heart failure was the only se-
rious adverse event with a frequency greater than 2% and was reported with similar fre-
quency in the placebo and carvedilol groups (6.4% vs 5.1%).
Conclusions These data suggest that, in clinically euvolemic patients, the relation
of benefit to risk during initiation of treatment with carvedilol is similar to that seen
during long-term therapy with the drug. Our findings should provide the reassurance
needed to encourage the high levels of use that are warranted by the results of long-
term clinical trials.
JAMA. 2003;289:712-718 www.jama.com
Author Affiliations: Monash University, Mel- Physicians and Surgeons, Columbia University, New
bourne, Victoria, Australia (Dr Krum); University of York, NY (Dr Packer).
Wisconsin, Madison (Dr Roecker); University Hospi- The COPERNICUS Study Investigators and Coordi-
tal, Bern, Switzerland (Dr Mohacsi); Silesian School nators are listed at the end of the article.
of Medicine, Katowice, Poland (Dr Tendera); Uni- Corresponding Author and Reprints: Henry Krum,
versity Health Network and Mt Sinai Hospital, MD, National Health and Medical Research Council
Toronto, Ontario, Canada (Dr Rouleau); Royal Center of Clinical Research Excellence in Therapeu-
Brompton Hospital, London, England (Dr Coats); tics, Dept of Medicine and Epidemiology and Preven-
Universitaets Klinikum Luebeck, Luebeck, Germany tive Medicine, Monash University, Alfred Hospital, Mel-
(Dr Katus); Stanford University Medical Center, bourne, Victoria, 3181 Australia, (e-mail: henry.krum
Stanford, Calif (Dr Fowler); and the College of @med.monash.edu.au).
©2003 American Medical Association. All rights reserved.

initiation of ␤-blocker therapy carries
important risks and few immediate ben-
efits has contributed to the underuti-
lization of these drugs in the manage-
ment of heart failure.7
Most of the information we have about
the responses to ␤-blocker therapy have
been derived from uncontrolled stud-
ies,9,13,15 and thus, it has been difficult to
determine if the effects reported were re-
lated to treatment or to underlying dis-
ease. To date, only 2 controlled trials
(with metoprolol and bucindolol) have
described in detail the clinical events
occurring following the initiation of
therapy.16-18 In these studies, initiation of
␤-adrenergic blockade appeared to be
well-tolerated in patients with mild heart
failure but was associated with an early
increase in risk of worsening heart fail-
ure and drug withdrawal in patients with
severe heart failure.
We describe the initiation of treat-
ment with the ␣, ␤-adrenergic blocker
carvedilol in the Carvedilol Prospec-
tive Randomized Cumulative Survival
(COPERNICUS) study.19 The primary
objective of the COPERNICUS trial was
to evaluate the long-term effects of carve-
dilol on the survival of patients with se-
vere heart failure. In the overall study
(mean follow-up, 10.4 months), carve-
dilol reduced the risk of death by
35% compared with placebo. The
COPERNICUS study provides an ideal
setting in which to evaluate the early
benefits and risks of treatment, since this
trial focused on patients with severe
heart failure who might be expected to
have the greatest difficulty starting treat-
ment with a ␤-blocker.8,9,13
METHODS
Study Participants
COPERNICUS study patients were en-
rolled from 334 hospital centers and 21
countries between October 28, 1997,
and March 20, 2000. Patients were eli-
gible if they had dyspnea or fatigue at
rest or on minimal exertion for at least
2 months and a left ventricular ejec-
tion fraction less than 25% due to is-
chemic or nonischemic cardiomyop-
athy. All patients were treated with a
diuretic (which was adjusted to mini-
©2003 American Medical Association. All rights reserved.
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INITIATING CARVEDILOL IN PATIENTS WITH SEVERE CHF
mize the degree of volume retention)
and treated with an angiotensin-
converting enzyme inhibitor or an
angiotensin II receptor antagonist (un-
less these were not tolerated). Treat-
ment with digitalis, spironolactone, va-
sodilators, and amiodarone were
allowed, but not required.
Patients were excluded if they had a
reversible or correctable cause of heart
failure; had severe primary pulmonary,
renal, or hepatic disease; had a contra-
indication to ␤-blocker therapy; or had
an acute illness that required continued
hospitalization. In addition, patients
were not allowed to have had within
the past 2 months cardiac surgery or an-
gioplasty, a myocardial or cerebral is-
chemic event, or sustained or hemody-
namically destabilizing ventricular
tachyarrhythmia. Patients also were ex-
cluded if they had received an ␣-blocker,
calcium channel blocker, or class I an-
tiarrhythmic drug within 4 weeks; a
␤-blocker within 2 months; or an intra-
venous positive inotropic agent or vaso-
dilator within 4 days of screening. Other
exclusion criteria included systolic blood
pressure less than 85 mm Hg, heart rate
less than 68/min, serum creatinine level
greater than 2.8 mg/dL (213.5 µmol/L),
or a serum potassium level less than 3.5
mEq/L or greater than 5.2 mEq/L.
Study Design
Details of the study design have been
previously published.19 In this double-
blind trial, eligible patients were ran-
domly assigned to receive either carve-
dilol or placebo (in a 1:1 ratio provided
as capsules identical in size and shape),
in addition to their usual medications for
heart failure. Study medication was la-
beled with sequential randomization
numbers linked up to a block random-
ization scheme; at the randomization
visit, each patient was assigned the low-
est number available at each site. The
starting dosage was 3.125 mg of carve-
dilol or placebo twice daily, which if tol-
erated then was increased to 6.25 mg
twice daily after 2 weeks, to 12.5 mg
twice daily after 4 weeks, and finally to
a target dosage of 25 mg twice daily or
placebo after 6 weeks. At each visit, pa-
(Reprinted) JAMA, February 12, 2003—Vol 289, No. 6 713
Figure 1. Patient Flow During Initiation and
Up-titration of Study Drug
3106 Screened
2289 Randomized
1133 Assigned to 1156 Assigned to
Receive Placebo Receive Carvedilol
59 Withdew from 51 Withdew from
Study Drug Study Drug
0 Lost to follow-up
of Vital Status
0 Lost to follow-up
of Vital Status
25 Died 19 Died
1133 Included in 1156 Included in
Analysis Analysis
tients were asked about the occurrence
of any clinical event or adverse effect, vi-
tal signs and body weight were mea-
sured, the dose of the study drug was re-
corded, and patients were administered
the next level of the study drug if they
were tolerating the drug at a dosage less
than 25 mg twice daily and had not re-
ceived a higher dose. The intent of the
up-titration phase was to identify the
highest dose of carvedilol that each pa-
tient could tolerate, and patients were
considered to have completed the up-
titration phase when they were able to
tolerate this dose for 2 weeks. Thus, the
duration of the up-titration period was
expected to be 8 weeks, although the ra-
pidity of up-titration could be slowed if
deemed appropriate.
If warranted by clinical circum-
stances, the dose of carvedilol or pla-
cebo could be reduced or temporarily
discontinued, the doses of all concomi-
tant drugs could be adjusted, and the
investigator could implement any new
treatments, except for open-label treat-
ment with a ␤-blocker. Following
completion of the up-titration phase,
patients entered the maintenance phase
and continued in the double-blind
therapy until the entire trial ended. The
COPERNICUS trial was stopped on
March 20, 2000, when the finding of a
marked beneficial effect of carvedilol on
survival led to a recommendation by the
trial’s data and safety monitoring board
for early termination.19
 INITIATING CARVEDILOL IN PATIENTS WITH SEVERE CHF

Statistical Analysis present report focused on the effects of were assessed in a very high risk sub-
A major clinical event was defined as treatment during initiation and up- group consisting of patients with re-
death, hospitalization, or permanent titration, the period of principal inter- cent or recurrent cardiac decompensa-
withdrawal of the study medication est was 8 weeks, which corresponded tion or very depressed cardiac function.
for any reason. Cumulative incidence to the expected duration of the up- These high-risk patients were charac-
curves for the occurrence of these events titration period. These specific out- terized by 1 or more of the following:
were constructed by the Kaplan-Meier comes and the 8-week period also were the presence of pulmonary rales, asci-
method, using a time-to-first-event ap- the focus of an earlier analysis of the up- tes, or edema at randomization; 3 or
proach.20 Cox proportional hazards re- titration period in the Metoprolol CR/XL more hospitalizations for heart failure
gression models were used to estimate Randomised Intervention Trial in Con- within the last year; hospitalization at
hazard ratios (HRs) and 95% confi- gestive Heart Failure Study Group.16 the time of screening or randomiza-
dence intervals (CIs).21 The analyses of Because earlier studies had raised tion; need for intravenous positive ino-
major outcome variables included all concerns that patients at highest risk tropic agent or vasodilator drug within
randomly assigned patients according to might respond poorly to ␤-adrenergic 14 days before randomization; or left
the intention-to-treat principle. Since the blockade,14,22 the effects of carvedilol ventricular ejection fraction of 15% or
less.19 The baseline variables that de-
fined this high-risk group were iden-
Figure 2. Effect of Carvedilol on Risk of Major Clinical Events in All Randomizly Assigned
Patients and in Patients at Highest Risk During First 8 Weeks and During the Entire Trial tified a priori without knowledge of
their influence on the treatment effect.
All Randomized Patients First 8 Weeks Entire Trial The safety of carvedilol was assessed
Placebo Carvedilol by changes in vital signs (summarized as
No./ Total Kaplan-Meier No./ Total Kaplan-Meier Hazard Favors Favors a mean [SE] change from baseline) and
Event Rate, % Event Rate, % Ratio Carvedilol Placebo by reports of adverse events with onset
(95% CI)
All-Cause Mortality within 8 weeks of randomization. All re-
First 8 Weeks 25/1133 2.3 19/1156 1.7 0.75 (0.41-1.35) ports of adverse events were included
Entire Trial 0.65 (0.52-0.81) whether or not they were deemed by the
Death or Hospitalization for Any Reason investigator to be related to treatment.
First 8 Weeks 153/1133 14.4 134/1156 12.3 0.85 (0.67-1.07)
Entire Trial 0.76 (0.67-0.87)
Adverse events with a frequency of at
Death, Hospitalization, or Permanent Study Drug
least 2% among all randomly assigned
Withdrawal for Any Reason patients in either treatment group, and
First 8 Weeks 188/1133 17.5 162/1156 14.8 0.83 (0.68-1.03) differences between treatment groups of
Entire Trial 0.76 (0.67-0.86)
at least 2% in the frequencies of the event
.05 0.1 1.0 2.0
were considered clinically significant. An
Hazard Ratio adverse event was defined in the study
protocol as serious if it was fatal or life-
High-Risk Patients threatening, required or prolonged hos-
Placebo Carvedilol pitalization, or resulted in persistent or
No./ Total Kaplan-Meier No./ Total Kaplan-Meier Hazard Favors Favors significant disability or incapacity. Sta-
Event Rate, % Event Rate, % Ratio Carvedilol Placebo
(95% CI)
tistical analyses were performed using
All-Cause Mortality SAS (versions 6.12 and 8.0; SAS Insti-
First 8 Weeks 15/316 5.0 3/308 1.0 0.20 (0.06-0.70) tute, Cary, NC).
Entire Trial 0.61 (0.41-0.89)
Death or Hospitalization for Any Reason RESULTS
First 8 Weeks 63/316 20.9 44/308 15.0 0.71 (0.48-1.04)
Entire Trial 0.71 (0.56-0.89)
Of the 2289 patients who were enrolled
Death, Hospitalization, or Permanent Study Drug
into the trial, 1133 were randomly as-
Withdrawal for Any Reason signed to the placebo group and 1156 to
First 8 Weeks 76/316 25.0 51/308 17.3 0.67 (0.47-0.96) the carvedilol group (FIGURE 1). Of these,
Entire Trial 0.68 (0.54-0.84)
624 (27.3%) patients fulfilled the crite-
.05 0.1 1.0 2.0 ria for recent or recurrent cardiac de-
Hazard Ratio compensation or very depressed car-
diac function, of whom 316 were
CI indicates confidence interval. Patients at highest risk are patients with recent or recurrent cardiac decom-
pensation or very depressed cardiac function and characterized by 1 or more of the following: the presence of
randomly assigned to placebo and 308
pulmonary rales, ascites, or edema at randomization; greater than 3 hospitalizations for heart failure within to carvedilol. As reported previously,18
the last year; hospitalization at the time of screening or randomization; need for intravenous positive inotropic the 2 treatment groups were similar with
agent or vasodilator drug within 14 days of randomization; or left ventricular ejection fraction less than 15%.
respect to all baseline characteristics. En-
714 JAMA, February 12, 2003—Vol 289, No. 6 (Reprinted) ©2003 American Medical Association. All rights reserved.

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 INITIATING CARVEDILOL IN PATIENTS WITH SEVERE CHF

rolled patients had a mean age of 63.3
years, a median left ventricular ejection
fraction of 20%; 79.7% were male and
67.2% had ischemic heart disease.
The majority of patients were suc-
cessfully titrated to the target doses of
the study medication specified for each
visit. At 2 weeks, 97.2% of placebo pa-
tients and 97.1% of carvedilol patients
were receiving at least 3.125 mg twice
daily. At 4 weeks, 87.6% of placebo pa-
tients and 84.0% of carvedilol patients
were receiving at least 6.25 mg twice
daily. At 6 weeks, 79.1% of placebo pa-
tients and 71.7% of carvedilol patients
were receiving at least 12.5 mg twice
daily. At 8 weeks, 70.9% of placebo pa-
tients and 58.6% of carvedilol patients
were receiving 25 mg twice daily. The
Kaplan-Meier curves suggest that Changes in Vital Signs
the differences between the carvedilol During the First 8 Weeks
and placebo groups begin to appear as There were small changes in mean (SE)
early as 14 to 21 days following initia- systolic blood pressure (placebo group,
tion of treatment for both all-cause –2.0 [0.5] mm Hg and carvedilol group,
mortality and for the combined end –3.6 [0.5] mm Hg) and in diastolic blood
point of death, hospitalization, or pressure (placebo group, –1.8 [0.3]
withdrawal, in the analysis of all ran- mm Hg and carvedilol group, –2.7 [0.3]
domly assigned patients and in the mm Hg) at the end of 8 weeks. At 8
analysis of patients at highest risk weeks, heart rate slowed progressively
(FIGURE 3). in the carvedilol group as the dose of the
Figure 3. Kaplan-Meier Analysis for All Randomly Assigned Patients and for Patients at
Highest Risk During the First 8 Weeks Following Initiation of Therapy
All Randomized Patients
All-Cause Mortality Death, Hospitalization,
or Study Drug Withdrawal
3 20

mean dosages of placebo at 2, 4, 6 and

8 weeks were 3.5, 6.7, 12.5, and 19.8 15
% of Patients With Event

Placebo Placebo
mg twice daily, respectively; the mean 2
dosages of carvedilol at 2, 4, 6, and 8
10
weeks were 3.5, 6.5, 11.6, and 17.8 mg
twice daily, respectively. 1
Carvedilol Carvedilol
5
Death, Hospitalization,
or Permanent Withdrawal
0 Hazard Ratio (95% CI), 0.75 (0.41-1.35) 0 Hazard Ratio (95% CI), 0.83 (0.68-1.03)
During First 8 Weeks
During the first 8 weeks, the carvedilol 0 2 4 6 8 0 2 4 6 8
Weeks After Randomization Weeks After Randomization
group, compared with the placebo group, No. at Risk
Placebo 1133 1100 1054 1023 986 1133 1071 970 896 837
had fewer patients with a major clinical Carvedilol 1156 1119 1079 1048 1009 1156 1087 1005 944 876
event and had fewer patients who died,
who died or were hospitalized, or who High-Risk Patients
died, were hospitalized, or were perma- All-Cause Mortality Death, Hospitalization,
nently withdrawn from double-blind or Study Drug Withdrawal
treatment (FIGURE 2). The direction and 6 30

magnitude of these effects during the first

8 weeks were similar to those observed
% of Patients With Event

Placebo
during the entire study. 4 Placebo 20
Similar effects were observed for all 3
end points when the analyses were con-
fined to patients at highest risk, that is, 2 10
those patients with recent or recurrent Carvedilol
Carvedilol
decompensation or a very depressed left
ventricular ejection fraction (Figure 2). 0 0
Hazard Ratio (95% CI), 0.20 (0.06-0.70) Hazard Ratio (95% CI), 0.67 (0.47-0.96)
The carvedilol group , when compared
with the placebo group, had a lower risk 0 2 4 6 8 0 2 4 6 8
Weeks After Randomization Weeks After Randomization
of death, of death or hospitalization, and No. at Risk
Placebo 316 309 295 281 270 316 294 257 227 214
of death, hospitalization, or with- Carvedilol 308 299 290 282 268 308 286 258 241 221
drawal of double-blind treatment. Again,
Patients at highest risk are patients with recent or recurrent cardiac decompensation or very depressed cardiac
the direction and magnitude of these ef- function and characterized by 1 or more of the following: the presence of pulmonary rales, ascites, or edema
fects seen in this cohort during the first at randomization; greater than 3 hospitalizations for heart failure within the last year; hospitalization at the
8 weeks were similar to those observed time of screening or randomization; need for intravenous positive inotropic agent or vasodilator drug within
14 days of randomization; or left ventricular ejection fraction less than 15%.
during the entire study.
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 INITIATING CARVEDILOL IN PATIENTS WITH SEVERE CHF

study medication and duration of treat-
ment increased (placebo group, − 2.2
[0.4] bpm and carvedilol group, −12.5
[0.4] bpm), but body weight did not
change in either group (placebo group,
0 [0.07] kg and carvedilol group, 0.1
[0.07] kg).
Adverse Events During
the First 8 Weeks
Overall, 59 patients (5.2%) in the pla-
cebo group and 51 patients (4.4%) in
the carvedilol group permanently with-
drew from double-blind medication for
Table. Adverse Events During the First 8 Weeks*
All Randomized Patients
Bradycardia
Serious adverse event
Trial drug decreased due to adverse event
Withdrawn due to adverse event
Dizziness
Serious adverse event
Trial drug decreased due to adverse event
Withdrawn due to adverse event
Edema
Serious adverse event
Trial drug decreased due to adverse event
Withdrawn due to adverse event
Hypotension
Serious adverse event
Trial drug decreased due to adverse event
Withdrawn due to adverse event
Patients at Highest Risk
Bradycardia
Serious adverse event
Trial drug decreased due to adverse event
Withdrawn due to adverse event
Dizziness
Serious adverse event
Trial drug decreased due to adverse event
Withdrawn due to adverse event
Edema
Serious adverse event
Trial drug decreased due to adverse event
Withdrawn due to adverse event
Hypotension
Serious adverse event
Trial drug decreased due to adverse event
Withdrawn due to adverse event
*Includes adverse events with a frequency of at least 2% in all randomly assigned patients in either treatment group
and differences between treatment groups in the frequency of the event of at least 2%. An adverse event was de-
fined in the study protocol as serious if it was fatal or life-threatening; required or prolonged hospitalization or re-
sulted in persistent or significant disability or incapacity.
716 JAMA, February 12, 2003—Vol 289, No. 6 (Reprinted)
any reason other than death. There was quency greater than 2%, namely wors-
no difference between placebo and ening heart failure, and it was reported
carvedilol in the number of patients with a similar frequency with placebo
withdrawn for worsening heart failure and carvedilol (6.4% vs 5.1%, respec-
(0.7% vs 0.6%, respectively, for all pa- tively, among all randomly assigned pa-
tients and 1.9% vs 1.6%, respectively, tients; and 11.4% and 8.8%, respec-
for highest risk patients). In addition, tively, in patients at highest risk).
fewer patients in the carvedilol group Patients in the carvedilol group were
than in the placebo group experi- more likely than in the placebo group
enced a serious adverse event (13.8% to report dizziness, hypotension, edema,
vs 15.0% among all randomly as- and bradycardia (TABLE). In general,
signed patients and 16.2% vs 22.2% these reactions were not considered se-
among high-risk patients). Only 1 se- rious, but in a small number of cases
rious adverse event occurred with a fre- required withdrawal of double-blind
medication. Clinically significant dif-
ferences (ie, greater than 2% differ-
ence) between the treatment groups
No. (%) were not observed during the up-
Placebo Carvedilol titration period for any other adverse
event.
(n = 1133) (n = 1156)
COMMENT
1 (0.1) 10 (0.9)
Many physicians believe that for pa-
3 (0.3) 27 (2.3)
tients with severe chronic heart fail-
0 4 (0.3)
ure to experience the long-term ben-
4 (0.4) 5 (0.4) efits of ␤-adrenergic blockade, they
22 (1.9) 67 (5.8) must undergo a period of initiation and
3 (0.3) 10 (0.9) up-titration that may be trouble-
some.8 There is concern that the with-
5 (0.4) 3 (0.3) drawal of sympathetically mediated ino-
3 (0.3) 11 (1.0) tropic support following the start of
2 (0.2) 1 (0.1) treatment with a ␤-blocker carries a
high risk of worsening heart failure, pul-
2 (0.2) 6 (0.5)
11 (1.0) 38 (3.3)
monary edema, or cardiogenic shock.
0 (0.0) 5 (0.4)
Patients with severe heart failure are
considered most likely to experience
early worsening and delayed benefit of
(n = 316) (n = 308)
treatment,8,9,13,14 since such individu-
0 3 (1.0) als show the most marked activation of
2 (0.6) 8 (2.6) the sympathetic nervous system23 and
0 2 (0.6) are assumed to be the most dependent
on adrenergically mediated circula-
1 (0.3) 0
tory support.24
7 (2.2) 17 (5.5)
The findings of the COPERNICUS
2 (0.6) 2 (0.6)
study with carvedilol challenge beliefs
1 (0.3) 2 (0.6) about the efficacy and safety of ␤-block-
0 3 (1.0) ade during the first several weeks of treat-
0 1 (0.3) ment. During both initiation and up-
titration, patients treated with carvedilol
1 (0.3) 1 (0.3) had no increase in the risk of worsen-
3 (0.9) 14 (4.5) ing heart failure, pulmonary edema, car-
0 2 (0.6) diogenic shock, or other serious ad-
verse cardiovascular events, including
death. The principal adverse events at-
tributable to carvedilol during the first
©2003 American Medical Association. All rights reserved.

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8 weeks of therapy were those expected
as a result of the inhibitory effects of the
drug on ␣-receptors (dizziness and hy-
potension) and ␤-receptors (bradycar-
dia and peripheral edema).10,24 How-
ever, these adverse reactions were mild
and infrequent, occurring in 3 to 7 more
patients in the carvedilol group per 100
patients treated. Importantly, because
these adverse reactions were self-
limited and not considered serious, they
rarely led to the discontinuation of ef-
fective treatment.
The results of the COPERNICUS
study also challenge the belief that the
benefits of ␤-adrenergic blockade in pa-
tients with heart failure are delayed. Dur-
ing the first 8 weeks of treatment, fewer
patients died or were hospitalized in the
carvedilol group, and the magnitude of
risk reduction by carvedilol during this
early phase of therapy was similar to that
seen during the entire study. The abil-
ity of carvedilol to produce beneficial ef-
fects early during the course of treat-
ment was particularly striking in the
patients at highest risk, that is, those with
recent or recurrent decompensation or
a very depressed left ventricular ejec-
tion fraction. These observations indi-
cate that the clinical benefits of sympa-
thetic antagonism are not necessarily
delayed and suggest that the mecha-
nisms by which such benefits are me-
diated are not of necessity dependent on
changes in left ventricular function or
geometry, which are known to require
months to become apparent.15,25 It also
is noteworthy that the Kaplan-Meier
curves for the placebo and carvedilol
groups (Figure 3) began to separate af-
ter about 21 days of treatment; this was
at a time when patients were generally
receiving a dosage of only 6.25 mg of
carvedilol twice daily. This finding in
patients with severe heart failure is
consistent with the results of an earlier
study, which showed that even
6.25 mg of carvedilol twice daily was
effective in patients with mild-to-
moderate symptoms.26,27
The findings of the present study
should be interpreted in light of the fact
that the investigators and coordina-
tors were highly experienced in the
©2003 American Medical Association. All rights reserved.
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INITIATING CARVEDILOL IN PATIENTS WITH SEVERE CHF
treatment of heart failure, and they se-
lected patients carefully and followed
them closely during the course of the
trial. Furthermore, the protocol speci-
fied that patients were to be clinically
euvolemic before they were randomly
assigned, and every effort was made to
maintain euvolemia during initiation
and up-titration of the study medica-
tion. Patients were encouraged to re-
port any adverse effects or weight gain,
and the dose of other medications could
be modified or the rapidity of upward
titration of the dose of the study drug
could be decreased, if such adjust-
ments were clinically warranted. These
approaches will need to be followed in
clinical practice; similar precautions
have been recommended for general use
in recent guidelines.28
In conclusion, the relation of ben-
efit to risk during initiation of treat-
ment with carvedilol is similar to that
seen during long-term treatment with
the drug. In clinically euvolemic
patients with advanced heart failure,
initiation of treatment with carvedilol
was well-tolerated and was associated
with fewer major adverse events than
initiation of treatment with placebo. If
concerns about efficacy and safety
during the initiation of ␤-blocker
therapy have caused physicians to
deny or delay the use of these drugs,
our findings should provide the reas-
surance needed to encourage the high
levels of use that are warranted by the
results of clinical trials.
Author Contributions: Dr Roecker has had full ac-
cess to the data for the COPERNICUS study and takes
responsibility for the accuracy of the data analysis pre-
sented in this article.
Study Concept and Design:Krum, Roecker, Mohacsi,
Rouleau, Tendera, Coats, Katus, Fowler, Packer.
Acquisition of Data: Krum, Mohacsi, Rouleau, Tendera,
Coats, Katus, Fowler, Packer.
Analysis and Interpretation Data: Krum, Roecker,
Mohacsi, Rouleau, Tendera, Coats, Katus, Fowler,
Packer.
Drafting of Manuscript: Krum, Roecker, Packer.
Critical Revision of Manuscript for Important Intel-
lectual Content: Krum, Roeker, Mohacsi, Rouleau,
Tendera, Coats, Katus, Fowler, Packer.
Statistical Expertise: Roecker.
Obtained Funding: Packer.
Administrative, Technical or Material Support: Krum,
Roeker, Mohacsi, Rouleau, Tendera, Coats, Katus,
Fowler, Packer.
Study Supervision: Krum, Mohacsi, Rouleau, Tendera,
Coats, Katus, Fowler, Packer.
Financial Disclosures: Drs Krum, Mohacsi, Rouleau,
(Reprinted) JAMA, February 12, 2003—Vol 289, No. 6 717
Tendera, Coats, Katus, Fowler, and Packer have served
as consultants for Roche Pharmaceuticals and/or Glaxo-
SmithKline Ltd. Dr Roecker has received salary sup-
port from a research contract with GlaxoSmithKline
Ltd. Dr Fowler has received honararia from Glaxo-
SmithKline Ltd, Roche Pharmaceuticals, Astra Zen-
eca and has served as a consultant to Bristol-Meyers
Squibb, GlaxoSmithKline Ltd, and Scios Inc. Dr Packer
has served as a consultant to GlaxoSmithKline Ltd and
Roche Pharmeceuticals.
Funding/Support: This study was supported by grants
from Roche Pharmaceuticals and Glaxo SmithKline Ltd.
Acknowledgment: We thank Christoph Staiger, MD,
Ildiko Amann-Zalan, MD, and Diethelm Messinger,
MS, of Roche Pharmaceuticals; Ellen L. Curtin, MD,
Terry L. Holcslaw, PhD, and Neil Shusterman, MD, of
GlaxoSmithKline, Ltd; and Melissa K. Schultz, MS, and
Barbara Kowalcyk, MS, of the University of Wiscon-
sin for their invaluable contributions to the study.
COPERNICUS study group coordinators: Steering
Committee: M. Packer (Chair), A. Castaigne, A. Coats,
M. Fowler, H. Katus, H. Krum, P. Mohacsi, J-L. Rou-
leau, M. Tendera. Data and Safety Monitoring Board:
K. Swedberg (Chair), E. Angermann, R. Campbell (de-
ceased), J. Cohn, A. Maseri, S. Pocock. Biostatistics
Center: D. DeMets, E. Roecker, M. Schultz. End-
point Committee: P. Carson (Chair), V. Bernstein, C.
O’Connor, M. Haass, V. Mareev, A. Miller, S. Per-
rone, B. Rauch, G. Sutton. Roche/GlaxoSmithKline Op-
erating Committee: I. Amann-Zalan, E. Curtin, M.
Harsch, T. Holcslaw, E. Kroener-Bentel, D. Mess-
inger, C. Staiger.
List of investigators: Argentina: F. Diez, E. Kuschnir,
S. Perrone. Australia: P. Garrahy, J. Horowitz, I. Jef-
fery, J. Karrasch, H. Krum, P. McDonald, J. Waites.
Austria: B. Eber, F. Schmalzl, J. Slany, R. Spinka,
W. Weihs. Canada: P. Alain, M. Arnold, R. Baigrie,
M. Bentley-Taylor, J. Bonet, J. Champagne, P. Costi,
T. Cuddy, D. Dion, D. Fell, D. Gossard, M. Gupta,
W. Hui, J. Howlett, D. Humen, J. Hynd, T. Kashour,
M. Khouri, P. Klinke, S. Kouz, M. Langlais, M. H. Le-
blanc, S. Lepage, B. Lubelsky, D. Manyari, M. Matangi,
G. Moe, A. Morris, J. Nasmith, M. Palaic, P. Pflug-
felder, D. C. Phaneuf, A. Rajakumar, T. Rebane, J. Ricci,
J. Rouleau, F. Sestier, S. Smith, J. Stone, P. Talbot, M.
White. Czech Republic: P. Bocek, I. Gajdosová, J. Gre-
gor, P. Gregor, I. Kotik, A. Linhart, J. Lukl, P. Petr,
J. Popelova, B. Semrad, V. Stanek, R. Stipal. France:
A. Gabriel, J. L. Guermonprez, G. Mougeot, J. Puel,
R. Roudaut. Germany: T. Beyer, A. Costard-Jäckle, W.
Döring, F. Freytag, H. Katus, H. Koch, F. Menzel,
S. Peters, U. Sechtem, W. Sehnert, H. F. Vöhringer, E.
Wunderlich, H. Zebe, R. Zotz. Great Britain: R. Bain,
P. Bennett, A. Coats, D. Davies, S. Gibbs, T. Green-
wood, M. Heber, A. Lahiri, R. Mattu, J. McComb, I.
McLay, D. Nichols, R. Northcote, B. Silke, S. Ste-
phens, J. Swan, C. Weston. Hungary: M. Csanády,
L. Cserhalmi, I. Édes, T. Gesztesi, E. Kaló, A. Katona,
A. Jánosy, F. Poór, M. Rusznák, K. Simon, F. Szabóki,
J. Tarján, J. Tenczer, S. Timár, P. Vályi, K. Zámoly. Israel:
G. Avinader, A. Caspi, A. Darausha, D. David, Y. Kishon,
E. Klainman, B. Lewis, A. Marmor, M. Mitelman, M.
Omary, L. Reisin, T. Rosenfeld, S. Shasha,
Z. Vered, R. Zimlichman. Italy: E. Arosio, A. Branzi,
C. Campana, M. Casaccia, L. Dei Cas, A. Di Lenarda,
P. Fioretti, M. Frigerio, A. L’Abbate, M. Modena.
Lithuania: A. Kibarskis, P. Serpytis, D. Vasiliauskas,
P. Zabiela. Mexico: N. Garcia-Hernández. The Neth-
erlands: R. Breedveld, J. Cornel, M. Daniels, P. Dun-
selman, B. Hamer, L. van Kempen, G. Linssen, A. Maas,
P. de Milliano, S. Twisk, A. Willems. Poland: L. Cer-
emuzynski, A. Cieslinski, M. Dalkowski, J. Dubiel, B.
Filipek, H. Halaczkiewicz, M. Janion, K. Kawecka-
Jaszcz, M. Krzeminska-Pakula, B. Kusnierz, K. Loboz-
Grudzien, A. Malinski, T. Mandecki, W. Musial, W.
Piotrowski, W. Pluta, W. Prastowski, W. Ruminski, A.
Rynkiewicz, W. Smielak-Korombel, M. Tendera, R. Tro-
jnar, M. Ujda, J. Wodniecki, K. Wrabec, M. Zalewski.
 INITIATING CARVEDILOL IN PATIENTS WITH SEVERE CHF
Portugal: M. Carrageta, R. Seabra-Gomes. Russia:
G. Arutyunov, R. Charchoglian, A. Gruzdev, A. Ivleva,
Y. Karpov, V. Kostenko, V. Mareev, V. Moisejev,
L. Oblinskaya, V. Orlov, N. Perepech, E. Shlyhatkho,
B. Sidorenko, A. Smirnov, A. Starodubsev, G. Storazha-
kov. South Africa: P. Jordaan, P. Manga, D. Naidoo,
I. Radevski, N. Ranjith. Switzerland: B. Caduff,
P. Mohacsi, C. Röthlisberger, F. Widmer. Ukraine:
E. Amosova, G. Dzyak, G. Knyshov, V. Kovalenko,
V. Netyazhenko, S. Pavlyk, N. Seredjuk, Y. Serenko,
L. Voronkov, A. Zmuro. United States: K. Aaronson,
W. Abraham, J. Alexander, J. Allen, J. Anderson, J. Ber-
gin, P. Berman, P. Binkley, N. Bittar, J. Bowers, L. Brook-
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