Journal of Cardiac Failure Vol. 17 No.

9 2011

Clinical Trials
Comparative Long Term Effects of Nebivolol and Carvedilol in
Hypertensive Heart Failure Patients
GIUSEPPE MARAZZI, MD, PhD,1 MAURIZIO VOLTERRANI, MD,1 GIUSEPPE CAMINITI, MD,1 LUIGI IAIA, MD,2
ROSALBA MASSARO, MD,1 CRISTIANA VITALE, MD, PhD,1 BARBARA SPOSATO, MD,1 GIUSEPPE MERCURO, MD,3 AND
GIUSEPPE ROSANO, MD, PhD1

Rome and Cagliari, Italy

ABSTRACT
Background: Beta-blockers improve left ventricular (LV) systolic function and prognosis in patients with
chronic heart failure (CHF), but their different pleiotropic properties may influence their cardiovascular
effects. This open-label study compared the effects of long-term treatment with nebivolol versus carvedilol
on LV ejection fraction (LVEF), in hypertensive CHF patients. Secondary end points were to assess the
effect of the 2 beta-blockers on exercise capacity and clinical outcome.
Methods and Results: A total of 160 hypertensive CHF patients, with LVEF !40% and in New York
Heart Association (NYHA) functional class I, II, or III, were randomly assigned to receive nebivolol or
carvedilol for 24 months. At baseline and at the end of treatment, all patients underwent clinical evalua-
tion, echocardiography, and 6-minute walking test. The target doses were 10 mg/d for nebivolol and 50
mg/d for carvedilol. Compared with baseline values, LVEF increased by a similar extent in the carvedilol
(C) and nebivolol (N) groups (C from 36.1% (SD 1.5%) to 40.9% (SD 1.9%), P ! .001; N from 34.1%
(SD 1.8%) to 38.5% (SF 2.2%), P ! .001). Heart rate and NYHA functional class decreased significantly
in both groups, and the 6-minute walking distance increased (C from 420 m (SD 104 m) to 490 m (SD
115 m), P ! .001; N from 421 m (SD 118 m) to 487 m (SD 138 m), P ! .001). During 24 months,
21 carvedilol recipients (26%) and 18 nebivolol recipients (22%) had cardiac events, including 3 and
4 deaths, respectively.
Conclusion: In the long term, nebivolol and carvedilol appear to be similarly effective in the treatment of
hypertensive patients with CHF. (J Cardiac Fail 2011;17:703e709)
Key Words: Beta-adrenergic receptor blocker, heart failure, hypertension.

It is well established that beta-blockers substantially
improve symptoms and outcome of patients with chronic
heart failure (CHF) and left ventricular systolic dysfunction.
From the 1Istituto di Ricovero e Cura a Carattere Scientifico San
Raffaele, Rome, Italy; 2Fatebenefratelli Hospital, Isola Tiberina, Rome,
Italy and 3University of Cagliari, Cagliari, Italy.
Manuscript received May 14, 2010; revised manuscript received May 1,
2011; revised manuscript accepted May 3, 2011.
Reprint requests: Giuseppe Marazzi, MD, PhD, Via della Pisana 235,
00163, Rome, Italy. Tel: þ39-06-5225-5553; Fax: þ39-06-66059-1.
E-mail: giuseppe.marazzi@sanraffaele.it
See page 708 for disclosure information.
Clinical Trial Registration: http://clinicaltrials.gov; registration no.
NCT00511888.
1071-9164/$ - see front matter
Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.cardfail.2011.05.001
Four of these drugs, carvedilol, bisoprolol, metoprolol succi-
nate, and nebivolol are recommended by international guide-
lines for the treatment of CHF1,2 owing to the demonstration
of their efficacy in improving survival and event-free sur-
vival in large randomized controlled trials.3e6 However,
beta-blockers are a very heterogeneous family of drugs
that differ, in some cases significantly, in receptor selectiv-
ity,7 lipophilicity,8 degree of inverse agonism,9 presence of
intrinsic sympathomimetic activity,10 and ancillary proper-
ties.7 The different pleiotropic properties of beta-blockers
influence their cardiovascular effects. Several studies have
demonstrated that the third-generation beta-blocker carvedi-
lol improves cardiac performance to a greater extent than
the second-generation agent metoprolol tartrate during the
long-term treatment of patients with CHF.11,12 Nebivolol is
a long-acting cardioselective beta-blocker with vasodilating

703
704 Journal of Cardiac Failure Vol. 17 No. 9 September 2011
properties attributed to its interaction with the L-argininee
nitric oxide pathway, a property not shared by other beta-
blockers.13 Nebivolol has been used for over a decade for
the treatment of hypertension with a similar efficacy to
that of other antihypertensive agents14 and other beta-
blockers.15,16 Data have shown that nebivolol administration
is also effective in the treatment of both systolic and diastolic
CHF. In a large randomized controlled trial,6 nebivolol ad-
ministration reduced the composite end point of mortality
and cardiovascular hospitalization in elderly patients with
CHF regardless of their left ventricular ejection fraction
(LVEF). Moreover in a subgroup analysis of patients (age
!75 y and LVEF !35%) enrolled in the trial, nebivolol
demonstrated a reduction of mortality similar to that ob-
served with other beta-blockers.
Only 2 studies have compared the effects of nebivolol
and carvedilol in CHF patients, and the results were incon-
clusive about their comparative effects on left ventricular
function and functional capacity.17,18 However, both studies
presented a trend in favor of carvedilol.
The primary objective of the present study was to com-
pare effects of long-term treatment with nebivolol versus
carvedilol on LVEF in hypertensive patients with stable
heart failure. We tested the hypothesis that carvedilol
improves LVEF to a greater extent than nebivolol. The sec-
ondary objective of the study was to assess the effect of the
2 beta-blockers on exercise capacity and clinical outcome.
Methods
The study was performed as a randomized, prospective,
parallel-group, active controlled open-label, single-blind study.
The study population included 160 hypertensive patients with
new diagnosis of heart failure.
Patients were included in the study if they had LVEF !40%,
New York Heart Association (NYHA) functional class I, II or
III, and clinical stability without hospital admission for heart fail-
ure in the preceding 3 months. Patients were excluded if they had
a history of asthma or severe chronic obstructive pulmonary dis-
ease, severe liver or kidney diseases, cardiac contraindication for
beta-blockers, such as second-degree or third degree heart block
without a permanent pacemaker, sick sinus syndrome, heart rate
!60 beats/min, systolic blood pressure !90 mm Hg, or concom-
itant treatment with other beta-blockers.
Study Design
Patient Enrollment and Randomization Method.
Each participating clinician assigned patients to nebivolol or car-
vedilol in an alternating manner using a preprepared list. Clini-
cians communicated weekly to reconcile numbers. In an attempt
to ensure similar numbers of male and female patients, initial en-
rolment was restricted to male patients, followed by enrollment of
female patients.
Baseline Visit. At the baseline visit, inclusion and exclu-
sion criteria were evaluated and informed consent was signed. El-
igible patients were randomized to either nebivolol or carvedilol
and the first dose of drug dispensed (nebivolol 1.25 mg once daily,
carvedilol half of a 3.125 mg tablet twice daily). Echocardiogra-
phy and the 6-minute walking test (6MWT) were performed.
Up-Titration Phase. Patients were followed with weekly
visits during the up-titration phase. For nebivolol, the initial
dose was 1.25 mg once daily. If tolerated, it was increased to
2.5 mg once daily by the end of week 1, 5 mg once daily by
week 2, and 10 mg once daily by week 4. For carvedilol the initial
dose was half of a 3.125 mg tablet twice daily. If tolerated, it was
increased to 3.125 mg twice daily by end of week 1, 6.25 mg BID
by week 2, 12.5 mg BID by week 4, and 25 mg BID by week 6. If
side effects attributable to the study medications occurred, up-
titration was delayed, the dose was decreased, or the administra-
tion of the drug was temporarily discontinued.
Maintenance Phase. On achievement of the target dose or
the maximum tolerated dose, patients were followed clinically ev-
ery month for the first 3 months, then every 3 months until the end
of the study at 24 months. NYHA functional class was evaluated
and any complications and deaths occurring during the study pe-
riod noted. Echocardiography and 6MWT were performed at the
final visit (24 months).
Efficacy and Safety Variables
Echocardiography. The primary efficacy variable was the
change in LVEF after 24 months of treatment (dLVEF). Two-
dimensional, M-mode, and Doppler echocardiography was per-
formed at baseline and at 24 months using standard recording
methodology and measurements in all patients according to the
recommendations of the American Society of Echocardiogra-
phy,19 with tan Acuson Sequoia echocardiographic device and
a 2.5-MHz wide-angle phased-array transducer. LV volumes
were measured from the apical 4- and 2-chamber views of the
2-dimensional echocardiogram. LVEF was calculated with the
Simpson rule algorithm. Echocardiography was performed and in-
terpreted by a single blinded observer.
Exercise Capacity. A 6MWT was performed at the base-
line visit and at the end of the study. The 6MWT was performed
according to standardized procedure.20,21 The test was supervised
by a physical therapist blinded to patient treatment. Patients were
asked to walk at their own maximum pace a 100-m-long hospital
corridor. Every minute a standard phrase of encouragement was
said to them. Patients were allowed to stop if signs or symptoms
of significant distress occurred (dyspnea, angina), although they
were instructed to resume walking as soon as possible. Results
of the 6MWT are expressed in distance walked (m).
Clinical Outcomes. Symptom severity was evaluated at
baseline and at maintenance follow-up visits with the NYHA clas-
sification. Vital signs, including heart rate and blood pressure,
were measured at every visit. Any complications, discontinua-
tions, and deaths occurring during the study period were noted.
Statistical Analyses
Summary data for continuous variables are expressed as mean
values and SD, and categoric data are expressed as number of pa-
tients and percentage. Baseline characteristics between groups
were compared with the use of linear regression models or tests
as appropriate. For continuous variables, the change from baseline
within groups was analyzed with the use of paired t test. Within-
group changes in NYHA functional class were evaluated with the
use of the Wilcoxon signed rank test.
The effect of treatment on change in LVEF (dLVEF) and
6MWT (d6MWT) was evaluated by regression analysis adjusted
 Long-Term Effects of Nebivolol and Carvedilol  Marazzi et al 705

for baseline values. Results of unadjusted regression analysis are
also presented. Analyses of change were performed on all patients
for which baseline and 24-month follow-up data were available. A
2-tailed P value of !.05 was considered to be statistically
significant.
On the basis of changes in LVEF observed in earlier studies, the
trial was designed to enroll 160 patients, which would provide
90% power to detect a predefined clinically significant difference
in change in LVEF of 3 units between the nebivolol and carvedilol
treatment groups (a 5 .05), assuming a 20% drop-out rate.22
The Kaplan-Meier method was used for analysis of clinical out-
comes with the use of a combined end point of overall cardiac
events, including the first of myocardial infarction or unstable an-
gina, worsening heart failure, hospital readmission, or death.
The analyses included all randomized patients, and all events
were attributed to the patient’s original randomly assigned treat-
ment group (according to the intention-to-treat principle).
The rate of all event-free survival between nebivolol and carve-
dilol groups was compared by log-rank test. All analyses were per-
formed with a commercially available statistical package (Stata 9;
Statacorp LP, College Station, TX).
Comparison between baseline patient characteristics re-
vealed some imbalances between the treatment groups.
The carvedilol group had a significantly higher proportion
of patients with ischemic heart failure than the nebivolol
group (P ! .01). In addition, baseline LVEF and heart
rate were significantly lower in the nebivolol group than
in the carvedilol group (P ! .001 and P 5 .008, respec-
tively), and patients in the nebivolol group had higher sys-
tolic and diastolic blood pressure than those in the
carvedilol group (P ! .05). Although statistically signifi-
cant, these differences were not considered to be clinically
significant. There were no other statistically significant dif-
ferences between the 2 groups.
Most of the patients were on diuretics, angiotensin-
converting enzyme inhibitors or angiotensin receptor II an-
tagonists. The overall number of drugs needed to control
blood pressure levels were 2.6 6 1.1 in patients receiving
nebivolol and 2.4 6 0.8 in those receiving carvedilol
(P O .05; Table 1).
Treatment and Duration of Follow-Up

Result Target dose was reached in 60 patients (75%) in the ne-

Patient Disposition
Out of 221 consecutive patients screened, 160 eligible
patients were randomized to receive either nebivolol (80
patients) or carvedilol (80 patients). No patients were lost
to follow-up regarding mortality.
Patient Baseline Characteristics
bivolol group and in 57 patients (71%) in the carvedilol
group (P 5 .593). Symptoms that precluded other patients
from attaining the target dose of the study medications in-
cluded bradychardia, hypotension, and asthenia. Mean
(SD) durations of follow-up were 22.8 (4.2) and 23.5
(2.2) months for patients receiving nebivolol and carvedi-
lol, respectively.
Efficacy Evaluation

The baseline clinical characteristics of the study patients Primary Outcome. The baseline and end point
are reported in Table 1. LVEFs, dLVEFs, and estimates of treatment effects are

Table 1. Patient Baseline Characteristics

Treatment Nebivolol Group (n 5 80) Carvedilol Group (n 5 80) P Value
Age, y, mean (SD) 67.5 (8.9) 64.6 (11.8) .076
Male/female 47/33 51/29 .516
Cause of heart failure: CAD/IDC 53/27 68/12 .006
NYHA functional class, n (%) I: 26 (33%) I: 29 (36%) .729
II: 41 (51) II: 36 (45%)
III: 13 (16%) III: 15 (19%)
Heart rate, beats/min, mean (SD) 74.3 (7.2) 77.6 (8.2) .008
Systolic blood pressure, mm Hg, mean (SD) 125 (10.3) 121 (10.1) .014
Diastolic blood pressure, mm Hg, mean (SD) 92 (7.6) 89 (9.5) .023
Dyslipidemia, n (%) 45 (56) 52 (65) .257
LVEF, %, mean (SD) 34.1 (1.8) 36.0 (1.5) !.001
Distance walked at 6MWT, m, mean (SD) 416.6 (121.0) 422.9 (101.4) .718
Concomitant therapy/device, n (%)
ACE inhibitor/ARB 67 (84) 71 (89) .359
Diuretics 22 (27) 18 (22) .391
Antialdosterone agents 16 (20) 13 (16) .538
Digoxin 37 (46) 35 (43) .751
Antiplatelet agents 72 (90) 78 (97) .05
Anticoagulants 7 (8) 11 (13) .317
Statins 42 (52) 49 (61) .264
Pacemaker/biventricular pacemaker 0 0 d
ICD 0 0 d

CAD, coronary artery disease (ischemia); IDC, idiopathic dilated cardiomyopathy (nonischemic); NYHA, New York Heart Association; ACE, angiotensin-
converting enzyme; ARB, angiotensin II receptor blocker; ICD, implantable cardioverter-defibrillator.
706 Journal of Cardiac Failure Vol. 17 No. 9 September 2011

Table 2. Effect of Treatment on Left Ventricular Ejection Fraction (LVEF)

LVEF, %, Mean (SD)

Nebivolol Carvedilol

24 mo 24 mo
[P Value vs dLVEF [P Value vs dLVEF* Treatment Effect, DdLVEF,y
Baseline Baseline] [95% CI]* Baseline Baseline] [95% CI] Mean (95% CI); P Value
34.1 (1.8) 38.5 (2.2) 4.38 (1.1) 36.1 (1.5) 40.9 (1.9) 4.79 (1.1) Adjusted for baseline
[P ! .0001] [4.12e4.63] [P ! .0001] [4.53e5.04] LVEFs: 0.39 (0.03e0.80);
P 5 .066
Unadjusted: 0.41 (0.05e0.77); P 5 .024

*dLVEF 5 LVEFendpointLVEFbaseline.
y
Dd LVEF 5 dLVEFendpointdLVEFbaseline.

presented in Table 2. There were similar statistically signif-
icant improvements in LVEF with nebivolol and carvedilol
treatments. The estimated mean difference in dLVEF be-
tween treatments was 0.39 units (P 5 .066) when adjusted
for baseline LVEF, a difference that was not statistically nor
clinically significant based on predefined criteria (absolute
change in LVEF of 3 units).
Secondary Outcomes. Exercise capacity. The effect
of treatment on 6MWT is presented in Table 3. Treatment
with both nebivolol and carvedilol significantly improved
exercise capacity to a similar extent in heart failure patients.
The estimated mean difference in d6MWT between treat-
ments was 4.3 m (P 5 .033) when adjusted for baseline
6MWT. Similar results were obtained from unadjusted
analyses (4.0 m; P 5 .196)). These differences were not
considered to be clinically significant, representing !10%
of the within-group improvement in exercise capacity
obtained over the study period.
NYHA Functional Class. The effect of treatment on
symptom severity measured by NYHA classification is pre-
sented in Table 4. Treatment with both nebivolol and carve-
dilol significantly improved NYHA functional class in
hypertensive patients with CHF after 24 months of
follow-up. There were no significant differences between
groups (P 5 .085).
Heart Rate and Blood Pressure. Nebivolol and carvedilol
treatment resulted in significant decreases in heart rate and
systolic blood pressure. The magnitude of the effects was
broadly similar in both treatment groups. Nebivolol treat-
ment had a significantly greater decrease of diastolic blood
pressure than carvedilol (P 5 .041; Table 5).
Side Effects. Adverse events leading to permanent discon-
tinuation of the study medication occurred in 6 patients. Of
these, worsening heart failure occurred in 3 patients receiv-
ing nebivolol and in 2 receiving carvedilol, and symptom-
atic hypotension occurred in 1 patient receiving nebivolol
and 2 receiving carvedilol. Cardiac events occurring during
follow-up are summarized in Table 6.
Of the 160 patients included in the study, 39 (24%) had
cardiac events. Worsening heart failure occurred in 12 pa-
tients receiving nebivolol and 17 patients receiving carvedi-
lol, and it was treated by an increased dose of furosemide in
14 patients (5 taking nebivolol and 9 taking carvedilol) but
required hospitalization and intravenous medications in 13
patients (5 taking nebivolol and 8 taking carvedilol). Three

Table 3. Effect of Treatment on 6-Minute Walk Distance (6MWD)

6MWD, m, Mean (SD)

Nebivolol Carvedilol
Treatment effect,
24 mo 24 mo Dd6MWD,y
[P Value vs d6MWD* [P Value vs d6MWD* Mean (95% CI);
Baseline Baseline] [95% CI] Baseline Baseline] [95% CI] P Value
421 (118) 487 (138) 66 (23) 420 (104) 490 (115) 70 (16) Adjusted for baseline
[P ! .001] [61e71] [P ! .001] [66e73] 6MWD: 4.3 (0.3e8.2);
P 5 .033
Unadjusted: 4 (2.2e10.6);
P 5 .196

*d6MWD 5 6MWDendpoint6MWDbaseline.
y
Dd6MWD 5 d6MWDendpointd6MWDbaseline.
 Long-Term Effects of Nebivolol and Carvedilol  Marazzi et al 707

Table 4. Symptom Severity: New York Heart Association Functional Class, n (%)
Nebivolol Carvedilol

Baseline 24 mo [P Value vs Baseline] Baseline 24 mo [P Value vs Baseline]

I: 26 (32%) I: 55 (76%) I: 29 (36%) I: 69 (92%)
II: 41 (51%) II: 14 (19%) II: 36 (45%) II: 6 (8%)
III: 13 (16%) III: 3 (4%) [P ! .001] III: 15 (19%) III: 0 (0%) [P ! .001]

patients had acute coronary syndrome (2 unstable angina, 1
in each group), and 1 had an acute myocardial infarction
(carvedilol group) requiring hospitalization.
During the 24 months of follow-up, 4 patients in the ne-
bivolol group and 3 patients in the carvedilol group died.
The survival model did not show any significant difference
in all-eventefree survival between the 2 groups: log-rank
test 0.34; P 5 .56; Fig. 1).
Discussion
The present study shows that carvedilol and nebivolol
have similar effects on left ventricular function, exercise ca-
pacity, and clinical outcomes in hypertensive patients with
CHF. Therefore, our original hypothesis of a clinically sig-
nificant superior effect of carvedilol on nebivolol was not
confirmed.
Two earlier trials compared the effects of nebivolol and
carvedilol in patients with heart failure. In the study by
Lombardo et al,17 after a 6-month follow-up there were
similar improvements in LVEF in the carvedilol and nebi-
volol groups which did not reach statistical significance.
In another study,18 in patients with nonischemic dilated car-
diomyopathy, after 12 months of follow-up the percentage
increase of LVEF from baseline was significantly greater
in carvedilol recipients than in nebivolol. Of note, these
studies had a shorter follow-up than ours, and beneficial ef-
fects of beta-blockers on ventricular size and ejection frac-
tion were probably not fully observed. In contrast, the
present study had sufficient power and duration to detect
relevant differences between the treatments. Moreover,
ours is the only study to use the target dose of nebivolol rec-
ommended for the treatment of CHF (10 mg daily),
whereas both Patrianakos et al and Lombardo et al used
the target dose recommended for the treatment of hyperten-
sion (5 mg daily). We think that the reason our hypothesis
was not met is that it was based on 2 studies that used only
half of the recommended dose of nebivolol for the treat-
ment of CHF. The improved performance of this drug in
our trial could be related to the higher dosage of the drug.
In our study, nebivolol and carvedilol demonstrated sim-
ilar efficacy on systolic blood pressure reduction. This re-
sult is in agreement with several comparative studies that
found a similar reduction in 24-hour ambulatory blood
pressure with nebivolol compared with other beta-
blockers, such as atenolol, and drugs of other groups,
such as lisinopril, enalapril, and nifedipine.23 In our study,
however, nebivolol led to a greater reduction of diastolic
blood pressure than carvedilol. This result is in line with
its vasodilatory properties related to nitric oxide production
at the endothelial level.13
Both beta-blockers were well tolerated and the drop-out
rate was very low. Moreover, the target dose was reached in
O70% of patients without significant differences between
groups. These observations are consistent with the results
of SENIORS (Study of Effects of Nebivolol Intervention
on Outcomes and Rehospitalization in Seniors with Heart
Failure),6 in which the tolerability of nebivolol was

Table 5. Heart Rate and Blood Pressure Outcomes, mean (SD)

Nebivolol Carvedilol

24 mo 24 mo
Baseline [P Value vs [P Value vs Treatment Effect, Dd
Mean (SD) Baseline] d [95% CI] Baseline Baseline] d [95% CI] (95% CI); P Value
SBP, mm Hg 125 (10.3) 116.6 (10.4) 8.4 (2.5) 121 (10.1) 110 (9.7) 11 (2.9) Adjusted for baseline SBP: 2.9
[P ! .0001] [10.9e11.2] [P ! .0001] [9.6e13.2] (0.7e4.8 ); P 5 .225
Unadjusted:
2.6 (1.2e4.6); P 5 .136
DBP, mm Hg 92 (7.5) 80 (5.9) 12 (4.0) 89 (9.5) 83 (7.3) 6 (1.5) Adjusted for baseline DBP:
[P ! .0001] [10.9e13.6] [P ! .0001] [5.2e8.5 ] 6.0 (4.4e9.7); P 5 .077
Unadjusted:
6.0 (3.1e8.4); P 5 .041
HR,* beats/min 74.3 (7.2) 64.9 (7.4) 9.4 (3.1) 77.6 (8.2) 62.0 (7.8) 15.6 (6.4) Adjusted for baseline HR
[P ! .0001] [8.2, 10.6 ] [P ! .0001] [13.9, 16.6] 5.7 (3.9e7.2); P 5 .136
Unadjusted:
6.2 (4.4e10.1); P 5 .096

SBP, systolic blood pressure; DBP, diastolic blood pressure.

*Resting heart rate.
708 Journal of Cardiac Failure Vol. 17 No. 9 September 2011
Table 6. Clinical Events According to Study Group and
Cause, n (%)
Nebivolol Group Carvedilol Group
(n 5 80) (n 5 80)
All 18 (22) 21 (26)
Unstable angina/myocardial 2 (2) 1 (1)
infarction
Worsening heart failure 12 (15) 17 (21)
Hospital readmission 7 (9) 9 (11)
Death (all noncardiac) 4 (5) 3 (4)
considered to be excellent because two-thirds of the elderly
people enrolled reached the target dose of 10 mg/d. The
percentage of patients tolerating the target dose in that trial
was higher than that of similar population groups in other
studies of beta-blockers, such as MERIT-HF (Metoprolol
CR/XL Randomized Intervention Trial in Congestive Heart
Failure) and COPERNICUS (Effect of Carvedilol on Sur-
vival in Severe Chronic Heart Failure). In the study by Pat-
rianakos et al,18 4 patients discontinued nebivolol and 3
patients stopped carvedilol.
We observed an improvement of performance status
measured by NYHA functional class and 6MWT. Patriana-
kos et al18 demonstrated a transitory decline in exercise per-
formance in the nebivolol group at 3 months. However, at
the end of follow-up the nebivolol and carvedilol groups
had a similar exercise performance. We assessed the perfor-
mance in the 6MWT only at the beginning and end of the
study and do not have data at 3 months.
In this trial we assessed changes in functional capacity
by 6MWT. However, some concerns have been recently ad-
vanced regarding the validity of 6MWT in the identification
of effective pharmacologic interventions.24 We did not col-
lect data on ergometric test or oxygen consumption.
Study Limitations
This trial was not designed as a noninferiority study. The
trial was powered to show superiority of carvedilol
Fig. 1. Kaplan-Meier curves of all eventsefree survival in nebivo-
lol (dotted blue line) and carvedilol patients (solid red line).
assuming, as effect size, a difference in LVEF improvement
between treatment groups of 3 units. Therefore, despite our
results suggesting similar effects of carvedilol and nebivo-
lol on LVEF, we cannot conclude that these 2 drugs are
equivalent. Given the results presented in this study, further
investigations should be designed to specifically test the hy-
pothesis of noninferiority between nebivolol and carvedilol
for the treatment of CHF. The patient population in our
study had a history of hypertensive CHF. This limits our
conclusion to the hypertensive CHF population and it
may not apply to a general systolic CHF patient population.
Finally, our results could be affected by baseline clinical
differences between the 2 groups. Based on our results, ne-
bivolol seems to be as effective as carvedilol on clinical
outcomes: After 24 months, we observed a similar rate of
hospital readmission and cardiac deaths in the nebivolol
and carvedilol groups. However, this study was not pow-
ered to detect differences in clinical outcome between the
nebivolol and carvedilol groups. Further trials focused on
morbidity and mortality are needed.
Conclusion
The present study confirms earlier data on efficacy of ne-
bivolol administration in patients with CHF.
In the long term, nebivolol and carvedilol appear to be
similarly effective in the treatment of hypertensive CHF
patients.
Disclosures
None.
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