Download Effects of Initiating Carvedilol in Patients With Severe Chronic Heart

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 practice 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 experience 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 Furthermore, many physicians have assumed
that the beneficial effects of ␤-blockers
are delayed9,15 so that a favorable effect
of treatment on symptoms, hospitalizations, or death may not become apparent for many months.2-4,16 Concerns that
See also pp 730 and 754.
712
Context ␤-Blockers remain underused despite their established utility for improving
outcome in heart failure. Concerns that initiation of treatment produces few immediate 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 dosage 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, 0.671.07); 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 ventricular 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 serious adverse event with a frequency greater than 2% and was reported with similar frequency 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 longterm clinical trials.
www.jama.com
JAMA. 2003;289:712-718
Author Affiliations: Monash University, Melbourne, Victoria, Australia (Dr Krum); University of
Wisconsin, Madison (Dr Roecker); University Hospital, Bern, Switzerland (Dr Mohacsi); Silesian School
of Medicine, Katowice, Poland (Dr Tendera); University Health Network and Mt Sinai Hospital,
Toronto, Ontario, Canada (Dr Rouleau); Royal
Brompton Hospital, London, England (Dr Coats);
Universitaets Klinikum Luebeck, Luebeck, Germany
(Dr Katus); Stanford University Medical Center,
Stanford, Calif (Dr Fowler); and the College of
JAMA, February 12, 2003—Vol 289, No. 6 (Reprinted)
Physicians and Surgeons, Columbia University, New
York, NY (Dr Packer).
The COPERNICUS Study Investigators and Coordinators are listed at the end of the article.
Corresponding Author and Reprints: Henry Krum,
MD, National Health and Medical Research Council
Center of Clinical Research Excellence in Therapeutics, Dept of Medicine and Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, 3181 Australia, (e-mail: henry.krum
@med.monash.edu.au).
©2003 American Medical Association. All rights reserved.
INITIATING CARVEDILOL IN PATIENTS WITH SEVERE CHF
initiation of ␤-blocker therapy carries
important risks and few immediate benefits has contributed to the underutilization of these drugs in the management of heart failure.7
Most of the information we have about
the responses to ␤-blocker therapy have
been derived from uncontrolled studies,9,13,15 and thus, it has been difficult to
determine if the effects reported were related to treatment or to underlying disease. 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 failure and drug withdrawal in patients with
severe heart failure.
We describe the initiation of treatment with the ␣, ␤-adrenergic blocker
carvedilol in the Carvedilol Prospective Randomized Cumulative Survival
(COPERNICUS) study.19 The primary
objective of the COPERNICUS trial was
to evaluate the long-term effects of carvedilol on the survival of patients with severe heart failure. In the overall study
(mean follow-up, 10.4 months), carvedilol 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 treatment with a ␤-blocker.8,9,13
METHODS
Study Participants
COPERNICUS study patients were enrolled from 334 hospital centers and 21
countries between October 28, 1997,
and March 20, 2000. Patients were eligible if they had dyspnea or fatigue at
rest or on minimal exertion for at least
2 months and a left ventricular ejection fraction less than 25% due to ischemic or nonischemic cardiomyopathy. All patients were treated with a
diuretic (which was adjusted to mini-
mize the degree of volume retention)
and treated with an angiotensinconverting enzyme inhibitor or an
angiotensin II receptor antagonist (unless these were not tolerated). Treatment with digitalis, spironolactone, vasodilators, 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 contraindication 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 angioplasty, a myocardial or cerebral ischemic event, or sustained or hemodynamically destabilizing ventricular
tachyarrhythmia. Patients also were excluded if they had received an ␣-blocker,
calcium channel blocker, or class I antiarrhythmic drug within 4 weeks; a
␤-blocker within 2 months; or an intravenous positive inotropic agent or vasodilator 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 doubleblind trial, eligible patients were randomly assigned to receive either carvedilol 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 labeled with sequential randomization
numbers linked up to a block randomization scheme; at the randomization
visit, each patient was assigned the lowest number available at each site. The
starting dosage was 3.125 mg of carvedilol or placebo twice daily, which if tolerated 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-
©2003 American Medical Association. All rights reserved.
Figure 1. Patient Flow During Initiation and
Up-titration of Study Drug
3106 Screened
2289 Randomized
1133 Assigned to
Receive Placebo
59 Withdew from
Study Drug
0 Lost to follow-up
of Vital Status
25 Died
1133 Included in
Analysis
1156 Assigned to
Receive Carvedilol
51 Withdew from
Study Drug
0 Lost to follow-up
of Vital Status
19 Died
1156 Included in
Analysis
tients were asked about the occurrence
of any clinical event or adverse effect, vital signs and body weight were measured, the dose of the study drug was recorded, 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 received a higher dose. The intent of the
up-titration phase was to identify the
highest dose of carvedilol that each patient could tolerate, and patients were
considered to have completed the uptitration 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 rapidity of up-titration could be slowed if
deemed appropriate.
If warranted by clinical circumstances, the dose of carvedilol or placebo could be reduced or temporarily
discontinued, the doses of all concomitant drugs could be adjusted, and the
investigator could implement any new
treatments, except for open-label treatment 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
(Reprinted) JAMA, February 12, 2003—Vol 289, No. 6 713
INITIATING CARVEDILOL IN PATIENTS WITH SEVERE CHF
Statistical Analysis
A major clinical event was defined as
death, hospitalization, or permanent
withdrawal of the study medication
for any reason. Cumulative incidence
curves for the occurrence of these events
were constructed by the Kaplan-Meier
method, using a time-to-first-event approach.20 Cox proportional hazards regression models were used to estimate
hazard ratios (HRs) and 95% confidence intervals (CIs).21 The analyses of
major outcome variables included all
randomly assigned patients according to
the intention-to-treat principle. Since the
present report focused on the effects of
treatment during initiation and uptitration, the period of principal interest was 8 weeks, which corresponded
to the expected duration of the uptitration period. These specific outcomes and the 8-week period also were
the focus of an earlier analysis of the uptitration period in the Metoprolol CR/XL
Randomised Intervention Trial in Congestive Heart Failure Study Group.16
Because earlier studies had raised
concerns that patients at highest risk
might respond poorly to ␤-adrenergic
blockade,14,22 the effects of carvedilol
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
All Randomized Patients
Placebo
First 8 Weeks
No./ Total Kaplan-Meier No./ Total Kaplan-Meier
Event Rate, %
Event Rate, %
First 8 Weeks
Entire Trial
25/1133
Entire Trial
Carvedilol
All-Cause Mortality
2.3
19/1156
1.7
Death or Hospitalization for Any Reason
First 8 Weeks 153/1133
134/1156
12.3
14.4
Entire Trial
Favors
Carvedilol
Hazard
Ratio
(95% CI)
Favors
Placebo
0.75 (0.41-1.35)
0.65 (0.52-0.81)
0.85 (0.67-1.07)
0.76 (0.67-0.87)
Death, Hospitalization, or Permanent Study Drug
Withdrawal for Any Reason
First 8 Weeks 188/1133
Entire Trial
17.5
162/1156
14.8
0.83 (0.68-1.03)
0.76 (0.67-0.86)
.05 0.1
1.0 2.0
Hazard Ratio
High-Risk Patients
Placebo
Carvedilol
No./ Total Kaplan-Meier No./ Total Kaplan-Meier
Event Rate, %
Event Rate, %
First 8 Weeks
Entire Trial
First 8 Weeks
Entire Trial
15/316
All-Cause Mortality
3/308
5.0
1.0
Death or Hospitalization for Any Reason
63/316
44/308
15.0
20.9
Favors
Carvedilol
Hazard
Ratio
(95% CI)
Favors
Placebo
0.20 (0.06-0.70)
0.61 (0.41-0.89)
0.71 (0.48-1.04)
0.71 (0.56-0.89)
Death, Hospitalization, or Permanent Study Drug
Withdrawal for Any Reason
First 8 Weeks
Entire Trial
76/316
25.0
51/308
17.3
0.67 (0.47-0.96)
0.68 (0.54-0.84)
.05 0.1
1.0 2.0
Hazard Ratio
CI indicates confidence interval. Patients at highest risk are patients with recent or recurrent cardiac decompensation or very depressed cardiac function and characterized by 1 or more of the following: the presence of
pulmonary rales, ascites, or edema at randomization; greater than 3 hospitalizations for heart failure within
the last year; hospitalization at the 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%.
714
JAMA, February 12, 2003—Vol 289, No. 6 (Reprinted)
were assessed in a very high risk subgroup consisting of patients with recent or recurrent cardiac decompensation or very depressed cardiac function.
These high-risk patients were characterized by 1 or more of the following:
the presence of pulmonary rales, ascites, or edema at randomization; 3 or
more hospitalizations for heart failure
within the last year; hospitalization at
the time of screening or randomization; need for intravenous positive inotropic agent or vasodilator drug within
14 days before randomization; or left
ventricular ejection fraction of 15% or
less.19 The baseline variables that defined this high-risk group were identified a priori without knowledge of
their influence on the treatment effect.
The safety of carvedilol was assessed
by changes in vital signs (summarized as
a mean [SE] change from baseline) and
by reports of adverse events with onset
within 8 weeks of randomization. All reports of adverse events were included
whether or not they were deemed by the
investigator to be related to treatment.
Adverse events with a frequency of at
least 2% among all randomly assigned
patients in either treatment group, and
differences between treatment groups of
at least 2% in the frequencies of the event
were considered clinically significant. An
adverse event was defined in the study
protocol as serious if it was fatal or lifethreatening, required or prolonged hospitalization, or resulted in persistent or
significant disability or incapacity. Statistical analyses were performed using
SAS (versions 6.12 and 8.0; SAS Institute, Cary, NC).
RESULTS
Of the 2289 patients who were enrolled
into the trial, 1133 were randomly assigned to the placebo group and 1156 to
the carvedilol group (FIGURE 1). Of these,
624 (27.3%) patients fulfilled the criteria for recent or recurrent cardiac decompensation or very depressed cardiac function, of whom 316 were
randomly assigned to placebo and 308
to carvedilol. As reported previously,18
the 2 treatment groups were similar with
respect to all baseline characteristics. En-
©2003 American Medical Association. All rights reserved.
INITIATING CARVEDILOL IN PATIENTS WITH SEVERE CHF
During the first 8 weeks, the carvedilol
group, compared with the placebo group,
had fewer patients with a major clinical
event and had fewer patients who died,
who died or were hospitalized, or who
died, were hospitalized, or were permanently withdrawn from double-blind
treatment (FIGURE 2). The direction and
magnitude of these effects during the first
8 weeks were similar to those observed
during the entire study.
Similar effects were observed for all 3
end points when the analyses were confined to patients at highest risk, that is,
those patients with recent or recurrent
decompensation or a very depressed left
ventricular ejection fraction (Figure 2).
The carvedilol group , when compared
with the placebo group, had a lower risk
of death, of death or hospitalization, and
of death, hospitalization, or withdrawal of double-blind treatment. Again,
the direction and magnitude of these effects seen in this cohort during the first
8 weeks were similar to those observed
during the entire study.
There were small changes in mean (SE)
systolic blood pressure (placebo group,
–2.0 [0.5] mm Hg and carvedilol group,
–3.6 [0.5] mm Hg) and in diastolic blood
pressure (placebo group, –1.8 [0.3]
mm Hg and carvedilol group, –2.7 [0.3]
mm Hg) at the end of 8 weeks. At 8
weeks, heart rate slowed progressively
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
% of Patients With Event
Death, Hospitalization,
or Permanent Withdrawal
During First 8 Weeks
Changes in Vital Signs
During the First 8 Weeks
Kaplan-Meier curves suggest that
the differences between the carvedilol
and placebo groups begin to appear as
early as 14 to 21 days following initiation of treatment for both all-cause
mortality and for the combined end
point of death, hospitalization, or
withdrawal, in the analysis of all randomly assigned patients and in the
analysis of patients at highest risk
(FIGURE 3).
20
15
Placebo
Placebo
2
10
1
Carvedilol
0
0
2
4
Carvedilol
5
Hazard Ratio (95% CI), 0.75 (0.41-1.35)
No. at Risk
Placebo 1133
Carvedilol 1156
6
0
8
Hazard Ratio (95% CI), 0.83 (0.68-1.03)
0
Weeks After Randomization
1100
1119
1054
1079
2
4
6
8
Weeks After Randomization
1023
1048
986
1009
1133
1156
1071
1087
970
1005
896
944
837
876
High-Risk Patients
All-Cause Mortality
Death, Hospitalization,
or Study Drug Withdrawal
6
% of Patients With Event
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 successfully titrated to the target doses of
the study medication specified for each
visit. At 2 weeks, 97.2% of placebo patients and 97.1% of carvedilol patients
were receiving at least 3.125 mg twice
daily. At 4 weeks, 87.6% of placebo patients and 84.0% of carvedilol patients
were receiving at least 6.25 mg twice
daily. At 6 weeks, 79.1% of placebo patients and 71.7% of carvedilol patients
were receiving at least 12.5 mg twice
daily. At 8 weeks, 70.9% of placebo patients and 58.6% of carvedilol patients
were receiving 25 mg twice daily. The
mean dosages of placebo at 2, 4, 6 and
8 weeks were 3.5, 6.7, 12.5, and 19.8
mg twice daily, respectively; the mean
dosages of carvedilol at 2, 4, 6, and 8
weeks were 3.5, 6.5, 11.6, and 17.8 mg
twice daily, respectively.
30
Placebo
Placebo
4
20
2
10
Carvedilol
Carvedilol
0
Hazard Ratio (95% CI), 0.20 (0.06-0.70)
0
No. at Risk
Placebo
Carvedilol
2
4
6
8
0
Hazard Ratio (95% CI), 0.67 (0.47-0.96)
0
Weeks After Randomization
316
308
309
299
295
290
2
4
6
8
Weeks After Randomization
281
282
270
268
316
308
294
286
257
258
227
241
214
221
Patients at highest risk are patients with recent or recurrent cardiac decompensation or very depressed cardiac
function and characterized by 1 or more of the following: the presence of pulmonary rales, ascites, or edema
at randomization; greater than 3 hospitalizations for heart failure within the last year; hospitalization at the
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%.
©2003 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 12, 2003—Vol 289, No. 6 715
INITIATING CARVEDILOL IN PATIENTS WITH SEVERE CHF
study medication and duration of treatment 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 placebo group and 51 patients (4.4%) in
the carvedilol group permanently withdrew from double-blind medication for
any reason other than death. There was
no difference between placebo and
carvedilol in the number of patients
withdrawn for worsening heart failure
(0.7% vs 0.6%, respectively, for all patients and 1.9% vs 1.6%, respectively,
for highest risk patients). In addition,
fewer patients in the carvedilol group
than in the placebo group experienced a serious adverse event (13.8%
vs 15.0% among all randomly assigned patients and 16.2% vs 22.2%
among high-risk patients). Only 1 serious adverse event occurred with a fre-
Table. Adverse Events During the First 8 Weeks*
No. (%)
Placebo
All Randomized Patients
(n = 1133)
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
1 (0.1)
3 (0.3)
0
Carvedilol
(n = 1156)
10 (0.9)
27 (2.3)
4 (0.3)
4 (0.4)
22 (1.9)
3 (0.3)
5 (0.4)
67 (5.8)
10 (0.9)
5 (0.4)
3 (0.3)
2 (0.2)
3 (0.3)
11 (1.0)
1 (0.1)
2 (0.2)
11 (1.0)
0 (0.0)
6 (0.5)
38 (3.3)
5 (0.4)
(n = 316)
(n = 308)
0
2 (0.6)
0
3 (1.0)
8 (2.6)
2 (0.6)
1 (0.3)
7 (2.2)
0
17 (5.5)
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
2 (0.6)
2 (0.6)
Edema
Serious adverse event
Trial drug decreased due to adverse event
Withdrawn due to adverse event
Withdrawn due to adverse event
1 (0.3)
0
0
2 (0.6)
3 (1.0)
1 (0.3)
Hypotension
Serious adverse event
Trial drug decreased due to adverse event
Withdrawn due to adverse event
1 (0.3)
3 (0.9)
0
1 (0.3)
14 (4.5)
2 (0.6)
*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 defined in the study protocol as serious if it was fatal or life-threatening; required or prolonged hospitalization or resulted in persistent or significant disability or incapacity.
716
JAMA, February 12, 2003—Vol 289, No. 6 (Reprinted)
quency greater than 2%, namely worsening heart failure, and it was reported
with a similar frequency with placebo
and carvedilol (6.4% vs 5.1%, respectively, among all randomly assigned patients; and 11.4% and 8.8%, respectively, in patients at highest risk).
Patients in the carvedilol group were
more likely than in the placebo group
to report dizziness, hypotension, edema,
and bradycardia (TABLE). In general,
these reactions were not considered serious, but in a small number of cases
required withdrawal of double-blind
medication. Clinically significant differences (ie, greater than 2% difference) between the treatment groups
were not observed during the uptitration period for any other adverse
event.
COMMENT
Many physicians believe that for patients with severe chronic heart failure to experience the long-term benefits of ␤-adrenergic blockade, they
must undergo a period of initiation and
up-titration that may be troublesome.8 There is concern that the withdrawal of sympathetically mediated inotropic support following the start of
treatment with a ␤-blocker carries a
high risk of worsening heart failure, pulmonary edema, or cardiogenic shock.
Patients with severe heart failure are
considered most likely to experience
early worsening and delayed benefit of
treatment,8,9,13,14 since such individuals show the most marked activation of
the sympathetic nervous system23 and
are assumed to be the most dependent
on adrenergically mediated circulatory support.24
The findings of the COPERNICUS
study with carvedilol challenge beliefs
about the efficacy and safety of ␤-blockade during the first several weeks of treatment. During both initiation and uptitration, patients treated with carvedilol
had no increase in the risk of worsening heart failure, pulmonary edema, cardiogenic shock, or other serious adverse cardiovascular events, including
death. The principal adverse events attributable to carvedilol during the first
©2003 American Medical Association. All rights reserved.
INITIATING CARVEDILOL IN PATIENTS WITH SEVERE CHF
8 weeks of therapy were those expected
as a result of the inhibitory effects of the
drug on ␣-receptors (dizziness and hypotension) and ␤-receptors (bradycardia and peripheral edema).10,24 However, 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 selflimited and not considered serious, they
rarely led to the discontinuation of effective treatment.
The results of the COPERNICUS
study also challenge the belief that the
benefits of ␤-adrenergic blockade in patients with heart failure are delayed. During 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 ability of carvedilol to produce beneficial effects early during the course of treatment was particularly striking in the
patients at highest risk, that is, those with
recent or recurrent decompensation or
a very depressed left ventricular ejection fraction. These observations indicate that the clinical benefits of sympathetic antagonism are not necessarily
delayed and suggest that the mechanisms by which such benefits are mediated 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 after 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-tomoderate symptoms.26,27
The findings of the present study
should be interpreted in light of the fact
that the investigators and coordinators were highly experienced in the
treatment of heart failure, and they selected patients carefully and followed
them closely during the course of the
trial. Furthermore, the protocol specified 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 medication. Patients were encouraged to report 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 adjustments 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 benefit to risk during initiation of treatment 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 reassurance needed to encourage the high
levels of use that are warranted by the
results of clinical trials.
Author Contributions: Dr Roecker has had full access to the data for the COPERNICUS study and takes
responsibility for the accuracy of the data analysis presented 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 Intellectual 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,
©2003 American Medical Association. All rights reserved.
Tendera, Coats, Katus, Fowler, and Packer have served
as consultants for Roche Pharmaceuticals and/or GlaxoSmithKline Ltd. Dr Roecker has received salary support from a research contract with GlaxoSmithKline
Ltd. Dr Fowler has received honararia from GlaxoSmithKline Ltd, Roche Pharmaceuticals, Astra Zeneca 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 Wisconsin 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. Rouleau, M. Tendera. Data and Safety Monitoring Board:
K. Swedberg (Chair), E. Angermann, R. Campbell (deceased), J. Cohn, A. Maseri, S. Pocock. Biostatistics
Center: D. DeMets, E. Roecker, M. Schultz. Endpoint Committee: P. Carson (Chair), V. Bernstein, C.
O’Connor, M. Haass, V. Mareev, A. Miller, S. Perrone, B. Rauch, G. Sutton. Roche/GlaxoSmithKline Operating Committee: I. Amann-Zalan, E. Curtin, M.
Harsch, T. Holcslaw, E. Kroener-Bentel, D. Messinger, C. Staiger.
List of investigators: Argentina: F. Diez, E. Kuschnir,
S. Perrone. Australia: P. Garrahy, J. Horowitz, I. Jeffery, 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. Leblanc, S. Lepage, B. Lubelsky, D. Manyari, M. Matangi,
G. Moe, A. Morris, J. Nasmith, M. Palaic, P. Pflugfelder, 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. Gregor, 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. Greenwood, M. Heber, A. Lahiri, R. Mattu, J. McComb, I.
McLay, D. Nichols, R. Northcote, B. Silke, S. Stephens, 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 Netherlands: R. Breedveld, J. Cornel, M. Daniels, P. Dunselman, B. Hamer, L. van Kempen, G. Linssen, A. Maas,
P. de Milliano, S. Twisk, A. Willems. Poland: L. Ceremuzynski, A. Cieslinski, M. Dalkowski, J. Dubiel, B.
Filipek, H. Halaczkiewicz, M. Janion, K. KaweckaJaszcz, M. Krzeminska-Pakula, B. Kusnierz, K. LobozGrudzien, A. Malinski, T. Mandecki, W. Musial, W.
Piotrowski, W. Pluta, W. Prastowski, W. Ruminski, A.
Rynkiewicz, W. Smielak-Korombel, M. Tendera, R. Trojnar, M. Ujda, J. Wodniecki, K. Wrabec, M. Zalewski.
(Reprinted) JAMA, February 12, 2003—Vol 289, No. 6 717
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. Storazhakov. 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. Bergin, P. Berman, P. Binkley, N. Bittar, J. Bowers, L. Brook-
field, J. Caplan, P. Carson, E. Carter, L. Christie, D.
Chromsky, M. Cishek, V. Corrigan, M. Costanza,
C. Curry, J. Davia, P. Deedwania, E. de Marchena, G.
Dennis, R. DiBianco, S. Dunlap, E. Eichhorn, U. Elkayam,
J. English, N. Erenrich, C. Fallick, R. Feldman, D. Ferry,
D. Fishbein, L. Ford, D. Forman, M. Fowler, J. Ghali,
E. Gilbert, R. Gillespie, M. Givertz, S. Goldman, D. Goldscher, S. Goldsmith, R. Gordon, A. Gradman, B. Greenberg, G. Hamroff, H. Haught, P. Hauptman, C. Heesch,
T. Heywood, M. Higginbotham, R. Hobbs,
J. Hosenpud, C. Hunter, M. James, M. Johnson, J. Kalman, R. Karlsberg, E. Kasper, D. Kereiakes, V. Kinhal,
R. Kipperman, J. Kirkpatrick, P. Kirlin, M. Klapholz,
R. Kohn, M. Koren, D. Korn, K. Labresh, G. Lamas, L.
Lancaster, C. Lawless, T. LeJemtel, C. Liang, G. Litman, E. Loh, B. Lorell, G. Luckesen, E. MacInerney, B.
Massie, M. Mathier, F. McGrew, M. McIvor, H.
Meilman, F. Messineo, S. Meymandi, A. Miller, P.
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Every quotation contributes something to the stability or enlargement of the language.
—Samuel Johnson (1709-1784)
718
JAMA, February 12, 2003—Vol 289, No. 6 (Reprinted)
©2003 American Medical Association. All rights reserved.