Metoprolol Versus Carvedilol in Patients With Heart

Failure, Chronic Obstructive Pulmonary Disease,

Diabetes Mellitus, and Renal Failure
Maurizio Sessa, PhDa,*, Daniel Bech Rasmussen, PhDb,c, Magnus Thorsten Jensen, PhDd,
Kristian Kragholm, PhDe, Christian Torp-Pedersen, PhDf, and Morten Andersen, PhDa

This study compared the survival and the risk of heart failure (HF), chronic obstructive
pulmonary disease (COPD), diabetes mellitus (DM), hypoglycemia, and renal failure (RF)
hospitalizations in geriatric patients exposed to carvedilol or metoprolol. Data sources
were Danish administrative registers. Patients aged ≥65 and having HF, COPD, and DM
were followed for 1 year from the first b-blocker prescription redemption. Patients’ char-
acteristics were used to 1:1 propensity score match carvedilol and metoprolol users. A
Cox regression model was used to compute the hazard ratio (HR) of study outcomes. For
statistically significant associations, a conditional inference tree was used to assess predic-
tors most associated with the outcome. In total, 1,424 patients were included. No statisti-
cally significant differences were observed for survival (HR 0.86; 95% confidence interval
[CI] 0.67 to 1.11, p = 0.240) between carvedilol/metoprolol users. The same applied to
COPD (HR 0.88; 95% CI 0.75 to 1.05, p = 0.177), DM (HR 0.95; 95% CI 0.82 to 1.10,
p = 0.485), hypoglycemia (HR 0.88; 95% CI 0.47 to 1.67, p = 0.707), and RF (HR 1.25;
95% CI 0.93 to 1.69, p = 0.142) hospitalizations. Carvedilol users had a 38% higher hazard
then metoprolol users of HF hospitalization during the follow-up period (HR 1.38; 95% CI
1.19 to 1.60, p <0.001). Artificial intelligence identified carvedilol exposure as the most
important predictor for HF hospitalization. In conclusion, we found an increased risk of
HF hospitalization for carvedilol users with this triad of diseases but no statistically signifi-
cant differences in survival or risk of COPD, DM, hypoglycemia, and RF hospitaliza-
tions. © 2020 Elsevier Inc. All rights reserved. (Am J Cardiol 2020;125:1069−1076)

Beta-blockade is recommended by clinical practice guide-
lines as first-line treatment for patients with heart failure due
to its positive effect on survival and morbidity.1 In Europe, 4
b-blockers are indicated for heart failure, 3 selective for the
beta-1 adrenoceptor (metoprolol, bisoprolol, and nebivolol)
and a nonselective for the abovementioned receptor (carvedi-
lol).2−6 Due to their different pharmacodynamics and phar-
macokinetic profiles, these drugs can exert different
pharmacologic effects on tissues and organs that, in the set-
ting of heart failure and multiple concurrent co-morbidities,
render one specific b-blocker preferable over the others.7
Multimorbidity is highly prevalent in geriatric patients with
heart failure and it has been associated with negative clinical
a
Department of Drug Design and Pharmacology, University of Copen-
hagen, København, Denmark; bRespiratory Research Unit Zealand,
Department of Respiratory Medicine, Naestved Hospital, Næstved, Den-
mark; cDepartment of Cardiology, Herlev and Gentofte University Hospi-
tal, Hellerup, Denmark; dHeart Centre, Copenhagen University Hospital
Rigshospitalet, København, Denmark; eUnit of Epidemiology and Biosta-
tistics, Aalborg University Hospital, Aalborg, Denmark; and fDepartment
of Cardiology and Clinical Research, Nordsjaellands Hospital, Hillerød,
Denmark. Manuscript received October 16, 2019; revised manuscript
received and accepted December 23, 2019.
Funding: Assist. Prof. Maurizio Sessa and Prof. Morten Andersen are sup-
ported by a grant from the Novo Nordisk Foundation to the University of
Copenhagen (NNF15SA0018404, Copenhagen, Denmark).
See page 1075 for disclosure information.
*Corresponding author: Tel: +4552755467.
E-mail address: maurizio.sessa@sund.ku.dk (M. Sessa).
outcome and poor prognosis.8 In multimorbid heart failure
patients, it is not uncommon to find patients with heart failure,
chronic obstructive pulmonary disease, and diabetes mellitus,
but currently, none of the most authoritative clinical practice
guidelines for the management of chronic heart failure pro-
vide recommendations on which b-blocker should be used in
patients with these diseases2−6 (Table 1). A recent study sug-
gested that physicians prefer carvedilol to other b-blockers in
this clinical scenario.7 However, evidence supporting this
clinical practice is missing in patients having this triad of dis-
eases (Supplementary Table 1). To fill this gap in knowledge,
this study aims to compare the survival and the risk of heart
failure, chronic obstructive pulmonary disease, diabetes
mellitus, hypoglycemia, and renal failure hospitalizations in
geriatric patients with heart failure, chronic obstructive pul-
monary disease, and diabetes mellitus exposed to carvedilol
or metoprolol. Additionally, this study aims to identify the
most import predictors for these study outcomes by using an
artificial intelligence technique and to evaluate subpopula-
tions of interest such as patients with concurrent lipid disorder
or chronic kidney disease.
Methods
This study is part of a project coordinated by the geriat-
ric pharmacoepidemiology team headed by Dr. Maurizio
Sessa at the University of Copenhagen that aims to evaluate
drug safety and effectiveness of medications in patients
aged ≥65.

0002-9149/© 2020 Elsevier Inc. All rights reserved. www.ajconline.org

https://doi.org/10.1016/j.amjcard.2019.12.048
1070 The American Journal of Cardiology (www.ajconline.org)
Table 1
Recommendations included in the clinical practice guidelines for the management of heart failure
Clinical guidelines
2016 ESC Guidelines for the diagnosis and treatment of acute and
chronic heart failure2
2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA
Guideline for the Management of Heart Failure3
Chronic heart failure in adults: diagnosis and management4
SIGN 147 Management of chronic heart failure
2017 Comprehensive Update of the Canadian Cardiovascular Soci-
ety Guidelines for the Management of Heart Failure5
National Heart Foundation of Australia and Cardiac Society of
Australia and New Zealand6
At birth or immigration, all residents in Denmark receive
a permanent unique identifier known as the civil registration
number. This number can be used to link data from the differ-
ent Danish registers enabling researchers to follow Danish
citizens for their lifetime and until permanent emigration. In
this study, we used the Danish Civil Registration System, the
Danish National Patient Registry, the Danish National Pre-
scription Registry, the Income Statistics Register, and the
National Causes of Death Registry as data sources. By using
these registers, we retrieved information on sociodemo-
graphic characteristics of the patients, claimed drug prescrip-
tions, in- and out-patient hospital discharge diagnoses, dates
of migration and death, and cause of death.
The study period considered was January 1, 1996 to July
31, 2018. The study population was composed of all Danish
citizens aged ≥65 with systolic heart failure, chronic
obstructive pulmonary disease, and diabetes mellitus that
during the study period redeemed the first prescription of
metoprolol or carvedilol. Considering the data coverage
(with data on claimed drug prescriptions from January 1,
1995 and onward), the study period guarantees a minimum
of 1-year washout period to define a patient as a new user
of metoprolol or carvedilol.
The date of the first dispensing of metoprolol or carvedi-
lol was defined as the index date. We followed patients
from the index date for 365 days, until the end of the data
coverage or censoring. Censoring causes included the
development of the study outcomes, permanent emigration,
end of the follow-up period, or death. The follow-up period
of 365 days was chosen because in the Glycemic Effects in
Diabetes Mellitus: Carvedilol-Metoprolol Comparison in
Hypertensive (GEMINI) trial the positive effect of carvedi-
lol on glycemic control, metabolic parameters, and microal-
buminuria was observed already during the first 5 months.9
The primary outcomes were overall survival and the
risk of hospitalization for heart failure, chronic obstructive
pulmonary disease, diabetes mellitus, renal failure, and
hypoglycemia within 365 days from the index date. Opera-
tive definitions for these outcomes are provided in Supple-
mentary Table 2. The choice of investigating these clinical
outcomes was based on the following considerations:
1) Diabetes mellitus is associated with worse clinical out-
comes in patients with chronic obstructive pulmonary
Heart failure
+ Diabetes mellitus + Chronic obstructive pulmonary disease
Carvedilol Metoprolol, bisoprolol or nebivolol
Not covered Not covered
Not covered Not covered
Carvedilol, metoprolol, Metoprolol, bisoprolol or nebivolol
bisoprolol or nebivolol
Not covered Not covered
Not covered Metoprolol, bisoprolol or nebivolol
disease10 or heart failure.11 Therefore, we aimed to
assess if the favorable effect of carvedilol described in
the GEMINI trial9 had an impact on survival or the risk
of hospitalization for heart failure or chronic obstructive
pulmonary disease in this study population from a real-
world setting.
2) The GEMINI trial9 describes a favorable effect of carve-
dilol on insulin sensitivity, glycemic control, and micro-
albuminuria. Therefore, we aimed to assess carvedilol
had an impact on the risk of hospitalization for diabetes
mellitus, renal failure, and hypoglycemia in this study
population from a real-world setting.
Age, sex, socioeconomic status, year of inclusion in the
cohort, and selected comedications/co-morbidities were
chosen as covariates. Socioeconomic status was defined
according to quartiles of patient’s equalized income in the
year before the index date. Co-morbidities were defined
according to the Elixhauser comorbidity index12 and opera-
tive definitions from the scientific literature (Supplementary
Table 2). Patients were defined as having lipid disorders if
they redeemed a prescription of a lipid-modifying agent
(Anatomical Therapeutic Chemical Classification codes,
ATC C10) within 180 days before the index date. To define
a patient as having specific co-morbidities, we used in- and
out-patient hospital discharge diagnoses before the index
date and, in particular, the International Classification of
Diseases system codes (ICD) 10 codes in the Danish
National Patient Registry. For comedications, we evaluated
redeemed prescriptions within 180 days before the index
date. In Denmark, dispensing do not usually cover more
than 90 days of treatment, so by using this approach, we
assessed ongoing pharmacologic treatments. The ATC and
the ICD 10 codes used to define exposure to comedications
along with an operative definition are provided in
Supplementary Table 2.
Propensity score analysis has shown multiple advantages
in comparative effectiveness research compared with multi-
variable methods when dealing with a large number of
covariates.13 Study covariates were used to compute the
propensity score for the exposure. Subsequently, the pro-
pensity score was used to 1:1 match patients exposed to car-
vedilol with those exposed to metoprolol by using the
nearest neighbor algorithm with a caliper of 0. To assess
 Heart Failure/Metoprolol vs Carvedilol in Multimorbid Patients
the performance of the matching algorithm, we used 3 dif-
ferent approaches. Firstly, we performed a graphical evalu-
ation of the balance of propensity score between carvedilol
and metoprolol users by using the jitter plot. Secondly, we
plotted the histograms of the propensity score between the
unmatched and matched cohorts of carvedilol and metopro-
lol users. Thirdly, we assessed the covariate distribution
between the 2 cohorts by using the t test or analysis of vari-
ance for continuous variables and the chi-square or Fisher
exact test for categorical variables.
In the main analysis, a Cox regression model was used to
compute the hazard ratio (HR) of overall survival and of
hospitalization for heart failure, chronic obstructive pulmo-
nary disease, diabetes mellitus, renal failure, and hypogly-
cemia between patients treated with carvedilol versus those
treated with metoprolol. Cumulative incidence proportions
curves for the study outcomes were drawn by taking into
account censoring and the Gray test was used to compare
the cumulative incidence proportions functions between
carvedilol and metoprolol users.14 For all statistically sig-
nificant outcomes, we used a conditional inference tree that
is a machine learning approach to recursively partition the
predictors most associated with the outcome.15 In 2 sensi-
tivity analyses, we replicated the main analysis restricted to
patients with chronic kidney disease and lipid disorders,
respectively. In an additional sensitivity analysis, we
included b-blocker discontinuation as a censoring cause.
Discontinuation of the b-blocker treatment was assessed by
using the CMA0 constructor from the AdhereR package,
which based on the concept of the maximum allowed tem-
poral distance between 2 consecutive prescriptions (gap
method).16 A patient was considered as discontinuing the
b-blocker if the temporal distance between 2 consecutive
prescriptions within the follow-up period was > the maxi-
mum permissible gap (90 days). For the computation of the
treatment persistence, we allowed the carry-over effect
within the observation window and the carry-over effect
only for the same medication. Additionally, we considered
switching between different b-blockers as cause of discon-
tinuation.17 We performed the abovementioned 3 sensitivity
analyses because (1) there is an evidence suggesting that
carvedilol is more beneficial than metoprolol on the lipid
profile and renal functions, however, there is a lack of stud-
ies providing real-world evidence from routine clinical
practice18; and (2) in the GEMINI trial a higher risk of met-
oprolol than carvedilol discontinuation was found.9
In the last sensitivity analysis, for all statistically signifi-
cant outcomes, we performed a correction of HRs estimates
and confidence intervals (CIs) for bias due to outcome mis-
classification based according to the Brenner and Gefeller’s
methodology.19 This method relies on available predictive
value and sensitivity estimates for the outcome. In our case,
we obtained the positive predictive value for a heart failure
hospitalization in the Danish National Patient Register from
the scientific literature.20 However, because we did not
have information on the sensitivity for this outcome for the
2 different exposure groups (e.g., carvedilol and metopro-
lol) we simulated 5 different scenarios by inputting a range
of different sensitivity values. In the first scenario, we
assumed nondifferential misclassification and equal sensi-
tivity for the outcome between carvedilol and metoprolol
1071
users with an equal positive predictive value of 76% (95%
CI 66% to 83%).20 In the other 4 scenarios, we used an equal
positive predictive value of 76% (95% CI 66% to 83%)
between the 2 exposure strata, but a differential misclassifica-
tion between the 2 exposure groups with a difference in sensi-
tivity of 5%, 10%, 15%, and 20%, respectively. In particular,
we maintained constant the sensitivity for heart failure hospi-
talization for metoprolol users (sensitivity 75%) and we
reduced the sensitivity for this outcome for carvedilol users to
70%, 65%, 60%, and 55%, respectively.
SAS statistical software (version 9.4, SAS Institute Inc.,
Cary, North Carolina) and R (version 3.6.1, R Development
Core Team) were used for the data management and analy-
sis, respectively. For all analyses, a 2-sided p value (p)
<0.05 was considered to be statistically significant.
Danish register-based cohort studies are exempted from
ethical approval and patient consent. Patient records/infor-
mation before the analysis was pseudonymized. The Uni-
versity of Copenhagen and Statistics Denmark (project
number 707278) have appropriate data approval from the
Regional Capital Area Data Protection Agency to facilitate
the conduct of the present study.
Results
In total, 712 (50.0%) patients were exposed to carvedilol
and they were 1:1 propensity score matched with 712
(50.0%) patients exposed to metoprolol (Figure 1). Clinical
and sociodemographic characteristics of the 1,424 patients
included in the study population are provided in Supplemen-
tary Table 3. No statistically significant differences for rele-
vant covariates were observed between the 2 cohorts.
Accordingly, the jitter plot and the histogram of the propen-
sity score between the 2 cohorts were similar (Appendix 1,
Supplementary Figures 1 and 2). The number of person-
years, median follow-up time, and the cumulative incidence
proportions of heart failure, chronic obstructive pulmonary
disease, diabetes mellitus, hypoglycemia, and renal failure
hospitalizations and survival for metoprolol and carvedilol
users are shown in Supplementary Table 4. Carvedilol users
had a 38% higher hazard then metoprolol users of heart fail-
ure hospitalization within 1 year following the first redemp-
tion of the drug (HR 1.38; 95% CI 1.19 to 1.60, p <0.001).
The cumulative incidence proportions curves started to
diverge significantly after 75 days from the index date
(Figure 2). Carvedilol users had a median of 1 more hospital-
ization for heart failure than metoprolol users during the
first year of treatment (median 1, interquartile range 0 to
2 vs median 0, interquartile range 0 to 1). No statistically
significant differences were observed for survival (HR
0.86; 95% CI 0.67 to 1.11, p = 0.240), or chronic obstruc-
tive pulmonary disease (HR 0.88; 95% CI 0.75 to 1.05,
p = 0.177), diabetes mellitus (HR 0.95; 95% CI 0.82 to
1.10, p = 0.485), hypoglycemia (HR 0.88; 95% CI 0.47 to
1.67, p = 0.707), and renal failure (HR 1.25; 95% CI 0.93
to 1.69, p = 0.142) hospitalizations.
The conditional inference tree (a machine learning tech-
nique) method identified carvedilol exposure (p <0.001) as
the most important predictor for heart failure hospitaliza-
tion within the first year of treatment with b-blockers
(Figure 3).
1072 The American Journal of Cardiology (www.ajconline.org)

Figure 1. Flowchart.

The results of the sensitivity analyses were consistent with
the results of the main analysis except in patients with lipid
disorders, where carvedilol users had an increased the risk of
hospitalization for renal failure (HR 1.46; 95% CI 1.01 to
2.12, p = 0.044) (Appendix 1, Supplementary Tables 5−8 and
Supplementary Figures 3−5).
Discussion
This is the first study providing real-world evidence on the
clinical implications associated with the choice of b-blocker
in geriatric patients with heart failure, chronic obstructive pul-
monary disease, and diabetes mellitus. In patients with this
triad of diseases, we found that carvedilol users had an
increased risk of heart hospitalizations but no significant dif-
ferences in the risk of chronic obstructive pulmonary disease
hospitalizations. These phenomena have been previously
observed in patients with heart failure and chronic obstructive
pulmonary disease who were exposed to carvedilol.21,22 It
has been hypothesized that causes for these associations are
the potential misclassification of heart failure/chronic obstruc-
tive pulmonary disease sign and symptoms23 and the dynamic
hyperinflation induced by carvedilol due to its prolonged
b2-adrenoreceptor antagonism.22 Additionally, it has been
associated with an alteration of the caliber of pulmonary veins
and of the intrathoracic blood volume, which are clinical
events well known to be associated with decompensation of
heart failure.22
 Heart Failure/Metoprolol vs Carvedilol in Multimorbid Patients 1073

Figure 2. Cumulative incidence proportions curves for (A) diabetes mellitus, (B) chronic obstructive pulmonary disease, (C) survival, (D) hypoglycaemia,
(E) heart failure, and (F) renal failure hospitalizations of carvedilol users versus metoprolol users.

Regarding the risk of hospitalization for diabetes mellitus
or hypoglycemia, we did not observe significant differences
between carvedilol and metoprolol users. These are crucial
results in a public health perspective because they show that
in a real-world setting where hard outcomes (e.g., hospitaliza-
tions) were considered, no significant differences were
observed between users of these 2 b-blockers. According to
the results of the GEMINI trial, it was reasonable to expect
an increased risk of diabetes mellitus hospitalization due to
poor glycemic control in metoprolol users. In this trial,
more than double of the number of metoprolol users had
>1% increase in hemoglobin A1c (HbA1c) when compared
1074 The American Journal of Cardiology (www.ajconline.org)
Figure 3. A conditional inference tree that uses significance test methods to select and split recursively the most related predictor variables to heart failure
hospitalization.
with carvedilol users, and this effect was actually hypothe-
sized to be underestimated due to the increased withdrawal
of the b-blocker in metoprolol users determined by worsen-
ing of glycemic control.9 Accordingly, in our study, we
also found that metoprolol users discontinued more phar-
macologic treatment than carvedilol users, however, when
this competing event for the outcome was taken into consid-
eration, no increased risk for diabetes mellitus hospitaliza-
tion was observed. Analogously, we expected an increased
risk of hypoglycemia hospitalizations in carvedilol users
considering that it has been observed that b-blocker with
lower beta-1 adrenoceptor selectivity (such as propranolol)
has worse metabolic adverse effects than b-blockers with
high beta-1 adrenoceptor selectivity (such as metoprolol or
atenolol).24 Hypoglycemia is a great concern in diabetic
patients treated with b-blockers considering that drug class
may worse a present hypoglycemic episode or delaying the
recovery time.25 Yet, in a real-world setting, we did not
find significant differences for this outcome between carve-
dilol and metoprolol users.
We expected a reduced risk of renal failure hospitaliza-
tions in patients treated with carvedilol in virtue of the results
of the GEMINI trial and other available evidence.26 Due to
its enhanced alfa1-blocking propriety, carvedilol was found
particularly beneficial for patients with chronic kidney disease
due to its ability to reduce cardiac output and renin release
through beta1-adrenergic receptor antagonism, as to its ability
to reduce renovascular constriction through alfa1 receptor
antagonism and provide enhanced renovascular dilation
through beta2-receptor antagonism. These effects, concur-
rently to the ability of all b-blockers in reducing sympathetic
over-activity, were found associated with attenuation in the
increases of albuminuria and hyperkalemia, but also to an
absence of an increase in serum creatinine, an event typically
observed in patients with chronic kidney disease. In addition,
these pharmacodynamic effects were found associated with
high effectiveness in protecting from cardiovascular events in
patients with chronic kidney disease.26−28 However, in our
study, we did not find an increased protective effect of carve-
dilol on the risk of renal failure hospitalizations and, in con-
trast, patients with lipid disorders, carvedilol users had an
increased risk of hospitalization for renal failure In this
regard, it should be mentioned that in the GEMINI trial, they
had a different study population (e.g., patients with hyperten-
sion, younger and with fewer co-morbidities/comedications)
than ours. Finally, it should be highlighted that, in line with
up-to-date evidence, no significant benefit has been observed
for carvedilol on survival during the first year of pharmaco-
logic treatment with b-blockers, neither in patients with
chronic kidney disease.29
Due to the observational nature of our study, we cannot
exclude that our results may be biased due to unmeasured
confounders. We did not have access to laboratory data to
evaluate their variation of biomarkers described in the GEM-
INI trial. Regarding the risk of hospitalization for hypoglyce-
mia, we cannot rule out an underestimation of the risk driven
by b-blockers due to their potential masking effect. In fact,
b-blockers may mask typical warning symptoms of hypogly-
cemia such as tremor and palpitation. Strengths include the
use of the entire Danish population aged ≥65 that minimize
the risk of selection bias. Additionally, other strengths include
the use of reliable data sources such as Danish registers, the
establishment of hardcore outcome with high internal/exter-
nal validity and the possibility of providing real-world evi-
dence from routine clinical practice.
In conclusion, this study found an increased risk of heart
failure hospitalization for carvedilol users compared with
metoprolol users with this triad of disease but no statisti-
cally significant differences in survival or risk of chronic
obstructive pulmonary disease, diabetes mellitus, hypogly-
cemia, and renal failure hospitalizations. Additionally, we
found that metoprolol users had increased risk of discontin-
uation within the first years of b-blocker treatment and that
in patients with concurrent lipid disorder, carvedilol use
was additionally associated with an increased risk of renal
failure hospitalizations.
 Heart Failure/Metoprolol vs Carvedilol in Multimorbid Patients
Author Contributions
Maurizio Sessa: Conceptualization, Methodology, Soft-
ware, Data curation, Writing- Original draft preparation;
Daniel Bech Rasmussen: Writing- Reviewing and Editing
Magnus Thorsten Jensen: Writing- Reviewing and Edit-
ing Kristian Kragholm: Writing- Reviewing and Editing
Christian Torp-Pedersen: Writing- Reviewing and Edit-
ing Morten Andersen: Supervision and Writing- Review-
ing and Editing.
Disclosures
Prof. Andersen reports grants from Novartis, during the
conduct of the study; grants from Pfizer, grants from Jans-
sen, grants from AstraZeneca, grants from H. Lundbeck &
Mertz, grants from Novo Nordisk Foundation, outside the
submitted work; and personal fees from Medicademy, the
Danish Pharmaceutical Industry Association, for leading
and teaching pharmacoepidemiology courses. Other authors
have nothing to disclose.
Supplementary materials
Supplementary material associated with this article can
be found in the online version at https://doi.org/10.1016/j.
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