Research

Original Investigation

Association of Treatment With Carvedilol vs Metoprolol

Succinate and Mortality in Patients With Heart Failure
Björn Pasternak, MD, PhD; Henrik Svanström, MSc; Mads Melbye, MD, DrMedSci; Anders Hviid, MSc, DrMedSci

Supplemental content at
IMPORTANCE The β-blockers carvedilol and metoprolol succinate both reduce mortality in jamainternalmedicine.com
patients with heart failure (HF), but the comparative clinical effectiveness of these drugs is
unknown.

OBJECTIVE To investigate whether carvedilol is associated with improved survival compared

with metoprolol succinate.

DESIGN, SETTING, AND PARTICIPANTS Cohort study of patients with incident HF with reduced
left ventricular ejection fraction (LVEF) (ⱕ40%) who received carvedilol (n = 6026) or
metoprolol succinate (n = 5638) using data from a Danish national HF registry linked with
health care and administrative databases.

MAIN OUTCOMES AND MEASURES All-cause mortality (primary outcome) and cardiovascular
mortality (secondary outcome) were analyzed using Cox regression with adjustment for a
propensity score, derived from a range of clinical, socioeconomic, and demographic
characteristics.

RESULTS The mean (SD) age of the patients was 69.3 (9.1) years, 71% were men, and 51%
were hospitalized at index HF diagnosis. During a median (interquartile range) 2.4 (1.0-3.0)
years of follow-up, 875 carvedilol users and 754 metoprolol users died; the cumulative
incidence of mortality was 18.3% and 18.8%, respectively. The adjusted hazard ratio for
carvedilol users vs metoprolol users was 0.99 (95% CI, 0.88 to 1.11), corresponding to an
absolute risk difference of –0.07 (95% CI, –0.84 to 0.77) deaths per 100 person-years.
Estimates were consistent across subgroup analyses by sex, age, levels of LVEF, New York
Heart Association classification, and history of ischemic heart disease. A higher proportion of
carvedilol users achieved the recommended daily target dose (50 mg; 3124 [52%]) than did
metoprolol users (200 mg; 689 [12%]); among patients who reached the target dose, the
adjusted hazard ratio was 0.97 (95% CI, 0.72-1.30). A robustness analysis with 1:1 propensity
score matching confirmed the primary findings (hazard ratio, 0.97 [95% CI, 0.84-1.13]). The
adjusted hazard ratio for cardiovascular mortality was 1.05 (95% CI, 0.88-1.26).

CONCLUSIONS AND RELEVANCE These findings from real-world clinical practice indicate that
the effectiveness of carvedilol and metoprolol succinate in patients with HF is similar.

Author Affiliations: Department of

Epidemiology Research, Statens
Serum Institut, Copenhagen,
Denmark (Pasternak, Svanström,
Melbye, Hviid); Department of
Medicine, Stanford School of
Medicine, Stanford, California
(Melbye).
Corresponding Author: Björn
Pasternak, MD, PhD, Department of
Epidemiology Research, Statens
Serum Institut, Artillerivej 5, 2300
JAMA Intern Med. 2014;174(10):1597-1604. doi:10.1001/jamainternmed.2014.3258 Copenhagen S, Denmark
Published online August 31, 2014. (bjp@ssi.dk).

1597

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 Research Original Investigation
β
-Blockers represent the mainstay of treatment for heart
failure (HF), with placebo-controlled randomized trial
evidence of prolonged survival with use of metoprolol
succinate (controlled release/extended-release metopro-
lol formula), carvedilol, and bisoprolol fumarate.1-3 Among the
3 β-blockers with trial evidence of efficacy in HF, no individual
drug is recommended over the other by major guidelines,4,5 thus
implying similar efficacy. However, whereas the magnitude of
mortality reduction vs placebo was similar in key trials,1-3 to our
knowledge, there are no published trials with mortality end points
that compare any 2 of the 3 specific agents head-to-head.
Metoprolol and bisoprolol are β1 receptor selective, whereas
carvedilol has β1, β2, and α1 receptor–blocking properties. Fur-
thermore, carvedilol exhibits antioxidant activity and is an in-
hibitor of endothelin.6,7 These pharmacological differences have
been suggested to underlie a potential benefit of carvedilol over
other β-blockers in patients with HF. This hypothesis was tested
in the Carvedilol or Metoprolol European Trial (COMET), which
found a significant 17% survival benefit with use of carvedilol
over metoprolol.8 However, COMET studied a short-acting im-
mediate-release metoprolol formulation (metoprolol tartrate)
that is not approved for HF and the appropriateness of the tar-
get metoprolol dose used in the trial has been the subject of ex-
tensive debate.9-12 A recent network meta-analysis of random-
ized trials did indirect head-to-head comparisons between
β-blockers and reported an odds ratio consistent with a poten-
tial benefit in favor of carvedilol over metoprolol (0.80 [95% CI,
0.59-1.08]),13 but a large proportion of metoprolol-treated pa-
tients were derived from COMET, which made interpretation rel-
evant to current clinical practice difficult.
To investigate whether carvedilol use is associated with
improved survival compared with metoprolol succinate use,
we conducted an observational study of real-world patients
with HF in Denmark.
Methods
We conducted a national cohort study in Denmark of adults 50
to 84 years of age who had an incident diagnosis of HF with re-
duced left ventricular ejection fraction (LVEF) and received treat-
ment with carvedilol or metoprolol succinate. In head-to-head
analyses with follow-up of up to 3 years, we investigated all-cause
mortality (primary outcome) and cardiovascular mortality (sec-
ondary outcome), adjusting for potential confounders through
propensity score methods. The study was approved by the Dan-
ish Data Protection Agency and the Danish HF Registry. Ethics
approval and informed consent are not required for register-based
research in Denmark.
Patients with incident HF were identified from the Danish
HF Registry,14 a database established in 2003 with the purpose
of documenting the quality of HF care in Denmark. All hospital
departments and clinics in the country that care for inpatients
and outpatients with HF are invited to participate and are rec-
ommended to include all patients with a clinical diagnosis of HF
consistent with the criteria of the European Cardiology Society.
Included in the registry are patients with a first-time primary di-
agnosis of HF. Additional details and a description of all other da-
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Carvedilol vs Metoprolol Succinate and Mortality
tabases used for this study, which also included the Central Per-
son Register,15 Statistics Denmark, the National Patient Register,16
the National Prescription Registry,17 and the Cause of Death
Register,18 are provided in the eMethods in the Supplement.
Cohort
Eligible for inclusion were all patients 50 to 84 years of age iden-
tifiable in the HF Registry between January 1, 2003, and De-
cember 31, 2012, who had reduced LVEF (≤40%). The study co-
hort included every eligible patient who had filled at least 2
prescriptions for a study medication within a maximum of 180
days following diagnosis (as a minimum standard for adher-
ence; requirement of first prescription fill within 60 days fol-
lowing diagnosis and second prescription fill within 120 days
of the first), did not receive multiple β-blockers on the same date,
and had been residing in Denmark for at least 2 years.
Propensity Score
To account for potential confounders, we used propensity score
methods.19 By means of logistic regression analysis, the individual
probability of carvedilol treatment was estimated given a total
of 126 variables including demographic variables, socioeconomic
characteristics, comorbidities, medications, HF characteristics,
lifestyle factors, measures of health care use, and a number of
2-way interactions (eTable 2 in the Supplement). Multiple impu-
tation (Markov chain Monte Carlo method) was used to handle
missing data20; all analyses were conducted using 10 imputed
data sets.
Statistical Analyses
Patients were observed from the date of the second prescrip-
tion for a study β-blocker and up to 3 years; censoring criteria
were switch to any other β-blocker than the first, loss to fol-
low-up (emigration, disappearance), and end of the study pe-
riod (June 30, 2013). In the analysis of cardiovascular mortal-
ity, other-cause death was an additional censoring criterion; data
on causes of death were available through 2011, and the cohort
was truncated accordingly for this analysis.
Cumulative incidence curves were generated using the
Kaplan-Meier method. Cox proportional hazards regression
analysis was used to estimate hazard ratios with 95% confidence
intervals; time since study entry was the timescale. Models were
adjusted for propensity scores categorized in deciles. The pro-
portional hazards assumption was assessed by a Wald test for in-
teraction between treatment status and time and was fulfilled
in all primary and secondary outcome analyses. The adjusted ab-
solute risk difference per 100 person-years of carvedilol use was
estimated as (adjusted hazard ratio [aHR] – 1) × crude rate among
metoprolol users. Subgroup analyses were conducted by sex, age,
New York Heart Association (NYHA) class, LVEF, and history of
ischemic heart disease. Differences were considered statistically
significant when the 95% confidence interval did not overlap 1.0.
Analyses were performed using SAS software, version 9.3.
We performed preplanned robustness analyses, as follows.
(1) Our primary analysis included both patients using study
β-blockers before HF diagnosis and those in whom this treatment
was initiated after diagnosis. Prevalent users may have survived
important adverse events of medication and might be at lower
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 Carvedilol vs Metoprolol Succinate and Mortality Original Investigation Research

Figure 1. Inclusion of Carvedilol and Metoprolol Succinate Users Table 1. Baseline Characteristics of Patients With Heart Failure (HF)
in Study Cohort and Reduced Left Ventricular Ejection Fraction (LVEF)
Metoprolol
20 011 Patients 50-84 years of age with incident Carvedilol Succinate
heart failure (LVEF ≤40%) identified from Users Users
Danish Heart Failure Registry (January 1, Characteristica (n = 6026) (n = 5638)
2003, through December 31, 2012) Demographic Characteristics
Age, mean (SD), y 68.6 (9.2) 69.9 (9.0)
14 453 Patients with first prescription for
any β-blocker within 60 days Male sex 4285 (71) 3959 (70)
following heart failure diagnosis
Country of birth
6580 Carvedilol
6787 Metoprolol succinate Denmark 5731 (95) 5331 (95)
1086 Other β-blocker
Other European 122 (2) 124 (2)

2505 Patients excluded

Other 145 (2) 146 (3)
1086 Started nonstudy β-blocker Region of residence
1406 Did not fill second prescription
for study β-blocker Capital 1336 (22) 1733 (31)
13 Filled prescriptions for multiple Zealand 957 (16) 1031 (18)
β-blockers on same day
North Jutland 257 (4) 587 (10)
11 948 Patients with second prescription for Mid Jutland 1559 (26) 1133 (20)
study β-blocker within 120 days Southern Denmark 1915 (32) 1154 (20)
following first prescription
6174 Carvedilol Missing 2 (0) 0
5774 Metoprolol succinate
Civil status
Married or living together 3755 (62) 3389 (60)
284 Patients excluded (did not live
in Denmark in the past 2 years) Single 2185 (36) 2076 (37)
Missing 86 (1) 173 (3)
11 664 Patients included in study cohort
Socioeconomic status
6026 Carvedilol
5638 Metoprolol succinate Pensioned 4242 (70) 4122 (73)
Employed, medium or high qualifications 332 (6) 288 (5)
LVEF indicates left ventricular ejection fraction. Employed, basic or unknown qualifications 922 (15) 721 (13)
Self-employed 220 (4) 177 (3)
Outside labor market 224 (4) 157 (3)
risk for the outcome studied. Therefore, we implemented the Missing 86 (1) 173 (3)
new-user design,21 defining new users as patients who initiated Net personal income in last year (quintile)
treatment after HF diagnosis and had no study drug use in the 1 1170 (19) 1162 (21)
previous 2 years. (2) Given the possible, albeit not definitive, im- 2 1230 (20) 1103 (20)
portance of β-blocker dose,22-25 we did an analysis restricted to 3 1193 (20) 1141 (20)
patients who achieved the recommended target daily dose (50 4 1231 (20) 1101 (20)
mg for carvedilol and 200 mg for metoprolol).4,5 For this analy- 5 1202 (20) 1131 (20)
sis, the dose was estimated from the tablet strength and patients Calendar year
were observed from the day they reached the target dose. (3) As 2003 174 (3) 164 (3)
an alternative method of confounder control, we adjusted for an 2004 436 (7) 307 (5)
empirical risk score for mortality (described in the eMethods in 2005 534 (9) 384 (7)
the Supplement).26 (4) We used an alternative time-updated defi- 2006 573 (10) 392 (7)
nition of drug exposure, in which each prescription generated 2007 643 (11) 530 (9)
3 months of drug use, and compared mortality while on treatment 2008 657 (11) 521 (9)
with carvedilol or metoprolol. Events that occurred during any 2009 650 (11) 586 (10)
treatment pauses or after treatment discontinuation were defined 2010 762 (13) 768 (14)
as occurring off treatment and did not contribute to the analy- 2011 786 (13) 861 (15)
sis. (5) On the assumption that propensity score matching might 2012 731 (12) 952 (17)
provide superior confounder control than adjustment or at least 2013 80 (1) 173 (3)
reduce any heterogeneity, we frequency-matched carvedilol and HF Characteristics
metoprolol users (1:1 ratio) according to propensity score using LVEF, %
the greedy 5→1 digit-matching algorithm.27,28 <25 2483 (41) 1496 (27)
25-35 2738 (45) 2770 (49)
36-40 805 (13) 1372 (24)

Results
A total of 6026 carvedilol users and 5638 metoprolol users were
included (Figure 1). Mean (SD) age in the cohort was 69.3 (9.1)
years, 71% were men, 51% had been hospitalized at index di-
(continued)
agnosis, and most patients were in NYHA class II or III; the dis-
tribution of most baseline characteristics was similar be-
tween the 2 groups (Table 1). History of cardiomyopathy was

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 Research Original Investigation Carvedilol vs Metoprolol Succinate and Mortality

Table 1. Baseline Characteristics of Patients With Heart Failure (HF) Table 1. Baseline Characteristics of Patients With Heart Failure (HF)
and Reduced Left Ventricular Ejection Fraction (LVEF) (continued) and Reduced Left Ventricular Ejection Fraction (LVEF) (continued)
Metoprolol Metoprolol
Carvedilol Succinate Carvedilol Succinate
Users Users Users Users
Characteristica (n = 6026) (n = 5638) Characteristica (n = 6026) (n = 5638)
HF Characteristics (continued) Medication Use in Past Year (continued)
NYHA classification Calcium channel blockers 1247 (21) 1372 (24)
I 587 (10) 678 (12) Anti-arrhythmics class I and III 453 (8) 454 (8)
II 3052 (51) 2677 (47) Digoxin 1192 (20) 1684 (30)
III 1388 (23) 1071 (19) Nitrates 1160 (19) 1331 (24)
IV 80 (1) 84 (1) Platelet inhibitors 4302 (71) 4182 (74)
Missing 919 (15) 1128 (20)
Anticoagulants 1656 (27) 2245 (40)
Index HF diagnosis
Lipid-lowering drugs 3586 (60) 3627 (64)
Hospitalized 2975 (49) 2930 (52)
Oral antidiabetic drugs 894 (15) 870 (15)
Outpatient 3051 (51) 2708 (48)
Insulin 427 (7) 356 (6)
Treating department
Antidepressants 962 (16) 825 (15)
Cardiology 3194 (53) 3005 (53)
Antipsychotics 222 (4) 201 (4)
Internal medicine 2832 (47) 2633 (47)
Anxiolytics, hypnotics, and sedatives 1613 (27) 1401 (25)
Time since HF diagnosis, d
β2-Agonist inhalants 902 (15) 734 (13)
<28 1958 (32) 798 (14)
Anticholinergic inhalants 407 (7) 355 (6)
28-55 2228 (37) 1714 (30)
56-180 1840 (31) 3126 (55) Corticosteroid inhalants 954 (16) 767 (14)

Lifestyle Factors Oral corticosteroids 642 (11) 593 (11)

Smoking NSAIDs 1502 (25) 1447 (26)

Current 1809 (30) 1664 (30) Opiates 1216 (20) 1118 (20)
Past 2319 (38) 2097 (37) Drugs used, No.
Never 1305 (22) 1205 (21) 0-4 149 (2) 91 (2)
Missing 593 (10) 672 (12) 5-9 1976 (33) 1818 (32)
Alcohol consumptionb 10-14 2186 (36) 2133 (38)
Below recommended limit 4439 (74) 4170 (74) 15-19 1115 (19) 1068 (19)
Above recommended limit 494 (8) 468 (8) ≥20 600 (10) 528 (9)
Missing 1093 (18) 1000 (18) Health Care Use in Past Year
Comorbid Disease Cardiovascular ED visits and/or
Acute coronary syndrome 1923 (32) 2301 (41) hospitalizations, No.
Other ischemic heart disease 3094 (51) 3165 (56) 0 996 (17) 614 (11)
Cardiomyopathy 1555 (26) 975 (17) 1-2 3488 (58) 3331 (59)
Valve disorders 417 (7) 418 (7) ≥3 1542 (26) 1693 (30)
Arrhythmia 2252 (37) 3000 (53) Other ED visits and/or
hospitalizations, No.
PCI and/or CABG 1563 (26) 1916 (34)
0 3686 (61) 3423 (61)
Other cardiac surgery or invasive procedure 714 (12) 694 (12)
1-2 1801 (30) 1717 (30)
Cerebrovascular 807 (13) 811 (14)
≥3 539 (9) 498 (9)
Arterial 823 (14) 736 (13)
Cardiovascular outpatient contacts, No.
Renal 366 (6) 322 (6)
Liver 116 (2) 108 (2) 0 603 (10) 565 (10)

Chronic lung 1053 (17) 902 (16) 1-2 4715 (78) 4394 (78)

Rheumatic 251 (4) 232 (4) ≥3 708 (12) 679 (12)

Cancer 689 (11) 675 (12) Other outpatient contacts, No.
Venous thromboembolism 272 (5) 234 (4) 0 1755 (29) 1866 (33)
Dementia 56 (1) 71 (1) 1-2 2707 (45) 2463 (44)
Other psychiatric disorder 235 (4) 195 (3) ≥3 1564 (26) 1309 (23)
Medication Use in Past Year Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor
ACE inhibitor and/or ARB 5806 (96) 5347 (95) blocker; CABG, coronary artery bypass grafting; ED, emergency department;
Loop diuretics 4763 (79) 3989 (71) NSAID, nonsteroidal anti-inflammatory drug; NYHA, New York Heart
Association; PCI, percutaneous coronary intervention.
Other diuretics 3121 (52) 2759 (49)
a
Aldosterone antagonists 2314 (38) 1887 (33) All values are given as number (percentage) and as current at the start of
follow-up, unless stated otherwise. Values may not total 100% due to
Study β-blockers 2225 (37) 3100 (55) rounding.
Other β-blockers 278 (5) 222 (4) b
Recommended alcohol limit was defined as no more than 14 standard units of
(continued) alcohol per week for women and no more than 21 for men.

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 Carvedilol vs Metoprolol Succinate and Mortality Original Investigation Research

Figure 2. Cumulative Incidence of All-Cause Mortality Among Patients With Heart Failure With Reduced
Left Ventricular Ejection Fraction and Using Carvedilol or Metoprolol Succinate

20

15
Cumulative Incidence, % Metoprolol succinate
Carvedilol

10

0
0 1 2 3
Time, y

Deaths per 100 Crude Hazard Adjusted Hazard

Patients Person-years Deaths Person-years Ratio (95% CI) Ratio (95% CI)a
Carvedilol 6026 12 652 875 6.9 0.98 (0.89-1.08) 0.99 (0.88-1.11)
Metoprolol succinate 5638 10 708 754 7.0 1 [Reference] 1 [Reference] a
Adjusted for propensity score
categorized in deciles.

Figure 3. Subgroup Analyses of All-Cause Mortality Among Patients With Heart Failure With Reduced Left Ventricular Ejection Fraction (LVEF)
and Using Carvedilol or Metoprolol Succinate

Carvedilol Metoprolol Succinate

Deaths per 100 Deaths per 100 Adjusted Hazard Favors Favors
Deaths Person-years Deaths Person-years Ratio (95% CI)a Carvedilol Metoprolol
Sex
Female 218 6.0 229 7.2 0.85 (0.68-1.06)
Male 657 7.3 525 7.0 1.04 (0.91-1.19)
Age, y
50-69 311 4.3 221 4.1 0.99 (0.80-1.21)
70-84 564 10.5 533 10.0 0.99 (0.87-1.14)
LVEF, %
<25 392 7.2 232 7.9 0.93 (0.77-1.12)
25-40 483 6.7 522 6.7 1.03 (0.89-1.18)
NYHA classification
I-II 498 5.6 447 5.7 0.96 (0.81-1.13)
III-IV 377 10.0 307 10.5 1.04 (0.85-1.27)
History of ischemic heart disease
Yes 523 7.3 474 7.2 1.00 (0.87-1.16)
No 352 6.4 280 6.8 0.95 (0.79-1.15)

0.5 1.0 1.5

Adjusted Hazard Ratio (95% CI)

NYHA indicates New York Heart Association.

a
Adjusted for propensity score categorized in deciles.

more common among carvedilol users, as was use of loop di- The median (interquartile range) overall follow-up was 2.4
uretics and aldosterone antagonists; a higher proportion of (1.0-3.0) years, 2.7 (1.1-3.0) years in carvedilol users and 2.1 (0.9-3.0)
carvedilol users were in the lowest LVEF category (<25%) and years in metoprolol users. The median (interquartile range) time
the higher NYHA categories. History of acute coronary syn- on treatment, defined as the time from start of follow-up through
drome, other ischemic heart disease, percutaneous coronary the last prescription, was 2.3 (0.9-2.9) years in carvedilol users and
intervention or coronary artery bypass grafting, arrhythmia, 1.8 (0.6-2.9) years in metoprolol users. A total of 18 patients in each
and cardiovascular hospitalization or emergency depart- group were censored as a result of switching to another β-blocker
ment visit was more common among metoprolol users, as was (n = 16 among carvedilol users; n = 14 among metoprolol users)
use of digoxin, nitrates, platelet inhibitors, anticoagulants, and and loss to follow-up (n = 2, carvedilol; n = 4, metoprolol).
lipid-lowering drugs. There were missing values in 6 of the vari-
ables (Table 1); the relative efficiency of the imputation pro- Primary and Secondary Outcomes
cedure was greater than 99%. The C statistic for the propen- Among carvedilol users, 875 deaths occurred, whereas there
sity score model was 0.80 in each imputation set. were 754 deaths among metoprolol users, corresponding to a

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 Research Original Investigation Carvedilol vs Metoprolol Succinate and Mortality

Table 2. Robustness Analyses of All-Cause Mortality Comparing Carvedilol With Metoprolol Succinate
in Patients With Heart Failure and Reduced Left Ventricular Ejection Fraction
Adjusted
Deaths per 100 Hazard Ratio
Analysis Patients Person-years Deaths Person-years (95% CI)
New user
Carvedilol 3706 7815 525 6.7 0.95 (0.81-1.12)a
Metoprolol 2479 4813 339 7.0 1 [Reference]
Target dose
Carvedilol 3124 6463 282 4.4 0.97 (0.72-1.30)a
Metoprolol 689 1375 72 5.2 1 [Reference]
Adjusted for risk score
Carvedilol 6026 12 652 875 6.9 0.99 (0.89-1.09)b
Metoprolol 5638 10 708 754 7.0 1 [Reference]
a
On-treatment Adjusted for propensity score
a categorized in deciles.
Carvedilol 6026 11 462 702 6.1 0.96 (0.84-1.08)
b
Adjusted for risk score categorized
Metoprolol 5638 9176 587 6.4 1 [Reference]
in deciles.

cumulative incidence of the primary outcome of all-cause mor-
tality of 18.3% and 18.8%, respectively (Figure 2). After adjust-
ment for propensity score, the risk of mortality did not differ
significantly between carvedilol and metoprolol users (aHR,
0.99 [95% CI, 0.88-1.11]) (Figure 2; the full multivariable model
is shown in eTable 3 in the Supplement). The corresponding
adjusted absolute risk difference was −0.07 (95% CI, −0.84 to
0.77) deaths per 100 person-years. Results were similar with
follow-up truncated at 1 year (aHR, 0.98 [95% CI, 0.83-1.16])
(eTable 4 in the Supplement). The risk of the secondary out-
come of cardiovascular mortality was not significantly differ-
ent between carvedilol and metoprolol users (aHR, 1.05 [95%
CI, 0.88-1.26]) (eTable 5 in the Supplement).
Subgroup Analyses
In subgroup analyses (Figure 3), the aHRs for carvedilol vs
metoprolol users were similar in subgroups stratified by sex,
age, LVEF, NYHA class, and history of ischemic heart disease.
Robustness Analyses
First, in the analysis restricted to new users of the study
β-blockers, the aHR for mortality was 0.95 (95% CI, 0.81-1.12)
(Table 2). Second, a higher proportion of carvedilol users
achieved the recommended daily target dose (50 mg; 3124
[52%]) than did metoprolol users (200 mg; 689 [12%]). Among
these patients, the risk of mortality was not significantly dif-
ferent between carvedilol and metoprolol users (aHR, 0.97 [95%
CI, 0.72-1.30]) (Table 2). Third, we estimated a risk score for mor-
tality and included this as an adjustment variable (instead of
propensity score). The C statistic for the risk score model was
between 0.91 and 0.92 (numbers varied with each imputation
set). Adjustment for risk score yielded an estimate that was very
similar to that in the primary analysis (aHR, 0.99 [95% CI, 0.89-
1.09]) (Table 2). Fourth, the aHR in the analysis using an on-
treatment definition of β-blocker exposure was 0.96 (95% CI,
0.84-1.08) (Table 2). Fifth and finally, 1:1 propensity score
matching yielded a cohort that was well balanced on all base-
line characteristics (eTable 6 in the Supplement). The hazard
ratios for all-cause and cardiovascular mortality in the pro-
pensity score–matched cohort were 0.97 (95% CI, 0.84-1.13) and
1.03 (95% CI, 0.82-1.29), respectively.
Discussion
In this large contemporary national cohort study of patients
with HF with reduced LVEF, we found no significant differ-
ence in all-cause mortality between carvedilol and metopro-
lol succinate users. The primary findings were consistent
through various analyses, including the secondary outcome
of cardiovascular mortality, key subgroups, and robustness
analyses. Given the limits of the confidence intervals, this study
could rule out a relative difference in mortality of more than
12% and an absolute difference of 1 death or more per 100 pa-
tient-years. This suggests that any difference between carve-
dilol and metoprolol succinate, if it exists, is unlikely to be clini-
cally meaningful.
We designed this study to investigate whether carvedilol
is associated with improved survival compared with meto-
prolol succinate, a hypothesis based on the different adren-
ergic receptor profiles of the 2 drugs, other mechanistic dif-
ferences, and results of the COMET trial and a recent network
meta-analysis.6-8,13 The magnitude of reduction in mortality
vs placebo was similar in the key carvedilol and metoprolol suc-
cinate trials,1,3 but the 2 drugs have not been compared in a
head-to-head trial adequately powered to investigate mortal-
ity. Given the required size and associated cost, it is unlikely
that a randomized trial that resolves this issue will be con-
ducted in the near future. Therefore, we did a cohort study of
real-world patients in clinical practice. Our results are consis-
tent with the notion that no clinically relevant differences be-
tween carvedilol and metoprolol succinate exist. To our knowl-
edge, no directly comparable studies have been published. A
few observational comparative effectiveness studies have been
conducted, but these only included metoprolol tartrate and did
not have data on LVEF and NYHA class 29,30 or were con-
ducted at a single center with a limited number of adjust-
ment variables.31

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 Carvedilol vs Metoprolol Succinate and Mortality Original Investigation Research

Given the paucity of published head-to-head data, our
study expands on the available evidence of the comparative
effectiveness of carvedilol and metoprolol succinate therapy
in HF by contributing an adequately powered analysis of mor-
tality in a well-characterized study cohort. It lends support to
current treatment recommendations,4,5 which do not explic-
itly support the use of one β-blocker with proven mortality ben-
efit in HF over the other and thereby regard the effectiveness
of these drugs as equivalent.
Our study has strengths and limitations. Treatment was
not randomly assigned and could therefore have been influ-
enced by unmeasured factors that, if also associated with the
outcome, could have introduced confounding. To reduce this
possibility, we took into account a range of potential confound-
ers through the use of a comprehensive propensity score
model. Of note, although some baseline differences between
the treatment groups were present, such as higher preva-
lence of ischemic heart disease among metoprolol users, po-
tentially introducing a certain level of heterogeneity that might
not have been captured by adjustment for propensity score,
the main results were replicated in a 1:1 propensity score–
matched analysis, which was based on a subcohort that was
well balanced on baseline characteristics. Despite this, our find-
ings should be interpreted considering the observational design
of the study and need replication in an independent popula-
tion. Furthermore, a study of clinical effectiveness in real-
world patients should be seen as complementary rather than
comparable to a trial.
The use of total population registers allowed detailed char-
acterization of included patients, minimal loss to follow-up,
and exact assessment of outcomes throughout the study pe-
riod. Concerns may be raised that a higher proportion of carve-
dilol users achieved the target dose than did metoprolol us-
ers; assuming dose-dependent effects, this could mask a true
benefit of metoprolol over carvedilol. However, these con-
cerns are not supported by the analysis restricted to patients
who reached the target dose, which was in line with the pri-
mary analysis. Furthermore, the issue of dose-dependent ef-
fects is not settled; although some data support this notion,22,23
a meta-analysis found that the magnitude of heart rate reduc-
tion was associated with reduction in mortality, whereas
β-blocker dose was not.25
The findings are likely generalizable to other populations
with similar characteristics. It should be kept in mind, how-
ever, that included patients represent a subset (ie, those start-
ing β-blocker treatment) of those included in an HF registry.
Therefore, frail patients with short expected survival may not
have had treatment initiated and would not have been in-
cluded. Furthermore, by design, our study did not include
those who died during index hospitalization and those with
poor adherence. Indeed, cumulative mortality reached ap-
proximately 18% during the median 2.4-year follow-up, which
is lower than reported in other observational studies (these,
on the other hand, included a large proportion of patients not
receiving evidence-based HF treatment).32
Conclusions
This large cohort study of real-world patients with HF with
reduced LVEF contributes new data on the comparative
effectiveness of carvedilol vs metoprolol succinate and sup-
ports similar clinical effectiveness of these 2 evidence-based
drugs.

ARTICLE INFORMATION REFERENCES Foundation/American Heart Association Task Force

Accepted for Publication: May 9, 2014.
Published Online: August 31, 2014.
doi:10.1001/jamainternmed.2014.3258.
Author Contributions: Dr Pasternak had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Pasternak.
Critical revision of the manuscript for important
intellectual content: Svanström, Melbye, Hviid.
Statistical analysis: Pasternak, Svanström.
Administrative, technical, or material support:
Melbye.
Study supervision: Melbye, Hviid.
Conflict of Interest Disclosures: None reported.
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