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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 Four of these drugs, carvedilol, bisoprolol, metoprolol succi-
improve symptoms and outcome of patients with chronic nate, and nebivolol are recommended by international guide-
heart failure (CHF) and left ventricular systolic dysfunction. 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,
From the 1Istituto di Ricovero e Cura a Carattere Scientifico San beta-blockers are a very heterogeneous family of drugs
Raffaele, Rome, Italy; 2Fatebenefratelli Hospital, Isola Tiberina, Rome, that differ, in some cases significantly, in receptor selectiv-
Italy and 3University of Cagliari, Cagliari, Italy. ity,7 lipophilicity,8 degree of inverse agonism,9 presence of
Manuscript received May 14, 2010; revised manuscript received May 1,
2011; revised manuscript accepted May 3, 2011. intrinsic sympathomimetic activity,10 and ancillary proper-
Reprint requests: Giuseppe Marazzi, MD, PhD, Via della Pisana 235, ties.7 The different pleiotropic properties of beta-blockers
00163, Rome, Italy. Tel: þ39-06-5225-5553; Fax: þ39-06-66059-1. influence their cardiovascular effects. Several studies have
E-mail: giuseppe.marazzi@sanraffaele.it
See page 708 for disclosure information. demonstrated that the third-generation beta-blocker carvedi-
Clinical Trial Registration: http://clinicaltrials.gov; registration no. lol improves cardiac performance to a greater extent than
NCT00511888. the second-generation agent metoprolol tartrate during the
1071-9164/$ - see front matter
Ó 2011 Elsevier Inc. All rights reserved. long-term treatment of patients with CHF.11,12 Nebivolol is
doi:10.1016/j.cardfail.2011.05.001 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 carvedilol half of a 3.125 mg tablet twice daily). Echocardiogra-
nitric oxide pathway, a property not shared by other beta- phy and the 6-minute walking test (6MWT) were performed.
blockers.13 Nebivolol has been used for over a decade for Up-Titration Phase. Patients were followed with weekly
the treatment of hypertension with a similar efficacy to visits during the up-titration phase. For nebivolol, the initial
that of other antihypertensive agents14 and other beta- 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
blockers.15,16 Data have shown that nebivolol administration
week 2, and 10 mg once daily by week 4. For carvedilol the initial
is also effective in the treatment of both systolic and diastolic
dose was half of a 3.125 mg tablet twice daily. If tolerated, it was
CHF. In a large randomized controlled trial,6 nebivolol ad- increased to 3.125 mg twice daily by end of week 1, 6.25 mg BID
ministration reduced the composite end point of mortality by week 2, 12.5 mg BID by week 4, and 25 mg BID by week 6. If
and cardiovascular hospitalization in elderly patients with side effects attributable to the study medications occurred, up-
CHF regardless of their left ventricular ejection fraction titration was delayed, the dose was decreased, or the administra-
(LVEF). Moreover in a subgroup analysis of patients (age tion of the drug was temporarily discontinued.
!75 y and LVEF !35%) enrolled in the trial, nebivolol Maintenance Phase. On achievement of the target dose or
demonstrated a reduction of mortality similar to that ob- the maximum tolerated dose, patients were followed clinically ev-
served with other beta-blockers. ery month for the first 3 months, then every 3 months until the end
Only 2 studies have compared the effects of nebivolol of the study at 24 months. NYHA functional class was evaluated
and carvedilol in CHF patients, and the results were incon- and any complications and deaths occurring during the study pe-
riod noted. Echocardiography and 6MWT were performed at the
clusive about their comparative effects on left ventricular
final visit (24 months).
function and functional capacity.17,18 However, both studies
presented a trend in favor of carvedilol. Efficacy and Safety Variables
The primary objective of the present study was to com-
pare effects of long-term treatment with nebivolol versus Echocardiography. The primary efficacy variable was the
change in LVEF after 24 months of treatment (dLVEF). Two-
carvedilol on LVEF in hypertensive patients with stable
dimensional, M-mode, and Doppler echocardiography was per-
heart failure. We tested the hypothesis that carvedilol
formed at baseline and at 24 months using standard recording
improves LVEF to a greater extent than nebivolol. The sec- methodology and measurements in all patients according to the
ondary objective of the study was to assess the effect of the recommendations of the American Society of Echocardiogra-
2 beta-blockers on exercise capacity and clinical outcome. 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
Methods 2-dimensional echocardiogram. LVEF was calculated with the
Simpson rule algorithm. Echocardiography was performed and in-
The study was performed as a randomized, prospective, terpreted by a single blinded observer.
parallel-group, active controlled open-label, single-blind study. Exercise Capacity. A 6MWT was performed at the base-
The study population included 160 hypertensive patients with line visit and at the end of the study. The 6MWT was performed
new diagnosis of heart failure. according to standardized procedure.20,21 The test was supervised
Patients were included in the study if they had LVEF !40%, by a physical therapist blinded to patient treatment. Patients were
New York Heart Association (NYHA) functional class I, II or asked to walk at their own maximum pace a 100-m-long hospital
III, and clinical stability without hospital admission for heart fail- corridor. Every minute a standard phrase of encouragement was
ure in the preceding 3 months. Patients were excluded if they had said to them. Patients were allowed to stop if signs or symptoms
a history of asthma or severe chronic obstructive pulmonary dis- of significant distress occurred (dyspnea, angina), although they
ease, severe liver or kidney diseases, cardiac contraindication for were instructed to resume walking as soon as possible. Results
beta-blockers, such as second-degree or third degree heart block of the 6MWT are expressed in distance walked (m).
without a permanent pacemaker, sick sinus syndrome, heart rate Clinical Outcomes. Symptom severity was evaluated at
!60 beats/min, systolic blood pressure !90 mm Hg, or concom- baseline and at maintenance follow-up visits with the NYHA clas-
itant treatment with other beta-blockers. 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.
Study Design
Statistical Analyses
Patient Enrollment and Randomization Method.
Each participating clinician assigned patients to nebivolol or car- Summary data for continuous variables are expressed as mean
vedilol in an alternating manner using a preprepared list. Clini- values and SD, and categoric data are expressed as number of pa-
cians communicated weekly to reconcile numbers. In an attempt tients and percentage. Baseline characteristics between groups
to ensure similar numbers of male and female patients, initial en- were compared with the use of linear regression models or tests
rolment was restricted to male patients, followed by enrollment of as appropriate. For continuous variables, the change from baseline
female patients. within groups was analyzed with the use of paired t test. Within-
Baseline Visit. At the baseline visit, inclusion and exclu- group changes in NYHA functional class were evaluated with the
sion criteria were evaluated and informed consent was signed. El- use of the Wilcoxon signed rank test.
igible patients were randomized to either nebivolol or carvedilol The effect of treatment on change in LVEF (dLVEF) and
and the first dose of drug dispensed (nebivolol 1.25 mg once daily, 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 Comparison between baseline patient characteristics re-
also presented. Analyses of change were performed on all patients vealed some imbalances between the treatment groups.
for which baseline and 24-month follow-up data were available. A The carvedilol group had a significantly higher proportion
2-tailed P value of !.05 was considered to be statistically of patients with ischemic heart failure than the nebivolol
significant.
group (P ! .01). In addition, baseline LVEF and heart
On the basis of changes in LVEF observed in earlier studies, the
rate were significantly lower in the nebivolol group than
trial was designed to enroll 160 patients, which would provide
90% power to detect a predefined clinically significant difference in the carvedilol group (P ! .001 and P 5 .008, respec-
in change in LVEF of 3 units between the nebivolol and carvedilol tively), and patients in the nebivolol group had higher sys-
treatment groups (a 5 .05), assuming a 20% drop-out rate.22 tolic and diastolic blood pressure than those in the
The Kaplan-Meier method was used for analysis of clinical out- carvedilol group (P ! .05). Although statistically signifi-
comes with the use of a combined end point of overall cardiac cant, these differences were not considered to be clinically
events, including the first of myocardial infarction or unstable an- significant. There were no other statistically significant dif-
gina, worsening heart failure, hospital readmission, or death. ferences between the 2 groups.
The analyses included all randomized patients, and all events Most of the patients were on diuretics, angiotensin-
were attributed to the patient’s original randomly assigned treat- converting enzyme inhibitors or angiotensin receptor II an-
ment group (according to the intention-to-treat principle).
tagonists. The overall number of drugs needed to control
The rate of all event-free survival between nebivolol and carve-
blood pressure levels were 2.6 6 1.1 in patients receiving
dilol groups was compared by log-rank test. All analyses were per-
formed with a commercially available statistical package (Stata 9; nebivolol and 2.4 6 0.8 in those receiving carvedilol
Statacorp LP, College Station, TX). (P O .05; Table 1).
Treatment and Duration of Follow-Up

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


bivolol group and in 57 patients (71%) in the carvedilol
Patient Disposition
group (P 5 .593). Symptoms that precluded other patients
Out of 221 consecutive patients screened, 160 eligible from attaining the target dose of the study medications in-
patients were randomized to receive either nebivolol (80 cluded bradychardia, hypotension, and asthenia. Mean
patients) or carvedilol (80 patients). No patients were lost (SD) durations of follow-up were 22.8 (4.2) and 23.5
to follow-up regarding mortality. (2.2) months for patients receiving nebivolol and carvedi-
lol, respectively.
Patient Baseline Characteristics 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- follow-up. There were no significant differences between
icant improvements in LVEF with nebivolol and carvedilol groups (P 5 .085).
treatments. The estimated mean difference in dLVEF be-
tween treatments was 0.39 units (P 5 .066) when adjusted Heart Rate and Blood Pressure. Nebivolol and carvedilol
for baseline LVEF, a difference that was not statistically nor treatment resulted in significant decreases in heart rate and
clinically significant based on predefined criteria (absolute systolic blood pressure. The magnitude of the effects was
change in LVEF of 3 units). broadly similar in both treatment groups. Nebivolol treat-
Secondary Outcomes. Exercise capacity. The effect ment had a significantly greater decrease of diastolic blood
of treatment on 6MWT is presented in Table 3. Treatment pressure than carvedilol (P 5 .041; Table 5).
with both nebivolol and carvedilol significantly improved
exercise capacity to a similar extent in heart failure patients. Side Effects. Adverse events leading to permanent discon-
The estimated mean difference in d6MWT between treat- tinuation of the study medication occurred in 6 patients. Of
ments was 4.3 m (P 5 .033) when adjusted for baseline these, worsening heart failure occurred in 3 patients receiv-
6MWT. Similar results were obtained from unadjusted ing nebivolol and in 2 receiving carvedilol, and symptom-
analyses (4.0 m; P 5 .196)). These differences were not atic hypotension occurred in 1 patient receiving nebivolol
considered to be clinically significant, representing !10% and 2 receiving carvedilol. Cardiac events occurring during
of the within-group improvement in exercise capacity follow-up are summarized in Table 6.
obtained over the study period. Of the 160 patients included in the study, 39 (24%) had
cardiac events. Worsening heart failure occurred in 12 pa-
NYHA Functional Class. The effect of treatment on tients receiving nebivolol and 17 patients receiving carvedi-
symptom severity measured by NYHA classification is pre- lol, and it was treated by an increased dose of furosemide in
sented in Table 4. Treatment with both nebivolol and carve- 14 patients (5 taking nebivolol and 9 taking carvedilol) but
dilol significantly improved NYHA functional class in required hospitalization and intravenous medications in 13
hypertensive patients with CHF after 24 months of 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 present study had sufficient power and duration to detect
in each group), and 1 had an acute myocardial infarction relevant differences between the treatments. Moreover,
(carvedilol group) requiring hospitalization. ours is the only study to use the target dose of nebivolol rec-
During the 24 months of follow-up, 4 patients in the ne- ommended for the treatment of CHF (10 mg daily),
bivolol group and 3 patients in the carvedilol group died. whereas both Patrianakos et al and Lombardo et al used
The survival model did not show any significant difference the target dose recommended for the treatment of hyperten-
in all-eventefree survival between the 2 groups: log-rank sion (5 mg daily). We think that the reason our hypothesis
test 0.34; P 5 .56; Fig. 1). was not met is that it was based on 2 studies that used only
half of the recommended dose of nebivolol for the treat-
Discussion ment of CHF. The improved performance of this drug in
our trial could be related to the higher dosage of the drug.
The present study shows that carvedilol and nebivolol In our study, nebivolol and carvedilol demonstrated sim-
have similar effects on left ventricular function, exercise ca- ilar efficacy on systolic blood pressure reduction. This re-
pacity, and clinical outcomes in hypertensive patients with sult is in agreement with several comparative studies that
CHF. Therefore, our original hypothesis of a clinically sig- found a similar reduction in 24-hour ambulatory blood
nificant superior effect of carvedilol on nebivolol was not pressure with nebivolol compared with other beta-
confirmed. blockers, such as atenolol, and drugs of other groups,
Two earlier trials compared the effects of nebivolol and such as lisinopril, enalapril, and nifedipine.23 In our study,
carvedilol in patients with heart failure. In the study by however, nebivolol led to a greater reduction of diastolic
Lombardo et al,17 after a 6-month follow-up there were blood pressure than carvedilol. This result is in line with
similar improvements in LVEF in the carvedilol and nebi- its vasodilatory properties related to nitric oxide production
volol groups which did not reach statistical significance. at the endothelial level.13
In another study,18 in patients with nonischemic dilated car- Both beta-blockers were well tolerated and the drop-out
diomyopathy, after 12 months of follow-up the percentage rate was very low. Moreover, the target dose was reached in
increase of LVEF from baseline was significantly greater O70% of patients without significant differences between
in carvedilol recipients than in nebivolol. Of note, these groups. These observations are consistent with the results
studies had a shorter follow-up than ours, and beneficial ef- of SENIORS (Study of Effects of Nebivolol Intervention
fects of beta-blockers on ventricular size and ejection frac- on Outcomes and Rehospitalization in Seniors with Heart
tion were probably not fully observed. In contrast, the 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 assuming, as effect size, a difference in LVEF improvement
Cause, n (%) between treatment groups of 3 units. Therefore, despite our
Nebivolol Group Carvedilol Group results suggesting similar effects of carvedilol and nebivo-
(n 5 80) (n 5 80) lol on LVEF, we cannot conclude that these 2 drugs are
equivalent. Given the results presented in this study, further
All 18 (22) 21 (26)
Unstable angina/myocardial 2 (2) 1 (1) investigations should be designed to specifically test the hy-
infarction pothesis of noninferiority between nebivolol and carvedilol
Worsening heart failure 12 (15) 17 (21) for the treatment of CHF. The patient population in our
Hospital readmission 7 (9) 9 (11)
Death (all noncardiac) 4 (5) 3 (4) 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.
considered to be excellent because two-thirds of the elderly Finally, our results could be affected by baseline clinical
people enrolled reached the target dose of 10 mg/d. The differences between the 2 groups. Based on our results, ne-
percentage of patients tolerating the target dose in that trial bivolol seems to be as effective as carvedilol on clinical
was higher than that of similar population groups in other outcomes: After 24 months, we observed a similar rate of
studies of beta-blockers, such as MERIT-HF (Metoprolol hospital readmission and cardiac deaths in the nebivolol
CR/XL Randomized Intervention Trial in Congestive Heart and carvedilol groups. However, this study was not pow-
Failure) and COPERNICUS (Effect of Carvedilol on Sur- ered to detect differences in clinical outcome between the
vival in Severe Chronic Heart Failure). In the study by Pat- nebivolol and carvedilol groups. Further trials focused on
rianakos et al,18 4 patients discontinued nebivolol and 3 morbidity and mortality are needed.
patients stopped carvedilol.
We observed an improvement of performance status
Conclusion
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 present study confirms earlier data on efficacy of ne-
the end of follow-up the nebivolol and carvedilol groups bivolol administration in patients with CHF.
had a similar exercise performance. We assessed the perfor- In the long term, nebivolol and carvedilol appear to be
mance in the 6MWT only at the beginning and end of the similarly effective in the treatment of hypertensive CHF
study and do not have data at 3 months. patients.
In this trial we assessed changes in functional capacity
by 6MWT. However, some concerns have been recently ad- Disclosures
vanced regarding the validity of 6MWT in the identification
of effective pharmacologic interventions.24 We did not col- None.
lect data on ergometric test or oxygen consumption.

Study Limitations References


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