A Novel, Sustainable, and Eco-Friendly Spectrophotometric and Chemometric Approach for Determination of Severely Overlapped Spectrum via Unified Regression Equation: Greenness and Whiteness Assessment.

BACKGROUND: Nebivolol and valsartan (VAL) in combination with each other successfully control blood pressure and improve hypertension patient outcomes. OBJECTIVE: To develop and validate innovative, simple, and sustainable spectrophotometric methods for the simultaneous analysis of nebivolol and valsartan. METHOD: The new modified difference amplitude modulation (MD-AM) method uses only unified regression equation and does not require any resolution techniques. Other different approaches were also applied for the determination of the same mixture including univariate and multivariate spectrophotometric methods. The multivariate methods were PLS and PCR, whereas the univariate methods were derivative ratio (DD1), ratio difference (RD), constant center (CC), constant center spectrum subtraction (CC-SS), constant value coupled with amplitude difference (CV-AD), advanced concentration value (ACV), and amplitude difference (AD). The proposed methods use a green solvent; thus, the environmental impact of the presented procedures was evaluated qualitatively and quantitatively using six well-known evaluation tools. RESULTS: All methods were applied successfully for the analysis of the studied drugs in their bulk powder, pharmaceutical dosage form Byvalson®, and in vitro release at intestinal pH (7.4) using a USP dissolution tester. Results obtained were compared statistically with the reported method and with each other using a one-way ANOVA statistical test, and no significant differences were found. CONCLUSIONS: All green and white analytical chemistry evaluation tools results confirm the safety, sustainability, and cost-effectiveness of the approaches, indicating that the methods are regarded green and sustainable. Results were agreeable, encouraging their applicability in quality control laboratories for dosage form and making these methods an eco-friendly substitute for the analysis of this combined dosage form and for evaluating the dissolution profile. HIGHLIGHTS: For the first time, a severely overlapped spectrum was determined using a unified regression equation without the need of extended part or zero contribution regions by the novel method MD-AM. The proposed methods are the first study of in vitro dissolution profiling of nebivolol hydrochloride (NEB) and VAL and the first sustainable and green methods applied without compromising the analytical criteria.

Outcomes of "diabetes-friendly" vs "diabetes-unfriendly" ß-blockers in older nursing home residents with diabetes after acute myocardial infarction.

AIMS: To assess whether nursing home (NH) residents with type 2 diabetes mellitus (T2D) preferentially received "T2D-friendly" (vs "T2D-unfriendly") ß-blockers after acute myocardial infarction (AMI), and to evaluate the comparative effects of the two groups of ß-blockers. MATERIALS AND METHODS: This new-user retrospective cohort study of NH residents with AMI from May 2007 to March 2010 used national data from the Minimum Data Set and Medicare system. T2D-friendly ß-blockers were those hypothesized to increase peripheral glucose uptake through vasodilation: carvedilol, nebivolol and labetalol. Primary outcomes were hospitalizations for hypoglycaemia and hyperglycaemia in the 90 days after AMI. Secondary outcomes were functional decline, death, all-cause re-hospitalization and fracture hospitalization. We compared outcomes using binomial and multinomial logistic regression models after propensity score matching. RESULTS: Of 2855 NH residents with T2D, 29% initiated a T2D-friendly ß-blocker vs 24% of 6098 without T2D (P < 0.001). For primary outcomes among residents with T2D, T2D-friendly vs T2D-unfriendly ß-blockers were associated with a reduction in hospitalized hyperglycaemia (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.21-0.97), but unassociated with hypoglycaemia (OR 2.05, 95% CI 0.82-5.10). For secondary outcomes, T2D-friendly ß-blockers were associated with a greater rate of re-hospitalization (OR 1.26, 95% CI 1.01-1.57), but not death (OR 1.06, 95% CI 0.85-1.32), functional decline (OR 0.91, 95% CI 0.70-1.19), or fracture (OR 1.69, 95% CI 0.40-7.08). CONCLUSIONS: In older NH residents with T2D, T2D-friendly ß-blocker use was associated with a lower rate of hospitalization for hyperglycaemia, but a higher rate of all-cause re-hospitalization.

Assessment of a Potential Pharmacokinetic Interaction between Nebivolol and Bupropion in Healthy Volunteers.

BACKGROUND/AIMS: The study aimed at investigating the effects of multiple-dose bupropion (potent inhibitor of CYP2D6) on the pharmacokinetics (PKs) of single-dose nebivolol (CYP2D6 substrate) and to evaluate the clinical relevance of this potential drug interaction. METHODS: This open-label, nonrandomized clinical study had a 2-period design: during period 1 (reference), a single dose of 5 mg nebivolol was administered, while during period 2 (test), 5 mg nebivolol + 300 mg bupropion were ingested concomitantly, after a pretreatment regimen with bupropion (7 days). The PK parameters of nebivolol and its active metabolite were analyzed by noncompartmental modeling, while the pharmacodynamic (PD) parameters (blood pressure and heart rate) were assessed at rest. RESULTS: Bupropion plus nebivolol increased the mean peak plasma concentrations (Cmax) of nebivolol (1.67 ± 0.69 vs. 3.80 ± 1.70 ng/ml) and its active metabolite (0.68 ± 0.22 vs. 1.13 ± 0.38 ng/ml) compared to nebivolol alone. After bupropion pretreatment, the exposure to nebivolol was increased by 7.2-fold for the parent drug and 4-fold for the hydroxylated active metabolite. The difference between the PD parameters measured during the 2 periods was not significant. CONCLUSION: The study concluded that bupropion influenced the PKs of nebivolol in healthy volunteers, but a clinical relevance was not established. However, this latter aspect requires further investigation.

Comprehensive Assessment of Coronary Plaque Progression With Advanced Intravascular Imaging, Physiological Measures, and Wall Shear Stress: A Pilot Double-Blinded Randomized Controlled Clinical Trial of Nebivolol Versus Atenolol in Nonobstructive Coronary Artery Disease.

BACKGROUND: We hypothesized that nebivolol, a ß-blocker with nitric oxide-mediated activity, compared with atenolol, a ß-blocker without such activity, would decrease oxidative stress and improve the effects of endothelial dysfunction and wall shear stress (WSS), thereby reducing atherosclerosis progression and vulnerability in patients with nonobstructive coronary artery disease. METHODS AND RESULTS: In this pilot double-blinded randomized controlled trial, 24 patients treated for 1 year with nebivolol 10 mg versus atenolol 100 mg plus standard medical therapy underwent baseline and follow-up coronary angiography with assessments of inflammatory and oxidative stress biomarkers, microvascular function, endothelial function, and virtual histology intravascular ultrasound. WSS was calculated from computational fluid dynamics. Virtual histology intravascular ultrasound segments were assessed for vessel volumetrics and remodeling. There was a trend toward more low-WSS segments in the nebivolol cohort (P=0.06). Low-WSS regions were associated with greater plaque progression (P<0.0001) and constrictive remodeling (P=0.04); conversely, high-WSS segments demonstrated plaque regression and excessive expansive remodeling. Nebivolol patients had decreased lumen and vessel areas along with increased plaque area, resulting in more constrictive remodeling (P=0.002). There were no significant differences in biomarker levels, microvascular function, endothelial function, or number of thin-capped fibroatheromas per vessel. Importantly, after adjusting for ß-blocker, low-WSS segments remained significantly associated with lumen loss and plaque progression. CONCLUSION: Nebivolol, compared with atenolol, was associated with greater plaque progression and constrictive remodeling, likely driven by more low-WSS segments in the nebivolol arm. Both ß-blockers had similar effects on oxidative stress, microvascular function, and endothelial function. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/. Unique identifier: NCT01230892.

A Review of Nebivolol Pharmacology and Clinical Evidence.

Nebivolol is a highly selective ß1-adrenergic receptor antagonist with a pharmacologic profile that differs from those of other drugs in its class. In addition to cardioselectivity mediated via ß1 receptor blockade, nebivolol induces nitric oxide-mediated vasodilation by stimulating endothelial nitric oxide synthase via ß3 agonism. This vasodilatory mechanism is distinct from those of other vasodilatory ß-blockers (carvedilol, labetalol), which are mediated via α-adrenergic receptor blockade. Nebivolol is approved for the treatment of hypertension in the US, and for hypertension and heart failure in Europe. While ß-blockers are not recommended within the current US guidelines as first-line therapy for treatment of essential hypertension, nebivolol has shown comparable efficacy to currently recommended therapies in lowering peripheral blood pressure in adults with hypertension with a very low rate of side effects. Nebivolol also has beneficial effects on central blood pressure compared with other ß-blockers. Clinical data also suggest that nebivolol may be useful in patients who have experienced erectile dysfunction while on other ß-blockers. Here we review the pharmacological profile of nebivolol, the clinical evidence supporting its use in hypertension as monotherapy, add-on, and combination therapy, and the data demonstrating its positive effects on heart failure and endothelial dysfunction.

Economic benefits associated with beta blocker persistence in the treatment of hypertension: a retrospective database analysis.

OBJECTIVES: To assess the association between medical costs and persistence with beta blockers among hypertensive patients, and to quantify persistence related medical cost differences with nebivolol, which is associated with improved tolerability, versus other beta blockers. METHODS: Adults who initiated hypertension treatment with a beta blocker were identified from the MarketScan * claims database (2008-2012). Patients were classified based on their first beta blocker use: nebivolol, atenolol, carvedilol, metoprolol, and other beta blockers. Patients with compelling indications for atenolol, carvedilol or metoprolol (acute coronary syndrome and congestive heart failure) were excluded. Patients enrolled in health maintenance organization or capitated point of service insurance plans were also excluded. Persistence was defined as continuous use of the index drug (<60 day gap). The average effect of persistence on medical costs (2012 USD) was estimated using generalized linear models (GLMs). Regression estimates were used to predict medical cost differences associated with persistence between nebivolol and the other cohorts. RESULTS: A total of 587,424 hypertensive patients met the inclusion criteria. Each additional month of persistence with any one beta blocker was associated with $152.51 in all-cause medical cost savings; continuous treatment for 1 year was associated with $1585.98 in all-cause medical cost savings. Patients treated with nebivolol had longer persistence during the 1 year study period (median: 315 days) than all other beta blockers (median: 156-292 days). Longer persistence with nebivolol translated into $305.74 all-cause medical cost savings relative to all other beta blockers. LIMITATIONS: The results may not be generalizable to hypertensive patients with acute coronary syndrome or congestive heart failure. CONCLUSIONS: Longer persistence with beta blockers for the treatment of hypertension was associated with lower medical costs. There may be greater cost savings due to better persistence with nebivolol than other beta blockers.

Cost-effectiveness analysis of nebivolol and metoprolol in essential hypertension: a pharmacoeconomic comparison of antihypertensive efficacy of beta blockers.

OBJECTIVE: To estimate and compare the cost-effectiveness and safety of nebivolol with sustained-release metoprolol in reducing blood pressure by 1 mm of Hg per day in hypertensive patients. MATERIALS AND METHODS: This was a prospective, randomized, open label, observational analysis of cost-effectiveness, in a questionnaire-based fashion to compare the cost of nebivolol (2.5 mg, 5 mg, 10 mg) and sustained released metoprolol succinate (25 mg, 50 mg, 100 mg) in hypertensive patients using either of the two drugs. A total of 60 newly detected drug naïve hypertensive patients were considered for the comparison, of which 30 patients were prescribed nebivolol and the other 30 were prescribed metoprolol succinate as per the recommended dosage. Based on the data, statistical analysis was carried out using GraphPad Prism 5 and MS Excel Spreadsheet 2007. RESULT: The cost of reducing 1 mm of Hg blood pressure per day with nebivolol was 0.60, 0.70, and 1.06 INR, whereas that of metoprolol succinate was 0.93, 1.18, and 1.25 INR at their respective equivalent doses, hence significantly lower with the nebivolol group as compared to the metoprolol group (P < 0.05). CONCLUSION: This pharmacoeconomic analysis shows that nebivolol is more cost-effective as compared to metoprolol when the cost per reduction in blood pressure per day is considered. This may affect the patients economically during their long-term use of these molecules for the treatment of hypertension.

[Postregistration study of comparative assessment efficacy of the use of fixed combination of nebivolol and amlodipine for the treatment of patients with moderate and high degree of arterial hypertension].

AIM: of the study was to assess efficacy of the use of fixed combination of nebivolol and amlodipine in patients with moderate and high degree of arterial hypertension (AH). MATERIAL AND METHODS: Patients with diagnosis of primary AH (n=124) were divided into 2 groups by random sample method. Patients of group 1 (n=62) received of fixed combination of nebivolol and amlodipine, while those of group 2 (n=62) received free combination of nebivolol and amlodipine. Study drugs were administered both as initial therapy and replacement of preceding treatment. Duration of observation was 3 months with visits after first 2 weeks and in 1, 2, and 3 months after enrollment. RESULTS: Starting from 2nd week visit of fixed combination of nebivolol and amlodipine treated patients had significantly lower levels of systolic and diastolic AP. Already after 2 weeks of combined two-component therapy 60% of group 1 and 52% of group 2 patients achieved target AP. Target AP was achieved by the end of month 1 by 86 and 71%, of month 2 - by 93 and 78% of patients in groups 1 and 2, respectively. In 3 months almost all patients had target AP, but in 1.6% of group 1 and 2.3% of group 2 patients this level was achieved after addition of a thiazide diuretic. Patients receiving of fixed combination of nebivolol and amlodipine achieved noromosyslolia more quickly compared with patients who received free combination of nebivolol and amlodipine. CONCLUSION: Combined therapy with fixed combination of nebivolol and amlodipine appears to be one of effective approaches to treatment of patients with moderate and high degree AH.

Economic impact of switching from metoprolol to nebivolol for hypertension treatment: a retrospective database analysis.

OBJECTIVE: To estimate the real-world economic impact of switching hypertensive patients from metoprolol, a commonly prescribed, generic, non-vasodilatory ß1-blocker, to nebivolol, a branded-protected vasodilatory ß1-blocker. METHODS: Retrospective analysis with a pre-post study design was conducted using the MarketScan database (2007-2011). Hypertensive patients continuously treated with metoprolol for ≥6 months (pre-period) and then switched to nebivolol for ≥6 months (post-period) were identified. The index date for switching was defined as the first nebivolol dispensing date. Data were collected for the two 6-month periods pre- and post-switching. Monthly healthcare resource utilization and healthcare costs pre- and post-switching were calculated and compared using Wilcoxon test and paired t-test. Medical costs at different years were inflated to the 2011 dollar. RESULTS: In total, 2259 patients (mean age: 60 years; male: 52%; cardiovascular [CV] disease: 37%) met the selection criteria. Switching to nebivolol was associated with statistically significant reductions in the number of all-cause hospitalization (-33%; p < 0.01), CV-related hospitalizations (-60%; p < 0.01), and outpatient visits (-7%; p < 0.01). Monthly inpatient costs were reduced by $111 (p < 0.01), while monthly drug costs increased by $52 (p < 0.01). No statistically significant differences were found in overall costs and costs of outpatient or ER visits. Sensitivity analyses, conducted using various lengths of medication exposure, controlling for spill-over effect or excluding patients with compelling indications for metoprolol, all found some level of reduction in resource utilization and no significant difference in overall healthcare costs. CONCLUSIONS: This real-world study suggests that switching from metoprolol to nebivolol is associated with an increase in medication costs and significant reductions in hospitalizations and outpatient visits upon switching, resulting in an overall neutral effect on healthcare costs. These results may be interpreted with caution due to lack of a comparator group and confounding control caused by design and limitations inherent in insurance claims data.

Assessment of effect of irbesartan and nebivolol on the left atrium volume and deformation in the patients with mild-moderate hypertension.

BACKGROUND: We aimed to assess the effects of irbesartan and nebivolol on the left atrium (LA) volume and deformation in the patients with mild-moderate hypertension. PATIENTS AND METHODS: The study comprised of 160 patients (mean age: 55.6±9.6 years), who had Stage 1 or 2 hypertension according to the European Society of Cardiology (ESC) and have not been receiving antihypertensive therapy. The patients were assigned to treatment groups; irbesartan (n=80) and nebivolol (n=80). The patients were clinically and echocardiographically reevaluated on the 6th and 12th months after the onset of treatment. RESULTS: There was no difference between the two treatment groups in terms of baseline demographic, clinical and echocardiographic characteristics. Moreover, no difference was observed between the treatment groups on the 6th and 12th months. Intragroup analyses revealed that systolic blood pressure (SBP) and diastolic blood pressure (DBP) significantly decreased in time and diastolic function parameters were improved. However, whilst significant increase was observed in conduit volume, decrease was observed in other volumes of the LA in the irbesartan and nebivolol groups. This significant change was observed on the 6th month in both treatment groups. LA global peak systolic strain (LAGLSs), LA global peak systolic strain rate (LAGLSRs), LA global peak strain rate during early ventricular diastole (LAGLSRe) and LA global peak strain rate (LAGLSRa) during late ventricular diastole (LAGLSRa) values began to be significantly increased after 6 months of treatment in both treatment groups. CONCLUSIONS: We found that nebivolol, which is a new generation beta blocker, is effective as irbesartan with proven efficacy in improving LA volume and LA myocardial performance in patients with mild-moderate hypertension. Moreover, we determined that strain and strain rate, which are the new echocardiographic parameters, are effective as LA volumes in assessing LA functions.

Efectividad y seguridad de nebivolol como tratamiento ambulatorio de primera línea para isquemia miocárdica, no complicada, en adultos / Effectiveness and safety of nebivolol as a first-line outpatient treatment for uncomplicated myocardial ischemia in adults

Antecedentes: Descripción de la condición de salud de interés (indicación): La isquemia miocárdica es un problema causado por el estrechamiento de las arterias que irrigan el corazón. Cuando hay obstrucciones en las arterias, se disminuye el flujo de sangre y oxígeno que irriga el músculo cardiaco. En el momento en que \r\naumentan los requerimientos de oxígeno, como con el ejercicio, el corazón no puede satisfacer la demanda del mismo, por lo cual se generan los síntomas. La cardiopatía isquémica es un síndrome que abarca una serie de patologías que incluyen: la angina estable e inestable, síndrome coronario agudo, y la cardiopatía isquémica crónica. Descripción de la tecnología: El nebivolol es un beta bloqueador selectivo ß-1 de los receptores cardíacos, posee acción vasodilatadora, su acción es prolongada. Es empleado en el tratamient o de la hipertensión arterial, angina de pecho, insuficiencia cardíaca congestiva. Evaluación de efectividad y seguridad: Pregunta de evaluación: En adultos mayores de 18 años con isquemia miocárdica, no complicada¿ Cuál es la efectividad y seguridad de nebivolol comparado con metoprolol como tratamiento ambulatorio de primer a línea? La pregunta de investigación fue refinada y validada con base en: autorización de mercadeo de la tecnología para la indicación de interés (registro sanitario INVIMA), listado de medicamentos vitales no disponibles, cobertura de las tecnologías en el Plan Obligatorio de Salud (POS) (Acuerdo 029 de 2011), revisión de grupos terapéuticos (código ATC: Anatomical, Therapeutic, \r\nChemical classification system), recomendaciones de guías de práctica clínica actualizadas, disponibilidad de evidencia sobre efectividad y seguridad (reportes de evaluación de tecnologías, revisiones sistemáticas de la literatura), uso de las tecnologías (listas nacionales de recobro, estadísticas de prescripción, etc), consulta con expertos temáticos (especialistas clínicos), y otros actores clave. No se identificaron otros comparadores relevantes para la evaluación. Población: Adultos mayores de 18 años con \r\nisquemia miocárdica, no complicada. Tecnología de interés: Nebivolol. Metodología: Búsqueda de literatura, Búsqueda en bases de datos electrónicas. Conclusiones: Efectividad: no se identificó evidencia de efectividad que describa el uso de nebivolol comparado con metoprolol para el tratamiento de la isquemia miocárdica. \r\nSeguridad: no se identificó evidencia de seguridad que describa el uso de nebivolol comparado con metoprolol para el tratamiento de la isquemia miocárdica. Costo-efectividad: no se identificaron estudios de costo-efectividad para Colombia.

Persistence with nebivolol in the treatment of hypertension: a retrospective claims analysis.

OBJECTIVE: Examine drug persistence by evaluating the hazard of discontinuation and of switching to different antihypertensive drugs in patients initiating treatment with a recently approved ß-blocker, nebivolol, versus other ß-blockers. METHODS: This retrospective analysis included all patients diagnosed with hypertension in the MarketScan Database (January 2007 - December 2008) with at least two medical claims and no prior ß-blocker prescriptions within 6 months of the initial prescription date. Multivariate Cox proportional hazard models (adjusted for baseline differences in demographics, previous use of other antihypertensive medications, initial doses and supply of medication, and number of distinct prescriptions at baseline) were used to assess the hazard of discontinuation, defined as the first prescription gap of ≥30 days, and to assess the hazard of switching to another antihypertensive drug, defined as a prescription fill for another antihypertensive drug within 15 days before and 30 days after discontinuation of the initial ß-blocker. RESULTS: Of the 173,200 patients included in the study population, the adjusted hazard of discontinuation for nebivolol-initiated patients was 8-20% lower than that of patients who initiated treatment with atenolol (hazard ratio [HR] 0.82, p < 0.001), metoprolol (HR 0.91, p < 0.001), carvedilol (HR 0.92, p < 0.001), or other ß-blockers (HR 0.80, p < 0.001). The adjusted hazard of nebivolol-treated patients switching to a different antihypertensive medication was 12-22% lower than that of the other four ß-blocker cohorts (atenolol: HR 0.80, p < 0.001; metoprolol: HR 0.86, p < 0.001; carvedilol: HR 0.88, p < 0.001; other ß-blockers: HR 0.78, p < 0.001). Sensitivity analyses defined discontinuation as prescription gaps of ≥45 days and ≥60 days and showed a lower hazard of discontinuation among patients initiating nebivolol than among patients initiating all other drug cohorts (p < 0.001). LIMITATIONS: Comparisons of non-randomized treatment groups may be confounded by unobserved differences in patients' baseline characteristics. CONCLUSIONS: Initiation with nebivolol was associated with greater persistence than initiation with atenolol, carvedilol, metoprolol, or other ß-blockers.

Rapid and economic chiral-HPLC method of nebivolol enantiomers resolution in dosage formulation.

A fast, economic, reproducible, accurate, effective, rugged and selective chiral-HPLC method was developed and validated for the enantiomeric resolution of nebivolol enantiomers [(+)-RRRS and (-)-SSSR)] in dosage formulation. The method was rapid as chiral separation occurred within only 12 min. The mobile phase used was n-heptane-ethanol-DEA (85:15:0.1, v/v) at 3.0 mL/min flow-rate with 225 nm detection. The column used was an amylase-based 3-AmyCoat (150 × 46 mm) [tris-(3,5-dimethylphenyl carbamate)]. The capacity factors of (+)-RRRS and (-)-SSSR enantiomers were 7.85 and 10.90 while the separation and resolution factors were 1.39 and 1.83, respectively. The limits of detection and quantitation for (+)-RRRS enantiomer were 4.5 and 10.00 µg/mL, while these values for (-)-SSSR enantiomer were 4.1 and 8.2 µg/mL, respectively. The linearity was observed in the concentrations range of 0.10-1.0 mg/mL for both enantiomers. The π-π interactions, hydrogen bonds, dipole-dipole interactions and steric effects control the chiral resolution of nebivolol enantiomers on the reported chiral column. The reported method can be used for the quality control of nebivolol in pharmaceutical preparations with good economy. In addition, this method can also be used for the analysis of (+)-RRRS and (-)-SSSR) enantiomers in biological and environmental samples.

Clinical and economic aspects of the use of nebivolol in the treatment of elderly patients with heart failure.

Heart failure is a common and disabling condition with morbidity and mortality that increase dramatically with advancing age. Large observational studies, retrospective subgroup analyses and meta-analyses of clinical trials in systolic heart failure, and recently published randomized studies have provided data supporting the use of beta-blockers as a baseline therapy in heart failure in the elderly. Despite the available evidence about beta-blockers, this therapy is still less frequently used in elderly compared to younger patients. Nebivolol is a third-generation cardioselective beta-blocker with L-arginine/nitric oxide-induced vasodilatory properties, approved in Europe and several other countries for the treatment of essential hypertension, and in Europe for the treatment of stable, mild, or moderate chronic heart failure, in addition to standard therapies in elderly patients aged 70 years old or older. The effects of nebivolol on left ventricular function in elderly patients with chronic heart failure (ENECA) and the study of effects of nebivolol intervention on outcomes and rehospitalization in seniors with heart failure (SENIORS) have been specifically aimed to assess the efficacy of beta-blockade in elderly heart failure patients. The results of these two trials demonstrate that nebivolol is well tolerated and effective in reducing mortality and morbidity in older patients, and that the beneficial clinical effect is present also in patients with mildly reduced ejection fraction. Moreover, nebivolol appears to be significantly cost-effective when prescribed in these patients. However, further targeted studies are needed to better define the efficacy as well as safety profile in frail and older patients with comorbid diseases.

Nebivolol: a third-generation beta-blocker for hypertension.

BACKGROUND: Nebivolol is a third-generation beta(1)-selective beta-blocker that is approved for the treatment of hypertension. OBJECTIVE: This article reviews the clinical pharmacology of nebivolol and its efficacy and safety profile in clinical studies of hypertension (the US Food and Drug Administration-approved indication) and heart failure (off-label use). METHODS: Pertinent articles were identified through searches of MEDLINE and Current Contents from 1966 through December 15, 2008, using the terms nebivolol, drug interaction, pharmacokinetics, and pharmacology. The reference lists of the identified publications were reviewed for additional references. Abstracts presented at meetings of the American Heart Association and the American Society of Hypertension from 2006 through 2008 were also reviewed. All human clinical trials were included, regardless of design. RESULTS: Twelve published clinical trials were identified that evaluated the use of nebivolol in the management of hypertension; 1 was placebo controlled, 1 was placebo and active controlled, and 10 involved direct comparisons with other antihypertensive agents. Nebivolol was reported to be as effective in lowering blood pressure (BP) as other beta-blockers (atenolol and bisoprolol), angiotensin-converting enzyme inhibitors (lisinopril and enalapril), the angiotensin-receptor blocker telmisartan, and calcium channel blockers (nifedipine and amlodipine). No published studies were identified that evaluated the effect of nebivolol on long-term cardiovascular outcomes. In data from a study in heart failure, nebivolol was associated with a 14% reduction in all-cause mortality and cardiovascular hospitalization at 12 months (P < 0.05). In comparative clinical studies, nebivolol appeared to be well tolerated relative to the other antihypertensive agents studied. The most commonly reported adverse events with nebivolol were fatigue (4%-79%), headache (2%-24%), paresthesia (7%-13%), bradycardia (6%-11%), rhinitis (1%-7%), and dizziness (2%-5%). Because of differences in its pharmacologic properties, nebivolol may have potential advantages in patients who are unable to tolerate traditional beta-blockers (eg, patients with asthma or chronic obstructive pulmonary disease, or men who experience erectile dysfunction while taking antihypertensive therapy). CONCLUSIONS: Nebivolol is a cardioselective beta-blocker that has been reported to be efficacious and well tolerated for achieving BP control in patients with hypertension. Preliminary evidence suggests a potential for reduced mortality in patients with heart failure.

Long-term cost-effectiveness analysis of nebivolol compared with standard care in elderly patients with heart failure: an individual patient-based simulation model.

BACKGROUND AND OBJECTIVE: The SENIORS trial demonstrated that nebivolol is effective in the treatment of heart failure in elderly patients (e.g. > or = 70 years). This analysis evaluates the cost effectiveness of nebivolol compared with standard treatment. METHODS: An individual patient-simulation model based on a Markov modelling framework was developed to compare costs and outcomes for nebivolol and standard care in patients with heart failure starting treatment at the age of 70 years. Health states were defined by New York Heart Association (NYHA) class and death. At a given NYHA class and a given cycle, patients could die, be hospitalized for cardiovascular disease or remain stable. Risks for these events were derived from individual patient data from the SENIORS trial. The risk of each event in a given cycle was based on the subject's baseline characteristics and time in the current health state. The economic analysis was conducted from the UK NHS perspective with a lifetime horizon. The costs (euro; year 2006 values) considered were drug costs for nebivolol and other cardiac drugs, costs of GP visits, outpatient specialist visits and cardiovascular-related hospitalizations. Univariate and probabilistic sensitivity analysis was conducted. RESULTS: In the baseline analysis, the total cost per patient was euro6740 and euro9288, and QALYs were 5.194 and 5.843 for patients aged 70 years at the start of treatment for the standard treatment and nebivolol groups, respectively. The probabilistic sensitivity analysis provided an incremental cost-effectiveness ratio of euro3926 (95% CI 3731, 4159) per QALY. CONCLUSIONS: This analysis indicates that nebivolol appears to be a cost-effective treatment for elderly patients with heart failure compared with standard care.

Nebivolol: a new antihypertensive agent.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, safety, economic issues, dosage, and place in therapy of nebivolol are reviewed. SUMMARY: Nebivolol is a novel, highly selective beta(1)-receptor blocker that causes peripheral vasodilation by increasing the production and release of nitric oxide and decreasing nitric oxide degradation. The nitric oxide-mediated effects of nebivolol lead to decreases in systemic vascular resistance and large artery stiffness and possible reversal of endothelial dysfunction. Clinical studies have shown nebivolol to be at least as effective at lowering blood pressure as other antihypertensive drugs, including other beta-blockers. The most frequent adverse events reported in nebivolol clinical trials were transient headache, dizziness, and tiredness. In a large trial in patients with heart failure, nebivolol was shown to reduce the composite endpoint of mortality and hospitalizations. Nebivolol is highly lipophilic and is rapidly absorbed after oral administration. The nebivolol dose most commonly used in clinical trials for hypertension was 5 mg daily; no significant further decreases in blood pressure were shown with higher doses. The average dose in clinical trials for patients with heart failure was 5-10 mg daily. Dosage adjustments are recommended in elderly patients and patients with severe renal impairment. CONCLUSION: Nebivolol is a unique, highly selective beta-blocker with vasodilatory properties mediated through the nitric oxide pathway; it may be useful in the treatment of uncomplicated mild-to-moderate essential hypertension and in patients with heart failure.

Pharmacoeconomic benefits of antihypertensive therapy.

BACKGROUND: Effective blood pressure reduction reduces cardiovascular risk and prevents later complications. OBJECTIVE: To consider the pharmacoeconomic benefits of antihypertensive therapy. SUMMARY: Every managed care pharmacist should consider the balance of cost and benefit of antihypertensive therapies, ensuring that best treatment options for patients with the lowest cost to the health care system are available and implemented. Pharmacists must also evaluate the direct and indirect cost associated with risk reduction for stroke and cardiovascular disease. CONCLUSION: Using an interdisciplinary approach to hypertension treatment, pharmacists can assume a major role in detection, management, and control of hypertensive patients. As the medical teams' drug expert, they will be expected to recommend best treatment options for effective blood pressure control and cardiovascular risk reduction.

Economic evaluation of nebivolol in the treatment of hypertension.

OBJECTIVE: To examine the economic consequences of effective antihypertensive treatment using the novel vasodilating beta1-adrenoceptor antagonist nebivolol (Nebilet) from the perspective of the healthcare provider. METHODS: The evaluation was based on a postmarketing surveillance study in Germany involving 8682 moderately hypertensive patients. Using the Framingham Risk Model, the antihypertensive effectiveness of nebivolol after 6 weeks of treatment was extrapolated to estimate the reductions in 10-year risks of cardiovascular events. Data sources included direct costs for medical and invasive cardiovascular interventions in Germany, costs of therapy in the US and the UK, and estimates on the prevalence of cardiovascular events issued by the American Heart Association. RESULTS: Six-week antihypertensive treatment resulted in a DBP reduction of 13.7 mm Hg. The rate of responders, defined as those patients achieving DBP <90 mm Hg, was 70%. SBP was reduced by 26.1 mm Hg. According to the Framingham Risk Model, 313 deaths would be avoided. Coronary heart disease (CHD) could be reduced by 94 cases (from 1339 to 1245 events) and 150 strokes would be avoided (from 518 to 368 events) in a 10-year period. This reduction of 244 cardiovascular events among the 8682 patients investigated corresponded to cost savings of between Euro 250,000 and Euro 2.5 million, depending on the healthcare environment and the intervention applied. CONCLUSION: Treatment of moderately hypertensive patients with nebivolol can be considered cost effective. Nebivolol has the potential to decrease the overall long-term costs of medical care for patients with hypertension.