Table 1.
Summary of nebivolol clinical trials in hypertension
| Study | Patient population | Design and intervention | Outcomes | Efficacy | Safety/tolerability |
|---|---|---|---|---|---|
| Nebivolol pivotal trials (monotherapy) | |||||
| Saunders et al. [43] |
N = 301 Inclusion: Blacks with stage I–II primary HTN (DBP 95–109 mmHg) Exclusion: secondary or malignant HTN, BMI >40 kg/m2, recent MI or stroke, uncontrolled type II diabetes, BB contraindication, severe renal/hepatic disease, or clinically relevant valvular disease/arrhythmia |
RCT, DB, PBO-controlled NEB: 2.5, 5, 10, 20, or 40 mg/day Randomization stratified by CYP2D6 metabolizing status, diabetes history, age, and sex Follow-up at 12 weeks |
Primary: change in sitting DBP Secondary: change in sitting SBP, response rate (DBP <90 mmHg or DBP decrease ≥10 mmHg), adverse events |
DBP (LS mean ± SE, mmHg) NEB: 2.5/5/10/20/40: −5.7 ± 2.1 (NS), −7.7 ± 2.1 (p = 0.004), −8.9 ± 2.0 (p < 0.001), −8.9 ± 2.1 (p < 0.001), −8.3 ± 2.0 (p < 0.001) PBO: −2.8 ± 2.1 SBP (LS mean ± SE, mmHg) NEB: −1.9 ± 3.7 (NS), −3.0 ± 3.7 (NS), −6.4 ± 3.6 (p = 0.044), −7.6 ± 3.7 (p = 0.005),−7.2 ± 3.5 (p = 0.002) PBO: −0.4 ± 3.8 Response rate (%) NEB: 36.7 (NS), 58.0 (p = 0.002), 58.8 (p < 0.001), 64.0 (p < 0.001), 56.9 (p < 0.001) PBO: 26.5 |
AEs (%) NEB (combined), 45.0 PBO, 38.8 |
| Weiss et al. [42] |
N = 913 Inclusion: mild–moderate primary HTN (DBP 95–109 mmHg) Exclusion: secondary or malignant HTN, BMI ≥35 kg/m2, recent MI or stroke, HF, uncontrolled diabetes, BB contraindication or previous NEB use, severe renal/ hepatic disease, and clinically relevant valvular disease/arrhythmia |
RCT, DB, PBO-controlled NEB: 1.25, 2.5, 5, 10, 20, or 40 mg/day Follow-up at 12 weeks |
Primary: change in sitting DBP Secondary: change in sitting SBP, response rate (DBP <90 mmHg or DBP decrease ≥10), adverse events NEB 40 mg/day dose was studied for safety purposes only—no efficacy hypothesis testing was done |
DBP (LS mean ± SE, mmHg) NEB: 1.25/2.5/5/10/20/40: −8.0 ± 1.1 (p < 0.001), −8.5 ± 1.1 (p < 0.001), −8.4 ± 1.0 (p < 0.001), −9.2 ± 0.9 (p < 0.001), −9.8 ± 0.9 (p < 0.001), −11.2 ± 0.9 PBO: −2.9 ± 1.1 SBP (LS mean ± SE, mmHg) NEB: −4.4 ± 1.9 (p = 0.002), −6.3 ± 1.9 (p < 0.001), −5.9 ± 1.6 (p < 0.001) −7.0 ± 1.6 (p < 0.001), −6.5 ± 1.6 (p < 0.001), −9.5 ± 1.5 PBO: +2.2 ± 1.9 Response rate (%) NEB: 45.8 (p = 0.008), 50.0 (p = 0.001), 50.3 (p < 0.001), 53.6 (p < 0.001), 59.6 (p < 0.001), 64.5 PBO: 24.7 |
AEs (%) NEB (combined), 46.1 PBO, 40.7 |
| Greathouse [44] |
N = 811 Inclusion: stage I–II HTN (DBP 95–109 mmHg) Exclusion: not specified in the manuscript |
RCT, DB, PBO-controlled NEB: 5, 10, or 20 mg/day Follow-up at 12 weeks |
Primary: change in sitting DBP Secondary: change in sitting SBP, response rate (DBP <90 mmHg or DBP decrease ≥10 mmHg), adverse events |
DBP (mean ± SD, mmHg) NEB: 5/10/20: −10.6 ± 7.7 (p = 0.002), −11.2 ± 8.1 (p < 0.001), −12.0 ± 8.4 (p < 0.001) PBO: −7.2 ± 8.2 SBP (mean ± SD, mmHg) NEB: −12.1 ± 14.1 (NS), −10.7 ± 14.8 (NS), −14.6 ± 15.4 (p < 0.001) PBO: −7.9 ± 12.8 Response rate (%) NEB: 66.0 (p = 0.009), 66.8 (p = 0.005), 68.9 (p = 0.002) PBO: 49.3 |
AEs (%) NEB (combined), 42.5 PBO, 36.0 Patients in NEB 20 mg reported significantly higher AE rates than those in PBO (48.4 %: p = 0.028) |
| Nebivolol monotherapy trials | |||||
| Lacourcière et al. [51] |
N = 29 Inclusion: adults, mild to moderate HTN (DBP 95–114 mmHg) Exclusion: secondary HTN, recent CVA or MI, HF, insulin-treated diabetes, BB or ACEI contraindication, severe renal or hepatic disease, or clinically relevant valvular disease or arrhythmia |
RCT, DB, cross over, active-controlled NEB: 2.5 mg/day titrated to 10 mg/day Lisinopril: 10 mg/day titrated to 40 mg/day Follow-up at 8 weeks |
Change in sitting DBP and SBP | DBP (mean ± SD, mmHg) NEB: −9.1 ± 7.3 Lisinopril: −9.9 ± 8.2 SBP (mean ± SD, mmHg) NEB: −13.9 ± 12.6 Lisinopril: −17.8 ± 17.9 |
AEs (N) NEB, 6 Lisinopril, 12 |
| Van Nueten et al. [55] |
N = 420 Inclusion: adults with HTN, DBP >95 mmHg Exclusion: secondary or malignant HTN, bradycardia, BB contraindication, severe renal or hepatic disease, recent MI or CVA, HF, Afib, insulin-treated diabetes |
RCT, DB, active-controlled NEB: 5 mg/day Nifedipine: 20 mg modified release twice daily Follow-up at 3 months |
Primary: changes in trough sitting DBP Secondary: response rate (trough sitting DBP <91 mmHg or decrease ≥10 mmHg) |
DBP (mean change, mmHg) NEB: −11.7 Nifedipine: −10.9 Both drugs were effective in lowering DBP from baseline (p < 0.001) Response rate (DBP <91 mmHg or DBP decrease ≥10 mmHg, %) NEB: 70 Nifedipine: 67 Response rate (DBP <91 mmHg, %) NEB: 54 (p = 0.007) Nifedipine: 42 |
AEs (%) NEB, 39 Nifedipine, 57 |
| Van Nueten et al. [54] |
N = 364 Inclusion: aged 18–71 years, mild to moderate HTN (DBP 95–115 mmHg) Exclusion: secondary or malignant HTN, bradycardia, recent MI or CVA, HF, BB contraindication, severe renal or hepatic disease, or clinically relevant valvular disease or arrhythmia |
RCT, DB, PBO- and active-controlled NEB: 5 mg/day Atenolol: 50 mg/day Follow-up at 1 month |
Primary: change in sitting DBP Secondary: changes in sitting SBP, response rate (sitting DBP ≤90 mmHg), adverse events |
Data are estimates of mean changes from graphs DBP (mean, mmHg) NEB: −12.5, Atenolol: −12.5, PBO: −5.0 SBP (mean, mmHg) NEB: −17.5, Atenolol: −17.5, PBO: −5.0 Response rate (%) NEB: 59, Atenolol: 59, PBO: 29 (p < 0.001 both drugs vs PBO) |
AEs (%) NEB, 28 Atenolol, 31 PBO, 25 |
| Grassi et al. [50] |
N = 205 Inclusion: aged 19–75 years, mild to moderate HTN (DBP 95–114 mmHg) Exclusion: secondary or malignant HTN, bradycardia, recent MI or CVA, HF, BB contraindication, severe renal/hepatic disease, or clinically relevant valvular disease or arrhythmia |
RCT, DB, active-controlled NEB: 5 mg/day Atenolol: 100 mg/day HCTZ: 12.5 mg/day added to each group at week 8 if BP ≥140/90 mmHg or decrease in DBP ≤10 mmHg Follow-up at 12 weeks |
Primary: change in sitting DBP and SBP Secondary: response rate (BP <140/90 mmHg or DBP reduction >10 mmHg), adverse events |
DBP (mean ± SD, mmHg) NEB: −14.8 ± 7.1, Atenolol: −14.6 ± 7.9 (p < 0.001 change from baseline for both) SBP (mean ± SD, mmHg) NEB: −19.1 ± 12.9, Atenolol: −18.2 ± 14.0 (p < 0.001 change from baseline for both) Response rate (%) NEB: 47.8 Atenolol: 36.9 |
AEs (%) NEB, 14 Atenolol, 25 (p < 0.001) |
| Van Bortel et al. [53] |
N = 298 Inclusion: adults with mild to moderate HTN (DBP 95–114 mmHg) Exclusion: SBP >200 mmHg, aged >70 years, uncontrolled concomitant illness, serum creatinine >1.8 mg/dL, recent MI/stroke, HF |
RCT, DB, active-controlled NEB: 5 mg/day Losartan: 50 mg/day HCTZ: 12.5 mg/day added to each group at week 6 if DBP ≥90 mmHg Follow-up at 12 weeks |
Changes in sitting DBP and SBP, response rate [complete responders (DBP ≤90 mmHg), partial responders (DBP >90 mmHg with decrease in DBP ≥10 mmHg)] | DBP (mean change, mmHg) NEB: −12 (p < 0.02 vs losartan) Losartan: −10 SBP (mean change, mmHg) NEB: −15 (NS vs losartan) Losartan: −18 Response rate (sum of partial and complete responders, %) NEB: 65.3 (NS vs losartan) Losartan: 58.3 |
AEs (%) NEB, 19 Losartan, 31 |
| Punzi et al. [49] |
N = 277 Inclusion: self-identified Hispanic, stage I–II HTN (DBP 95–114 mmHg) Exclusion: secondary/severe HTN, CAD requiring use of a BB, significant CVD, HF, uncontrolled type I or II diabetes, active liver or renal impairment |
RCT, DB, PBO-controlled NEB: 5 mg/day titrated to 40 mg/day to achieve BP control Follow-up at 8 weeks |
Primary: change in sitting DBP Secondary: change in sitting SBP, adverse events |
48.9 % titrated to NEB 40 mg/day DBP (mean ± SD, mmHg) NEB: −11.1 ± 8.8 (p < 0.0001) PBO: −7.3 ± 8.9 SBP (mean ± SD, mmHg) NEB: −14.1 ± 12.7 (p = 0.001) PBO: −9.3 ± 13.0 |
AEs (%) NEB, 17.0 PBO, 22.1 |
| Giles et al. [48] |
N = 641 Inclusion: aged 18–54 years with stage I–II HTN (DBP 90 to <110 mmHg if on anti-HTN meds or 95 to <110 without) Exclusion: secondary/severe HTN, on >2 HTN meds, upper arm circumference >42 cm, CAD, type I or uncontrolled type II diabetes, heart block, or sick sinus syndrome |
RCT, DB, PBO-controlled NEB: 5 mg/day titrated to 20 mg/day to achieve BP control Randomization stratified by BMI (<30 or ≥30 kg/m2) Follow-up at 8 weeks |
Primary: change in sitting DBP Secondary: change in sitting SBP, percent achieving treatment goal (<140/90 mmHg or <130/80 with diabetes), response rate (achieved treatment goal or decrease of ≥10 mmHg SBP or ≥8 mmHg DBP), adverse events |
DBP (mean ± SD, mmHg) NEB: −11.8 ± 8.8 (p < 0.001) PBO: −5.5 ± 9.5 SBP (mean ± SD, mmHg) NEB: −13.7 ± 14.5 (p < 0.001) PBO: −5.5 ± 13.9 BP control (%) NEB: 38.3 (p < 0.001) PBO: 25.1 Response rate (%) NEB: 72.8 (p < 0.001) PBO: 47.9 |
AEs (%) NEB, 34.7 PBO, 32.2 |
| Nebivolol add-on and combination trials | |||||
| Papademetriou [58] |
N = 845 Inclusion: adults with stage I–II HTN (DBP 95–109 mmHg) who finished 1 of 3 pivotal trials Exclusion: same as 3 pivotal trials |
RCT, DB, extension study NEB: 5, 10, or 20 mg/day Non-responders (DBP ≥90 mmHg) given higher NEB dose and/or thiazide or amlodipine 5 mg/day. At next follow-up could add thiazide with triamterene or amlodipine 10 mg/day Follow-up at 9 months |
Primary: change in sitting DBP Secondary: change in sitting SBP, response rate (DBP decrease ≥10 mmHg or DBP ≤90 mmHg) |
DBP (mean change [95% CI], mmHg) NEB monotherapy: −15.0 [−15.9 to −14.1] NEB + diuretic: −12.0 [−13.2 to −10.8] SBP (mean change [95% CI], mmHg) NEB monotherapy: −14.8 [−16.6 to −13.1] NEB + diuretic: −16.2 [−19.0 to −13.4] Response rate (%) NEB monotherapy: 74 NEB + diuretic: 65.5 Note: number of patients taking NEB + CCB too small to make meaningful comparisons |
AEs (%) NEB monotherapy, 15.6 NEB + diuretic, 18.5 |
| Neutel et al. [59] |
N = 669 Inclusion: uncontrolled stage I–II HTN (DBP 90–109 mmHg), background treatment with 1 or 2 anti-HTN meds (ACEI, ARB, or diuretic) Exclusion: secondary/malignant HTN, bradycardia, BMI >35 kg/m2, contraindication to BBs, uncontrolled diabetes, history of MI or cerebrovascular disease, HF, Afib or recurrent tachyarrhythmia, severe renal/hepatic disease |
RCT, DB, PBO-controlled NEB: 5, 10, or 20 mg/day added to ongoing therapy PBO added to ongoing therapy Follow-up at 12 weeks |
Primary: change in sitting DBP Secondary: change in sitting SBP, response rate (DBP <90 mmHg or decrease in DBP ≥10 mmHg), percent achieving treatment goal (<140/90 mmHg), adverse events |
DBP (LS mean change ± SE, mmHg) NEB: 5/10/20: −6.6 ± 1.0, −6.8 ± 1.0, −7.9 ± 1.1 (all p < 0.001 vs PBO) PBO: −3.3 ± 1.04 SBP (LS mean change ± SE, mmHg) NEB: 5/10/20: −5.7 ± 1.7 (p < 0.001), −3.7 ± 1.7 (p = 0.015), −6.3 ± 1.7 (p < 0.001) PBO: −0.1 ± 1.7 Response rate (%) NEB: 53.0 (p = 0.028), 60.1 (p = 0.001), 65.1 (p < 0.001) PBO: 41.3 BP control (%) NEB: 43.2, 41.3, 52.7 (all p ≤ 0.029) PBO: 29.3 |
AEs (%) NEB (combined doses), 40.2 PBO, 38.9 |
| Weber et al. [60] |
N = 656 Inclusion: untreated stage II diastolic HTN (DBP 100–110 mmHg) Exclusion: secondary HTN (SBP ≥180 mmHg or DBP ≥110 mmHg), recent stroke or MI, renal/hepatic disease, BB or ACEI contraindication |
RCT, DB, PBO-controlled NEB: 5 mg/day, titrated to 20 mg/day Lisinopril: 10 mg/day, titrated to 40 mg/day NEB + lisinopril: 5/20 + 10/40 mg/day Follow-up at 6 weeks |
Primary: change in sitting DBP Secondary: change in SBP, response rate (either BP <140/90 mmHg or <130/80 if diabetic), adverse events All statistical comparisons were versus combination treatment |
DBP (mean ± SD, mmHg) NEB + lisinopril: −17.2 ± 10.2 NEB: −13.3 ± 8.9 (p ≤ 0.001) Lisinopril: −12.0 ± 9.1 (p ≤ 0.001) PBO: −8.0 ± 9.2 (p ≤ 0.001) SBP (mean ± SD, mmHg) NEB + lisinopril: −19.2 ± 19.8 NEB: −14.4 ± 14.1 (p < 0.05) Lisinopril: −16.1 ± 17.2 (NS) PBO: −9.3 ± 16.4 (p ≤ 0.001) Response rate (%) NEB + lisinopril: 33.9 NEB: 21.6 (p = 0.003) Lisinopril: 21.7 (p = 0.003) PBO: 7.5 (p < 0.001) Note: large PBO effect on BP compared with baseline |
AEs (%) NEB + lisinopril, 30.7 NEB, 27.1 Lisinopril, 30.7 PBO, 30.5 |
| Weiss et al. [61] |
N = 491 Inclusion: primary HTN (SBP 170–200 mmHg untreated, 155–180 mmHg on 1 anti-HTN med, or 140–170 mmHg on 2 meds) Exclusion: secondary HTN, HF, recent MI/CVA, renal impairment, asthma/COPD, recent MI |
RCT, DB, PBO-controlled 4-weeks lead-in period, background treatment initiated (lisinopril 10–20 mg/day; losartan 50–100 mg/day) NEB: 5–40 mg/day, titrated to BP goal Follow-up at 12 weeks |
Primary: change in sitting SBP Secondary: change in DBP, percent achieving BP goal (<140/90 mmHg or <130/80 with diabetes), adverse events |
DBP (mean ± SD, mmHg) NEB: −7.8 ± 10.1 (p < 0.001) PBO: −3.5 ± 10.6 SBP (mean ± SD, mmHg) NEB: −10.1 ± 16.9 (NS) PBO: −7.3 ± 15.9 BP control (%) NEB: 17.6 (p = 0.022) PBO: 10.3 |
AEs (%) NEB, 28.3 PBO, 22.3 |
| Giles et al. [62] |
N = 4118 Inclusion: adults with stage I–II HTN (DBP 90–109 mmHg treated, 95–109 mmHg untreated) Exclusion: secondary HTN, SBP ≥180 mmHg or DBP ≥110 mmHg, >4 anti-HTN meds, HF, poorly controlled type II diabetes, renal impairment |
RCT, DB, PBO-controlled Randomized 2:2:2:2:2:2:2:1 NEB/VAL SPC: 5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day NEB: 5 or 20 mg/day VAL: 80 or 160 mg/day All doses were doubled at week 5 Follow-up at 8 weeks |
Primary: change in seated DBP Secondary: change in seated SBP, adverse events |
DBP (mean ± SD, mmHg) NEB/VAL SPC 20 and 320 mg/day: −15.7 ± 9.6 NEB 40: −14.4 ± 9.4 (p = 0.03) VAL 320: −11.2 ± 9.3 (p < 0.001) All other comparisons were significant favoring SPC SBP All comparisons significant favoring SPC |
Similar across all treatment groups |
ACEI angiotensin-converting enzyme inhibitor, AEs adverse events, Afib atrial fibrillation, ARB angiotensin II receptor blocker, BB β-blocker; BMI body mass index, BP blood pressure, CAD coronary artery disease, CCB calcium channel blocker, COPD chronic obstructive pulmonary disease, CVA cerebrovascular accident, CVD cardiovascular disease, DB double-blind, DBP diastolic blood pressure, HCTZ hydrochlorothiazide, HF heart failure, HTN hypertension, LS least squares, MI myocardial infarction, NEB nebivolol, NS not significant, PBO placebo, RCT randomized controlled trial, SBP systolic blood pressure, SD standard deviation, SE standard error, SPC single pill combination, VAL valsartan