Table 2.
Summary of nebivolol studies in heart failure
| References | Patient population | Design and intervention | Outcomes | Efficacy | Safety/tolerability |
|---|---|---|---|---|---|
| Hemodynamic studies | |||||
| Brune et al. [72] |
N = 10 Inclusion: angiographically confirmed CAD and HF (mean EF of 46 %) Exclusion: NA |
Cross-over, 3-day washout trial NEB: 5 mg/day No drug Off drug Follow-up 7 days |
Changes in Swan-Ganz measured PAP, PCWP, CO, MAP, HR and RAP at rest and during standardized bicycle ergometry pre- and post-intervention; AEs | No effect on work capacity, PAP, PCWP, CO or RAP Resting and exertion SBP (mmHg): 83–130 no drug, 80–121 NEB (p < 0.05); 103–140 off drug, 97–140 NEB (p < 0.05) Resting and exertion HR (bpm): 61–107 no drug, 51–75 NEB; 104–135 no drug, 85–121 NEB (p < 0.05) Resting and exertion stroke volume (mL): 51–108 no drug, 73–106 NEB (p < 0.05); 57–135 no drug, 64–163 NEB (p < 0.05) |
No significant AEs |
| Hemodynamic comparison studies | |||||
| Triposkiadis et al. [73] |
N = 20 Inclusion: LVEF ≤35 %, stable with chronic systolic ischemic/idiopathic HF NYHA III, on furosemide + ACEI Exclusion: BB treatment, hemodynamic instability, SBP <90 mmHg, HR <50 bpm, ACS or revascularization ≤3 months, mod-severe MR, other primary valve or congenital heart disease, frequent PVCs, non-sustained/sustained VT, Afib, high degree AV block, renal/hepatic failure, BB contraindications |
RCT Single oral dose NEB: 5 mg Metoprolol tartrate 50 mg |
Hemodynamics via PA catheter pre-intervention and hourly for 4 h post-intervention and at 6 h post-intervention; AEs | No changes in SBP, DBP, and MAP. HR decreased in both groups and was lower with metoprolol Mean RAP did not change with NEB, increased with metoprolol. PAP and PCWP did not change with NEB, increased with metoprolol PVR did not change with NEB, increased with metoprolol SVR decreased with NEB, increased with metoprolol CI did not change with NEB, decreased with metoprolol |
NEB AEs (N): headache, 2 nausea, 2 Metoprolol AEs (N): nausea, 2 dyspnea, 1 headache, 1 vomiting, 1 |
| Contini et al. [75] |
N = 61 Inclusion: aged 18–80 years, BB treatment ≥6 months, idiopathic or ischemic dilated cardiomyopathy, previous evidence of LVEF ≤40 %, stable NYHA class I–III Exclusion: history of pulmonary embolism, primary valvular heart disease, pericardial disease, severe obstructive lung disease, primary pulmonary hypertension, occupational lung disease, asthma, severe renal failure, significant peripheral vascular disease, second-degree atrioventricular block, exercise-induced angina and/or ischemic SVT changes and/or repetitive ventricular arrhythmias, BB contraindications, inability to perform pulmonary tests |
RCT, cross-over Maximal tolerated dose of carvedilol, NEB, or bisoprolol BID Follow-up at 8 weeks |
Clinical conditions, quality of life, laboratory data, echocardiographic evaluation, spirometry, alveolar capillary membrane diffusion, chemoreceptor response, cardiopulmonary exercise test, response to hypoxia during constant workload exercise | No changes in clinical conditions, NYHA class and Minnesota questionnaire, renal function, hemoglobin concentration, or BNP DLCO was lower on carvedilol than NEB or bisoprolol (p < 0.0001) With carvedilol, constant workload exercise showed in hypoxia a faster VO2 kinetic and a lower ventilation Peripheral and central sensitivity to CO2 was lower in carvedilol Response to hypoxia was higher with bisoprolol Ventilation efficiency (VE/VCO2 slope) was lower with carvedilol (26.9 ± 4.1; p < 0.001) than with NEB (28.8 ± 4.0), or bisoprolol (29.0 ± 4.4) Peak VO2 was lower with carvedilol (15.8 ± 3.6 mL/kg/min; p < 0.001), than with NEB (16.9 ± 4.1), or bisoprolol (16.9 ± 3.6) |
Carvedilol AEs (N): drug intolerance, 1 death, 1 Bisoprolol AEs (N): drug intolerance, 1 |
| Systolic heart failure/HFrEF studies | |||||
| Brehm et al. [76] |
N = 12 Inclusion: angiography prior to study, stable condition ≥4 weeks prior to study on standard therapy with ACEI, diuretics, digoxin Exclusion: NA |
RCT, DB, PBO-controlled NEB: 2.5 mg/day to 5 mg/day Follow-up of 12 weeks |
Bicycle ETT pre-intervention and at 12 weeks, weekly HR, BP, and Echo evaluation of left atrial diameter, end diastolic left ventricular dimensions, left ventricular systolic diameter, LVEF, and fractional shortening, and AEs | HR (bpm): 74.3 BL, 64.0 at 12 weeks with NEB (p ≤ 0.036). SBP (mmHg) increased from 120.0 to 127.8 after 3 weeks and was 126.7 at 12 weeks (NS); a minor decrease with PBO. DBP decreased by 10 mmHg at 2 weeks (p ≤ 0.019) and remained lower by 9 mmHg at weeks 12 (p ≤ 0.058); no change with PBO. NYHA: all patients were class III at BL; 4 from both groups increased to class II with remaining 4 unchanged. Bicycle ETT: work capacity was constant after 12 weeks NEB; test max duration was not different between groups; maximal HR during exercise decreased from 134.7 to 112.7 bpm (p ≤ 0.004) after 12 weeks Echo: LV end systolic diameter decreased from 56.5 to 50.2 mm after 12 weeks with NEB (p ≤ 0.019); no change with PBO LVEF improved by 34 % after 12 weeks with NEB (p ≤ 0.01); no acute worsening with drug up titration |
No significant AEs |
| Uhlir et al. [82] |
N = 91 Inclusion: aged 18–75 years, NYHA II/III due to ischemic heart disease or cardiomyopathy for ≥3 months, on diuretics and/or digoxin, reproducible exercise time of 6–20 min on 2 occasions, LVEF <40 %, competent Exclusion: resting SBP ≤100 mmHg and/or DBP ≤65 mmHg, asthma or COPD, HR <60 bpm, recurrent tachyarrhythmia, sick sinus syndrome, valvular heart disease, type I diabetes, obesity, significant renal/hepatic disease, ACEI treatment 3 months prior to trial, CCB within 1 month prior to trial, contraindications to BBs |
RCT, DB, PBO-controlled 1-month single-blind PBO run-in NEB: 2.5 or 5 mg/day Follow-up 14 weeks Concomitant NTG use was permitted |
Bicycle ETT, CT ratio, ECG, Echo, and blood/urine analysis at BL, weeks 4 of run-in, and weeks 8 and 14; visual analog scale, SE, and NYHA scaling at BL, weeks 4 of run-in and weeks 1, 2, 4, 8 and 14; HR and BP at BL, weeks 4 of run-in and weeks 1, 2, 4, 8, and 14; NEB level at weeks 14; AEs | ETT: BL was similar between groups and improved with NEB 2.5 mg gaining 109 s (17 % improvement; p = 0.003), 5 mg 61 s (8 %; p = 0.006), and PBO 89 s (10 %; p = 0.037) vs BL. No difference between groups at any point (2 pts in the PBO group were significant outliers) Echo: no change between the groups at endpoint. The 2.5-mg group did see a significant increase in EF from 30 % to 34 %, but this is within expected reader error Visual analog scale: all symptoms, except nocturnal dyspnea, improved with PBO and NEB 5 mg; the only difference between groups was on fatigue, favoring 2.5 mg over 5 mg (p = 0.013) and nocturnal dyspnea between the 2.5 mg and PBO group in favor of 2.5 mg (p = 0.049) NYHA: PBO: 19 patients in II, 10 in III at BL; at endpoint, 23 in II, 6 in III. 2.5 mg: 19 in II, 10 in III at BL; at endpoint, 1 in I, 26 in II, 1 in III. 5 mg: 27 in II, 6 in III at BL; at endpoint, 2 in I, 27 in II, 4 in III CT ratio: mean ratio decreased in NEB and PBO (2.5 mg vs PBO; p = 0.009 and 5 mg vs PBO; p = 0.012) BP and HR: no difference between groups in SBP; standing DBP was lower in NEB vs PBO (2.5 mg mean 84.4 mmHg and 5 mg 83.1 mmHg vs PBO 89.3 mmHg; p < 0.05 for both); HR was reduced with NEB vs PBO (2.5 mg mean 68 bpm and 5 mg 66.8 bpm vs PBO 76.3 bpm; p < 0.01 both) |
NEB 2.5 mg AEs (N): HF worsening, 1 NEB 5 mg AEs (N): angina worsening, 1 bradycardia, 1 |
| Edes et al. [83] |
N = 259 Inclusion: hospitalized or outpatient, aged >65 years, NYHA II–IV, stable, LVEF ≤35 %, and stable HF meds (ACEI/ARB, diuretics and/or digitalis) for ≥2 weeks Exclusion: ACS, MI ≤3 months, PTCA or CABG ≤1 month, HCM or HOCM, hemodynamically relevant congenital/valvular heart disease, treatment resistant tachyarrhythmia, bradycardia, recent BB therapy (≤4 weeks), BB contraindication |
Sequential RCT, PBO-controlled NEB: 1.25 mg/day, doubled bi-weekly to highest tolerated dose, up to 10 mg/day Follow-up: 8 months |
Efficacy: LVEF (primary), NYHA class change, QOL, hospitalizations, death, BP/HR, other medications, compliance Safety: AEs, ECG at rest, 24-h Holter monitor, laboratory studies |
LVEF: improved by 7 % (p = 0.027) vs PBO (4 %); relative improvement was 36 % NEB vs 19.2 % PBO (p = 0.008) No difference in improvement in NYHA or QOL score All patients had at least 1 ER visit and at least 1 hospitalization; no difference in survival BP/HR: by week 40, HR was lower with NEB (76.9–67.1 bpm; p < 0.001) with no change with PBO. No change in BP from BL |
Drug-related AEs (N): NEB, 40 PBO, 14 (p < 0.001) |
| Systolic heart failure/HFrEF comparison studies | |||||
| Lombardo et al. [77] |
N = 70 Inclusion: chronic HF, LVEF ≤40 %, NYHA II–III, stable ≥4 weeks Exclusion: SBP/DBP <90 mmHg/<60 mmHg, HR <50 bpm, CVA ≤6 months, heart or vascular surgery or MI ≤3 months, serious valvular conditions, AV conduction abnormality, malignancies, serious liver, kidney, connective tissue, respiratory or hematologic disease, allergies, intolerance to ACEI, unstable angina, diabetes, digoxin intolerance, BMI >30, exercise tolerance limited, patients on IC antiarrhythmic, CCB, α- or β-blockers/agonists |
RCT, open label NEB: 1.25–5 mg/day, based on tolerability Carvedilol (N = 35) 3.15–25 mg BID, based on tolerability Follow-up >6 months |
NYHA, BP, ECG, symptoms, 24-h Holter monitor, Echo evaluation LVEDV, LVESV, LVEF, LAD, transmitral peak E, peak A velocities, E/A ratio, mitral and tricuspic regurgitation, LV outflow tract velocity, RV systolic pressure, ventilatory function, proBNP, 6MWT, AEs | LVEDV decreased and LVEF increased in both groups; no change from BL in these and other Echo studies Resting HR decreased in both groups No difference between groups in ventilator function. BP decreased in both groups and NYHA class decreased with carvedilol The 6MWT showed a trend towards increased time in both groups. NEB was as effective as carvedilol |
No difference in AEs between groups |
| Marazzi et al. [78] |
N = 160 Inclusion: CHF, LVEF <40 %, NYHA I–III, HTN, clinically stable for last 3 months Exclusion: asthma, severe COPD, severe liver or kidney disease, cardiac contraindication to or currently on BB therapy |
RCT, open label NEB: 10 mg/day Carvedilol: 25 mg BID Follow-up >2 years |
Primary: LVEF by echo Secondary: 6MWT, NYHA, HR and BP, AEs |
LVEF increased in both groups (carvedilol 36–41 %; NEB 34–37 %, p < 0.001); adjusting EF changes for BL differences, there was no difference between groups Both groups had improvements in 6MWT, SBP, DBP, HR (p < 0.001) All other outcomes were similar between groups |
AE rates were similar between groups |
| Systolic and diastolic heart failure studies | |||||
| Flather et al. [79] |
N = 2128 Inclusion: aged ≥70 years, LVEF <35 % within 6 months or prior hospitalization for decompensated HF in previous year Exclusion: addition to HF therapy in last 6 weeks, change in cardiovascular drugs in last 2 weeks, HF from unrepaired valvular disease, current BB use, significant hepatic or renal dysfunction, CVA within last 3 months, on waiting list for PCI or cardiac surgery, other medical conditions leading to reduced survival rate during study, and BB contraindication |
RCT, DB, PBO-controlled NEB: 1.25–10 mg/day Follow-up >21 months |
Primary: composite of all-cause mortality or CV hospital admission Secondary: all-cause or CV mortality or hospital admissions |
Primary outcomes: 31 % NEB vs 35 % PBO group (p = 0.039); absolute risk reduction 4 %; NNT was 24 patients over 21 months; benefits occurred after 6 months of treatment and continued through follow-up Secondary outcomes: CV mortality or hospitalization rates were 29 % NEB vs 33 % PBO group (p = 0.027); all other outcomes did not differ. Note: patients with higher EF were enrolled in this study |
Bradycardia (%): NEB, 11 PBO, 3 |
| Cohen-Solal et al. [84] |
N = 2112 Inclusion: see Flather et al. [79] Exclusion: see Flather et al. [79] Additionally: SCr ≥250 µmol/L, recent change in drug therapy, and contraindication to BB |
RCT, DB, PBO-controlled NEB: 1.25–10 mg Patients stratified by eGFR tertiles Follow-up >21 months |
Primary: composite of all-cause mortality or CV hospital admission Secondary: all-cause or CV mortality or hospital admissions, AEs |
Primary outcomes: occurred in 29, 31, and 40 % of patients with high, mild, and low eGFR tertiles, respectively (p-value for trend <0.001) Secondary outcomes: all-cause mortality rates were 11.9, 15.6 and 23.3 per eGFR tertile (p < 0.001) The risk of death for patients in the lowest eGFR tertile was higher than for those in the highest eGFR tertile (p < 0.001) The effect of NEB on outcomes was similar between patients with varying levels of impaired renal function |
AEs were similar between groups |
| van Veldhuisen et al. [85] |
N = 2111 Inclusion: see Flather et al. [79] Exclusion: see Flather et al. [79] Additionally: recent changes in CV drug treatment, BB contraindications, or significant hepatic/renal dysfunction |
RCT, DB, PBO-controlled NEB 1.25–10 mg Patients stratified by EF: impaired (≤35 %) or preserved (>35 %) Follow-up >21 months |
Primary: composite of all-cause mortality or CV hospital admission Secondary: all-cause or CV mortality or hospital admissions |
BL characteristics: patients with preserved EF had less advanced HF, higher BP, and fewer prior MIs, compared with those with impaired EF (p < 0.001, all) All primary and secondary outcomes were similar between groups |
Not reported |
| Dobre et al. [86] |
N = 2061 Inclusion and exclusion: see Flather et al. [79] |
RCT, DB, PBO-controlled NEB: 1.25–10 mg Patients were stratified by NEB dose tolerability: intolerable, low (1.25–2.5 mg), medium (5 mg), or high (10 mg) Follow-up >21 months |
Primary: composite of all-cause mortality or CV hospital admission Secondary: all-cause or CV mortality or hospital admissions |
Patient dose: intolerable 74 (7 %), low 142 (14 %), medium 127 (12 %), high 688 (67 %) BL characteristics: younger patients with higher HR and BP or lower SCr were more likely to tolerate the high dose; the high-dose group had fewer patients with a PMH which included HTN, MI, PTCA and CABG; fewer patients in this group were on aldosterone antagonists, CCBs, and antiarrhythmics Primary outcomes: the high-dose group had a reduction in the primary outcome compared with PBO; NEB intolerant patients had a higher risk of the composite end point than PBO; no benefit for low or medium dose groups After accounting for variation in baseline statistics, the medium-dose group had a similar benefit to high dose with respect to composite endpoint; similarly, low doses were associated with more secondary outcomes |
Not reported |
| De Boer et al. [87] |
N = 2128 (diabetes, N = 555; no diabetes, N = 1573) Inclusion and exclusion: see Flather et al. [79] |
RCT, DB, PBO-controlled NEB: 1.25–10 mg Patients were stratified based on DM status Follow-up over 21 months |
Primary: composite of all-cause mortality or CV hospital admissions Secondary: all-cause or CV mortality or hospital admissions |
BL characteristics: patients in the DM group were younger, had greater rates of CAD, MI, HTN, hyperlipidemia and had worse renal function; HF severity (NYHA) was higher in the DM group; more DM patients were on lipid-lowering medications and aldosterone antagonists; LVEF was comparable between groups Primary outcomes: DM 40.2 % vs non-DM 30.8 % (p < 0.001). Composite outcome was significantly decreased in the non-DM NEB group vs PBO (p < 0.01); a similar decrease was not seen in the DM group Secondary outcomes: all-cause mortality was increased in the DM group (p < 0.01); the lesser response in the DM group to NEB was consistent for the other secondary outcomes |
Glucose levels did not change in NEB patients |
| Mulder et al. [88] |
N = 2128 (Afib, N = 738; sinus rhythm, N = 1039) Inclusion and exclusion: see Flather et al. [79] |
RCT, DB, PBO-controlled NEB: 1.25–10 mg PBO Patients were stratified based on Afib status Follow-up >21 months |
Primary: composite of all-cause mortality or CV hospital admissions Secondary: all-cause or CV mortality or hospital admissions |
BL characteristics: Afib patients were older, had worse HF (NYHA), and less CAD and DM; BL HR was higher in the Afib group (83 vs 77 bpm; p < 0.001) Primary outcomes: Afib 38.5 % vs non-Afib 30.4 % (p < 0.001); no benefit was observed in the AFib group with NEB (37.1 % vs PBO 39.8 %); the non-Afib group showed benefit with NEB (28.1 % vs PBO 32.9 %; p = 0.049). LVEF did not affect the results HR: NEB decreased HR in both groups (~10 bpm); there was no difference between Afib and sinus groups |
Not reported |
| Diastolic heart failure/HFpEF studies | |||||
| Background: Kamp et al. [89] Results: Conraads et al. [80] |
N = 116 Inclusion: aged ≥40 years, history of heart failure with persistent symptoms (NYHA II–III), LVEF ≥45 % and LVED diameter <3.2 cm/m2 or LVED volume index <102 mL/m2 by echo or nuclear study, or echo documented abnormal LV diastolic function Exclusion: inability to perform 6MWT, planned invasive cardiac procedures/cardiac surgery during the study, ACS or CVA in last 3 months, exercise-induced myocardial ischemia, concomitant disease limited exercise, BB contraindications or current use, diltiazem or verapamil, SBP <100 mmHg, breast feeding or pregnancy |
RCT, DB, PBO-controlled NEB: 2.5–10 mg/day Follow-up >6 months |
Primary: change from baseline in 6MWT after 6 months Secondary: symptoms, NYHA, Minnesota heart failure questionnaire, maximum exercise duration, peak oxygen consumption, slope of the minute ventilation to carbon dioxide relation, changes related to LV function (peak E/E’ velocity via Doppler of transmitral inflow and mitral valve annulus septal and lateral wall, E/E’ ratio), death, hospitalization, unexpected clinic visits, AEs |
Primary outcomes: no difference in 6MWT with NEB vs PBO Secondary outcomes: no change/improvement in peak oxygen consumption; similar improvement in NYHA and Minnesota Living with HF Questionnaire in both groups |
AEs (%): NEB, 35.1 PBO, 22.0 |
| Nodari et al. [74] |
N = 26 Inclusion: NYHA II-III ≥6 months, peak VO2 ≤25 mL/kg/min by cardiopulmonary exercise testing, normal LV systolic function (EF ≥50 % and an LVED diameter <32 mm/m2 by 2D echo, E/A <1 and/or PCWP >12 mmHg at rest or >20 mmHg at peak exercise) Exclusion: evidence of myocardial ischemia at stress or myocardial profusion testing, CAD on angiography, primary valve or congenital heart disease, resting SBP >200 mmHg or DBP >100 mmHg, Afib, concomitant diseases affecting prognosis or exercise capacity, BB contraindication or current treatment |
RCT NEB: 2.5–5 mg/day Atenolol: 50–100 mg/day Follow-up >12 months |
Resting and exercise hemodynamic parameters and maximal exercise capacity | Exercise capacity: both BBs improved clinical symptoms (per NYHA) NEB was associated with improvement from baseline in exercise capacity (peak VO2, VO2 at anaerobic threshold, and VE/VCO2 slope); no change with atenolol. LVEF and LVED diameter did not change in either group Hemodynamics: both drugs decreased HR and BP; the decrease in HR was associated with a decrease in CI, more so with atenolol NEB showed an increase in SVI and mPAP and PCWP at rest and with peak exercise; atenolol showed an increase in SVI NEB was associated with a greater hemodynamic improvement compared with atenolol |
Not reported |
6MWT 6-min walk test, ACEI angiotensin-converting enzyme inhibitor, ACS acute coronary syndrome, AE adverse event, Afib atrial fibrillation, ARB angiotensin II receptor blocker, AV atrioventricular, BB β-blocker, BID twice daily, BL baseline, BMI body mass index, BNP brain natriurtetic peptide, BP blood pressure, bpm beats per minute, CABG coronary artery bypass graft, CAD coronary artery disease, CCB calcium channel blocker, CHF congestive heart failure, CI cardiac index, CO cardiac output, COPD chronic obstructive pulmonary disease, CV cardiovascular, CVA cerebrovascular accident, DB double-blind, DBP diastolic blood pressure, DL CO diffusing capacity for carbon monoxide, DM diabetes mellitus, ECG electrocardiogram, Echo echocardiogram, EF ejection fraction, eGFR estimated glomerular filtration rate, ER emergency room, ETT exercise tolerance test, HCM hypertrophic cardiomyopathy, HF heart failure, HFpEF heart failure and preserved left ventricular ejection fraction, HFrEF heart failure and reduced ejection fraction, HOCM hypertrophic obstructive cardiomyopathy, HR heart rate, HTN hypertension, IC ischemic cardiomyopathy, LAD left anterior descending, LVED left ventricular end diastolic, LVEDV left ventricular end diastolic volume, LVEF left ventricular ejection fraction, LVESV left ventricular end-systolic volume, MAP mean arterial pressure, MI myocardial infarction, mPAP mean pulmonary arterial pressure, MR mitral regurgitation, MWT maintenance wakefulness test, NA not available, NEB nebivolol, NNT number needed to treat, NS not significant, NTG nitroglycerin, NYHA New York Heart Association, PA pulmonary artery, PAP pulmonary arterial pressure, PBO placebo, PCI percutaneous coronary intervention, PCWP pulmonary capillary wedge pressure, PMH past medical history, PTCA percutaneous transluminal coronary angioplasty, PVC premature ventricular contractions, PVR pulmonary vascular resistance, QOL quality of life, RAP right arterial pressure, RCT randomized controlled trial, SBP systolic blood pressure, SCr serum creatinine, SD standard deviation, SE standard error of the mean, SVI stroke volume index, SVR systemic vascular resistance, SVT supraventricular tachycardia, VCO 2, volume of carbon dioxide expired, VE ventilation efficiency, VO 2 volume of oxygen uptake, VT ventricular tachycardia