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  1. 1. Nebivolol: A Novel Beta-Blocker withNitric Oxide-Induced VasodilatationRobert WeissAuthor information ►Copyright and License information ►This article has been cited by other articles in PMC.Go to:AbstractNebivolol is a novel beta1-blocker with a greater degree of selectivity for beta1-adrenergicreceptors than other agents in this class and a nitric oxide (NO)-potentiating, vasodilatoryeffect that is unique among beta-blockers currently available to clinicians (nebivolol isapproved in Europe and is currently under review in the US). A NO-potentiating agentsuch as nebivolol may have an important role in hypertensive populations with reducedendothelial function such as diabetics, African-Americans and those with vasculardisease. Nebivolol is a racemic mixture with beta-blocker activity residing in the d-isomer; in contrast, l-nebivolol is far more potent in facilitating NO release. Nebivolol isunique among beta-blockers in that, at doses <10 mg, it does not inhibit the increase inheart rate normally seen with exercise. The efficacy of nebivolol has been testedsuccessfully in clinical trials against other agents including other beta-blockers,angiotensin-converting enzyme-inhibitors and calcium channel antagonists in patientswith hypertension, angina, and congestive heart failure. The tolerability of nebivolol hasbeen shown to be superior to that of atenolol and metoprolol. In controlled clinical trials,nebivolol has a side effect profile that is similar to placebo, in particular as it relates tofatigue and sexual dysfunction. This article will review published clinical data regardingthis cardioselective beta-blocker.Keywords: nebivolol, hypertension, beta-blockerGo to:IntroductionGoal blood pressure (BP), defined as <140/90 mm Hg in uncomplicated hypertension, isattained by only 34% of hypertensive patients in the US (Chobanian et al 2003), 24% ofpatients in France (Chamontin et al 1998), and 13% of patients in Canada (Joffres et al2001). These low rates of achieving goal BP indicate that a more aggressive approach toBP management is required on a global scale. One of the most important classes ofantihypertensive agents, beta-blockers play a critical role in reducing cardiovascular riskin hypertensive patients. A meta-analysis including almost 19 000 patients concluded thatbeta-blocker therapy was associated with a 42% reduction in heart failure, a 29%reduction in stroke risk, and a 7% reduction in coronary heart disease in hypertensivepatients (Psaty et al 1997). The specific mechanism of action of beta-blockers that
  2. 2. reduces BP is not completely understood, however, likely mechanisms include an effecton heart rate, inhibition of the sympathetic nervous system, and inhibition of the renin-angiotensin system. Nebivolol is a novel, highly selective beta-blocker withnonadrenergic vasodilating properties. It has been approved for the treatment of essentialhypertension and congestive heart failure in Europe and is currently under review for thetreatment of hypertension in the US.Go to:PharmacokineticsNebivolol is a racemic mixture of equal proportions of d- and l-isomers. The beta-blockeractivity resides in the d-isomer while the facilitation of nitric oxide (NO) release is foundin the l-enantiomer (Van Neuten and De Cree 1998; Mason et al 2005).Nebivolol is well absorbed after oral administration. Peak plasma concentrations arereached in 0.5–2 hours and steady-state plasma levels are reached in 24 hours (McNeelyand Goa 1999). Nebivolol has a superior trough-to-peak efficacy ratio compared withatenolol, allowing for “true” once daily dosing (Simon and Johnson 1993). Absorption ofthe drug following oral administration is not affected by food, age, gender or body weight(McNeely and Goa 1999; Cheymol et al 1997). Nebivolol is metabolized by the liver, andundergoes extensive first-pass metabolism to active moieties via the cytochrome(CYP)2D6 enzymatic pathway (Gu et al 2003; Weber 2005). The mean terminal half-lifeis approximately 10 hours (Cheymol et al 1997). Less than 0.1% of unchanged drug isexcreted in urine (Shaw, Liu, Zachwieja, et al 2005). Metabolism of nebivolol is subjectto a debrisoquine-type genetic polymorphism (Weber 2005). The small percentage ofpatients who are deficient in CYP2D6 enzyme activity (7% of Caucasians, 2% ofAfrican-Americans, 2% of Asians) are considered poor metabolizers of nebivolol(Relling et al 1991; Evans et al 1993; Mizutani 2003). The absolute oral bioavailability ofnebivolol is 12% in extensive metabolizers and 96% in poor metabolizers (Van Peer1991). However, a safety trial in both extensive and poor metabolizers has shown nosafety or efficacy differences between these patient groups (Lacourcière et al 2000).No significant difference in efficacy or safety have been found in patients with mild ormoderate renal disease; patients with severe renal impairment may need a lower initialdose due to impaired clearance (Shaw, Liu, Zachwieja, et al 2005). Similarly, a lowerstarting dose may be needed in patients with mild or moderate hepatic impairment due toalteration in the drugs pharmacokinetics in these patients (Shaw, Liu, Tu, et al 2005).Go to:Clinical perspectiveNebivolol has a hemodynamic effect suggestive of direct vasodilatation (Gao et al 1991;Van Rooy et al 1991). Evidence in the literature indicates that the vasodilation associated
  3. 3. with nebivolol is due to its effects on the L-arginine/NO pathway in the endothelium ofvarious regional vascular beds (Bowman et al 1994; Cockcroft et al 1995; Dawes et al1999; Ritter 2001; Tzemos et al 2001). Using the dorsal hand vein dilatation model,researchers found that nebivolol had a venodilator effect on the human hand whereasatenolol did not. Further, this effect was inhibited by L-NMMA (NG-monomethyl L-arginine), an inhibitor of NO synthase, indicating that the increased blood flow was dueto activation of the L-arginine/NO pathway (Bowman et al 1994). This finding wasconfirmed in hypertensive patients who showed signs of vasodilatation in forearmarteries after nebivolol infusion. The fact that this vasodilatation was inhibited by L-NMMA supports that it is due to activation of the L-arginine/NO pathway (Cockcroft etal 1995; Dawes et al 1999). The endothelial-dependent vasoconstrictive response seenwith L-NMMA infusion was inhibited by nebivolol and not by atenolol (Ritter 2001;Tzemos et al 2001).In another study, the effect of nebivolol on small artery distensibility in patients withhypertension was compared with that of atenolol. Both drugs were equivalent in reducingBP, but only nebivolol improved small artery distensibility, a measure of arterialcompliance or “stiffness” (Arosio et al 2002). Arterial stiffness has been shown to be anindependent predictor of mortality in patients with essential hypertension. Drugs thatreduce stiffness may therefore confer a survival advantage (Laurent et al 2001). In ananimal model comparison with atenolol, nebivolol infusion showed a statisticallysignificant reduction in a measure of arterial distensibility, namely pulse wave velocity,with no change in mean arterial pressure (McEniery et al 2004). In contrast, atenolol hadno effect on pulse wave velocity despite a small drop in mean arterial pressure. Thisdifference suggests that the release of NO mediated by nebivolol, independent of a beta-adrenoceptor-dependent mechanism, an effect not seen with older beta-blockers such asatenolol, may be of particular benefit in patients with impaired arterial compliance, suchas those with isolated systolic hypertension (McEniery et al 2004).Clinical trials also show that nebivolol has an anti-oxidative effect (de Groot et al 2004;Pasini et al 2005). In a study of 20 hypertensive patients compared with 20 matchedhealthy subjects, nebivolol reduced the oxidative inactivation of NO, a result not seenwith atenolol (Pasini et al 2005). In addition, nebivolol inhibited vascular smooth muscleproliferation in a rat aortic smooth muscle cell model via an apparent NO-dependentmechanism (Ignarro et al 2002). Both of these findings suggest that nebivolol may offeranti-atherosclerotic activity, a particular benefit, if verified, in patients with arterialdisease.Go to:Nebivolol comparative efficacyClinical trials suggest that on a weight-for-weight basis, nebivolol is ten times morepotent than atenolol. In one study, the effect of doses of nebivolol (2.5 mg/day, 5.0mg/day, and 10.0 mg/day) on exercise-induced increases in heart rate and blood pressurein 25 male hypertensive volunteers was compared with that of atenolol 50 mg/day and
  4. 4. 100 mg/day and of placebo using a double-blind, crossover design and a parallel, placebogroup (n=7) (Simon and Johnson 1993). At 24 hours after dosing, sitting and standingdiastolic and systolic blood pressures and heart rates (at rest and during submaximalexercise) were reduced to the same extent by nebivolol and atenolol.However, the hemodynamic effect of nebivolol appears to be different from that ofatenolol. In a double-blind, randomized, prospective study in patients with essentialhypertension, atenolol reduced cardiac output, stroke volume, and heart rate. In contrast,nebivolol reduced peripheral resistance and increased stroke volume, preserving cardiacoutput (Kamp et al 2003). The effects of nebivolol demonstrated in this study suggest thatthe drug may be important in treating heart failure, where preservation of cardiac outputis critical.Nebivolol 5 mg/day was compared with metoprolol 100 mg twice daily (BID) in 155patients with mild-to-moderate essential hypertension (Uhlir et al 1991). Target bloodpressure was attained in 79% of nebivolol-treated patients and 66% of those in themetoprolol group. There were fewer adverse events reported by patients in the nebivololgroup. In a second study, nebivolol 5 mg/day was compared with metoprolol 100 mg BIDin 80 newly diagnosed hypertensive patients (Celik et al 2006). After 6 months oftreatment, the researchers found that both drugs significantly reduced BP and heart rate,with a more profound bradycardic effect seen in the metoprolol group. In contrast, onlynebivolol significantly reduced oxidative stress, insulin resistance index, and plasmalevels of P-selectin, a cell-surface adhesion molecule believed to play a role in theinitiation of atherosclerosis (Celik et al 2006).Nebivolol 5 mg/day was also compared with the angiotensin-converting enzyme (ACE)inhibitor lisinopril 20 mg/day in 68 patients with uncomplicated mild-to-moderatehypertension, treated for 12 weeks. The primary endpoints of the study were responserate, where patients were defined as “normalized” responders if their blood pressurevalues were <140/90 mm Hg at study end, or as “non-normalized” responders if thereduction in blood pressure was ≥10 mm Hg compared with baseline; and changes insitting blood pressure at the end of the study. Patients were randomly assigned to one ofthe study arms, however, a significant difference in sitting diastolic blood pressure (DBP)was found between the 2 groups at baseline. Analysis of covariance of the raw dataincluding baseline values as covariate suggested that DBP and heart rate weresignificantly lower in the nebivolol-treated group at week 8. This difference disappeared,however, when an analysis of variance for repeated measures was performed, whichindicated a significant reduction in systolic blood pressure (SBP), DBP, and heart rate inboth groups. There was a statistically significant difference in favor of the nebivololgroup in the distribution of responders and non-responders at week 8. Lisinopril andnebivolol were equally well tolerated (Rosei et al 2003).Nebivolol 2.5–5 mg/day was compared with the calcium channel antagonist, amlopidine,5–10 mg/day (Mazza et al 2002) in elderly patients (≥65 years). In this double-blind,multicenter, randomized trial, efficacy was similar between the two groups. Both drugswere well tolerated, however, there was a higher incidence of adverse events such as
  5. 5. headache and ankle edema in the group treated with amlodipine. In a double-blind study,the efficacy of nebivolol 5 mg/day was compared with that of the sustained-releasecalcium channel antagonist, nifedipine, 20 mg/BID in 51 patients with mild-to-moderatehypertension over a 12 week-treatment period (Lacourcière et al 1992). The treatmentresponse rate was 69% for nebivolol and 59% for nifedipine. Both treatment groupsshowed a significant reduction in BP, with no significant difference in BP reductionbetween the groups either in clinic BP or in 24-hour ambulatory BP. Nebivolol appearedto be superior to nifedipine in preventing the usual early morning increase in BP. Beta-blockers have usually been found to increase plasma cholesterol (Ames 1986;Lacourcière et al 1990). However, both agents were associated with a significant decreasein cholesterol after 12 weeks of treatment, 5% and 3%, for nebivolol and nifedipine,respectively.The largest double-blind study in hypertension included 909 patients with mild-to-moderate hypertension (Weiss et al 2005). Nebivolol in doses of 1.25–40 mg/day werecompared with placebo over 12 weeks. Placebo-subtracted reductions in trough sitting BP(SBP/DBP) ranged from 6.6/5.1–11.7/8.3 mm Hg and were dose dependent. Reportedadverse events were: headache (7.1 vs 7.4% placebo, fatigue (3.6 vs 2.5% placebo,nasopharyngitis (2.9% vs 7.4% placebo), diarrhea (2.8% vs 2.5% placebo) and dizziness(2.8 vs 3.7% placebo). The incidence of typical beta-blocker adverse effects was very lowand no different from placebo including erectile dysfunction (0.2% vs 0.0% placebo),decreased libido (0.1% vs 0.0% placebo), dyspnea (1.0% vs 0.0% placebo) andbradycardia (0.7% vs 0.0% placebo).Go to:Nebivolol tolerabilityIn controlled clinical trials, nebivolol demonstrates a side effect profile similar toplacebo, most notably in regards to side effects commonly associated with beta-blockers,such as fatigue and sexual dysfunction (Weber 2005). Quality of life was evaluated in adouble-blind, randomized trial of 314 patients with hypertension who were treated witheither nebivolol 5 mg/day or losartan 50 mg/day for 12 weeks (Van Bortel et al 2005).The two agents had an equivalent effect in reducing SBP but the decrease in DBP wasslightly greater with nebivolol. Interestingly, the side effect profile of losartan, anangiotensin receptor antagonist known for few side effects, was no different than that ofnebivolol. In a separate study, nebivolol (5 mg/day) was compared with atenolol (50mg/day) and placebo in 364 patients in general practice (Van Nueten et al 1998). Therewas no significant difference in BP or in sitting heart rate between the treatment groups,and there was no significant difference in the incidence of side effects between thegroups, except for significantly more complaints of sexual dysfunction in the atenololgroup.Beta-blockers have been associated in the past with a risk of sexual dysfunction, howeverrecent meta-analysis suggests that the risk of this adverse event is not substantial (Ko etal 2002). A recent clinical trial studied 29 out of 44 hypertensive men who complained of
  6. 6. erectile dysfunction while taking atenolol, metoprolol or bisoprolol. The researchersfound that after switching to nebivolol therapy, 20 of the 29 noted significantimprovement in erectile function without a significant change in BP (Doumas et al 2006).It is reasonable to speculate that this improvement in erectile function may be due to theinvolvement of NO in erectile dysfunction and its potentiation with nebivolol therapy(Doumas et al 2006).Go to:Nebivolol in other cardiovascular diseasesNebivolol (5 mg/day) versus placebo has been evaluated in the treatment of angina(Cherchi et al 1991). In a placebo-controlled trial of 16 patients, nebivolol therapysignificantly prolonged treadmill time to 1 mm ST depression from 555 ± 37sec to 667.5± 49 sec (p<0.05). Anginal threshold was also significantly delayed from 697 ± 51 sec to767 ± 64 sec (p<0.05). Further testing of nebivolol in a dose ranging, single-blind trial(2.5 mg/day, 5 mg/day, and 10 mg/day) was performed in 10 patients with stable angina;5 of the patients also had a history of myocardial infarction (Ulvenstam 1991). The doseswere titrated in 2 week intervals in this trial. The time to 1 mm ST change increased at all3 doses of nebivolol compared with placebo.In a double-blind, placebo-controlled study of maximal and submaximal exercise testingconducted in patients with ischemic left ventricular dysfunction but no overt signs ofheart failure, both atenolol and propanolol reduced resting heart rate and improved leftventricular ejection fraction compared with placebo. Only nebivolol produced a parallel,downward shift of the pressure-volume relationship during early diastolic filling andimproved the early peak filling rate compared with placebo (Rousseau et al 1996). Inaddition, compared with baseline, nebivolol therapy increased maximal exercise durationby 44 sec, a statistically significant difference from baseline (p=0.007 vs baseline),whereas the improvements seen with placebo and atenolol, 7 sec and 13 sec respectively,were not statistically significant changes from baseline.In patients with ischemic left ventricular dysfunction without clinical congestive heartfailure (Stoleru et al 1993), maximal exercise function increased more in those treatedwith nebivolol 5 mg/day than in those treated with atenolol 50 mg/day (p<0.0077). Thiswas associated with an improved pressure-volume relationship during early diastolicfilling and improved early peak filling rate. An improvement in left ventricular ejectionfraction and cardiac output was found with nebivolol, but not with atenolol.The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation inSeniors with Heart Failure (SENIORS) was a double-blind, randomized, multicenterplacebo-controlled trial conducted in Europe. SENIORS was the first randomized,controlled clinical trial with the power to demonstrate efficacy specifically in elderlypatients with heart failure. The aim of the study was to assess the effect of nebivolol onmortality and cardiovascular hospital admissions in elderly patients (≥70 years) withheart failure, regardless of ejection fraction (Flather et al 2005). The SENIORS
  7. 7. researchers note that this age inclusion criterion makes the study population closelyresemble the actual population of heart failure patients, where the average age is 76years; in contrast, the average age of patients enrolled in previous, large heart failurestudies was 63 years.All 2128 patients enrolled in the SENIORS study had a history of chronic heart failure, asevidenced by hospital admission within the past 12 months with a diagnosis of congestiveheart failure on discharge or a documented ejection fraction of 35% or less within theprevious 6 months. Following randomization, 1067 patients received nebivolol 1.25mg/day titrated to 10 mg/day; 1061 patients received placebo. The primary outcome ofthe study was a composite of all-cause mortality or cardiac hospitalization (time to firstevent) during a 21 month follow up period. At baseline, the mean ejection fraction was36%, with 35% of patients having an ejection fraction >35%. More than two thirds ofpatients (68%) had a history of coronary artery disease. The primary outcome occurred in31.1% (n=332) of nebivolol-treated patients and 35.3% (n=375) of patients receivingplacebo (hazard ratio [HR] 0.86; 95% confidence interval [CI]: 0.74–0.99; p=0.039). Theall-cause mortality rate was 15.8% (n=169) in the nebivolol group and 18.1% (n=192) inthe placebo group (HR 0.88, 95% CI 0.71–1.08; p=0.21) Subgroup analysis by age lessthan the median age in SENIORS (75.2 years) in patients with an ejection fraction lessthan 35% allowed comparison with the results of previous trials; the HR for primaryoutcome was 0.73 (95% CI, 0.56–0.96), the HR for all cause mortality alone was 0.62(95% CI, 0.43–0.89). These results suggest that the efficacy of nebivolol in this patientsubgroup is similar to that seen in previous studies conducted with bisoprolol,metoprolol, and carvedilol (Flather et al 2005).Go to:Nebivolol efficacy in black hypertensive patientsThe efficacy and tolerability of nebivolol in black hypertensive patients was assessed in arandomized, placebo-controlled, multicenter trial conducted in Europe and the US thatincluded 509 patients with essential hypertension (Van Neuten et al 1997). Doses of 0.5mg/day, 1.0 mg/day, 2.5 mg/day, 5 mg/day and 10 mg/day of nebivolol were comparedwith placebo. Doses of nebivolol at 2.5 mg/day, 5 mg/day, and 10 mg/day were shown tobe more effective than placebo in a dose-dependent manner. There was no significantdifference in efficacy seen between black (22% of the study population) and whitepatients, with response rates of 58% and 62%, respectively (response defined as reductionof DBP to <90 mm Hg or by ≥10 mm Hg from baseline). The drug was well tolerated.The efficacy of nebivolol in black patients may in part be due to improved NO levels.The importance of NO in black patients has been shown in the treatment of congestiveheart failure where a regimen of hydralazine and nitrates reduced mortality by 43% overa standard regimen including an ACE inhibitor and a beta-blocker (Taylor et al 2004).Nebivolol has been shown to restore NO bioavailability in blacks to the level observed inwhites, independent of beta1-selective blockade, by augmenting NO release and reducingnitroxidative stress in the vascular endothelium (Mason et al 2005). These findings
  8. 8. suggest that nebivolol may be a more effective antihypertensive in black patients thanolder beta-blockers.Go to:ConclusionsBeta-blockers are important agents in cardiovascular medicine, proving criticallyimportant in the management of hypertension and heart failure and in reducingcardiovascular risk. Nebivolol is a novel highly cardioselective beta-blocker withantihypertensive efficacy similar to that of other beta-blockers, but with tolerability betterthan older agents in its class, which may permit nebivolol to be used more widely andeffectively than other beta-blockers. Nebivolols vasodilating effect, its anti-atherosclerotic effect, and its positive effects on arterial compliance suggest that it mayprovide more cardiovascular benefits than traditional beta-blockers, particularly inpatients with isolated systolic hypertension, diabetics, black patients, and patients withknown vascular disease.Go to:References1. Ames RP. The effects of antihypertensive drugs on serum lipids and lipoproteins.II. Non-diuretic drugs. Drugs. 1986;32:335–57. [PubMed]2. Arosio E, De Marchi S, Prior M, et al. Effects of nebivolol and atenolol on smallarteries and microcirculatory endothelium-dependent dilation in hypertensivepatients undergoing isometric stress. J Hypertens. 2002;20:1793–7. [PubMed]3. Bowman AJ, Chen CPL, Ford GA. Nitric oxide-mediated venodilator effects ofnebivolol. Br J Clin Pharmacol. 1994;38:199–204. [PMC free article] [PubMed]4. Celik T, Iyisoy A, Kursaklioglu H, et al. Comparative effects of nebivolol andmetoprolol on oxidative stress, insulin resistance, plasma adiponectin and solubleP-selectin levels in hypertensive patients. J Hypertens. 2006;24:591–6. [PubMed]5. Chamontin B, Poggi L, Lang T, et al. Prevalence, treatment, and control ofhypertension in the French population: Data from a survey on high blood pressurein general practice. Am J Hypertens. 1998;11:759–62. [PubMed]6. Cherchi A, Lai C, Pirisi R, Onnis E. Antianginal and anti-ischemic activity ofnebivolol in stable angina of effort. Drug Invest. 1991;3(Suppl 1):86–96.7. Cheymol G, Woestenborghs R, Snoeck E, et al. Pharmacokinetic study andcardiovascular monitoring of nebivolol in normal and obese subjects. Eur J ClinPharmacol. 1997;51:493–8. [PubMed]8. Chobanian AV, Bakris GL, Black HR, et al. National High Blood PressureEducation Program Coordinating Committee The seventh report of the JointNational Committee on Prevention, Detection, Evaluation, and Treatment of HighBlood Pressure: the JNC 7 report. JAMA. 2003;289:2560–72. [PubMed]
  9. 9. 9. Cockcroft JR, Chowienczyk PJ, Brett SE, et al. Nebivolol vasodilates humanforearm vasculature: evidence for an L-arginine/NO-dependent mechanism. JPharamcol Exp Ther. 1995;274:1067–71. [PubMed]10. Dawes M, Brett SE, Chowienczyk PJ, et al. The vasodilator action of nebivolol inforearm vasculature of subjects with essential hypertension. Br J Clin Pharmacol.1999;48:460–3. [PMC free article] [PubMed]11. Groot AA, Mathy MJ, van Zwieten PA, et al. Antioxidant activity of nebivolol inthe rat aorta. J Cardiovasc Pharmacol. 2004;43:148–53. [PubMed]12. Doumas M, Tsakiris A, Dourna S, et al. Beneficial effects of switching from β-blockers to nebivolol on the erectile function of hypertensive patients. Asian JAndrol. 2006;8:177–82. [PubMed]13. Evans WE, Relling MV, Rahman A, et al. Genetic basis for a lower prevalence ofdeficient CYP2D6 oxidative drug metabolism phenotypes in black Americans. JClin Invest. 1993;91:2150–4. [PMC free article] [PubMed]14. Flather MD, Shibata MC, Coats AJS, et al. the SENIORS InvestigatorsRandomized trial to determine the effect of nebivolol on mortality andcardiovascular hospital admission in elderly patients with heart failure(SENIORS) Eur Heart J. 2005;26:215–25. [PubMed]15. Gao Y, Nagao T, Bond RA, et al. Nebivolol induces endotheliumdependentrelaxations of canine coronary arteries. J Cardiovasc Pharmacol. 1991;17:964–9.[PubMed]16. Gu Z-M, Robinson RA, Cai L, et al. Metabolism Study Of 14C-Nebivolol InHumans With Different CYP2D6 Genotypes [online] [abstract] AAPS PharmSci.2003;5(4):T3362. Accessed 11 January 2006. URL: Ignarro LJ, Sisodia M, Trinh K, et al. Nebivolol inhibits vascular smooth musclecell proliferation by mechanisms involving nitric oxide but not cyclic GMP. NitricOxide. 2002;7:83–90. [PubMed]18. Joffres MR, Hamet P, MacLean DR, et al. Distribution of blood pressure andhypertension in Canada and the United States. Am J Hypertens. 2001;14:1099–105. [PubMed]19. Kamp O, Sieswerda GT, Visser CA. Comparison of effects on systolic anddiastolic left ventricular function of nebivolol versus atenolol in patients withuncomplicated essential hypertension. Am J Cardiol. 2003;92:344–8. [PubMed]20. Ko DT, Hebert PR, Coggey CS, et al. Beta-blocker therapy and symptoms ofdepression, fatigue, and sexual dysfunction. JAMA. 2002;288:351–7. [PubMed]21. Lacourcière Y, Poirier I, Boucher S, Spendar J. Comparative effects of diltiazemsustained-release formulation and metoprolol on ambulatory blood pressure andplasma lipoproteins. Clin Pharmacol Ther. 1990;48:318–24. [PubMed]22. Lacourcière Y, Poirer L, Lefebvre J, et al. Comparative effects of a newcardioselective beta-blocker nebivolol and nifedipine sustained-release on 24-hour ambulatory blood pressure and plasma lipoproteins. J Clin Pharmacol.1992;32:660–6. [PubMed]23. Lacourcière Y, van Neuten L, Binder C, et al. Evaluation of the safety ofnebivolol 5 mgo, d. in mild to moderate hypertensive subjects characterized as
  10. 10. poor metabolizers for debrisoquine, in comparison to extensive metabolizers.Janssen Research Foundation Clinical Research Report. 2000.24. Laurent S, Boutouyrie P, Asmar R, et al. Aortic stiffness is an independentpredictor of all-cause and cardiovascular mortality in hypertensive patients.Hypertension. 2001;37:1236–41. [PubMed]25. Mason RP, Kalinowski L, Jacob RF, et al. Nebivolol reduces nitroxidative stressand restores nitric oxide bioavailability in endothelium of black Americans.Circulation. 2005;12:3795–801. [PubMed]26. Mazza A, Gil-Extremera B, Maldonato A, et al. Nebivolol vs amlodipine as first-line treatment of essential arterial hypertension in the elderly. Blood Press.2002;11:182–8. [PubMed]27. McEniery CM, Schmitt M, Qasem A, et al. Nebivolol increases arterialdistensibility in vivo. Hypertension. 2004;44:305–10. [PubMed]28. McNeely W, Goa KL. Nebivolol in the management of essential hypertension: areview. Drugs. 1999;57:644–51. [PubMed]29. Mizutani T. PM frequencies of major CYPs in Asians and Caucasians. DrugMetab Rev. 2003;35:99–106. [PubMed]30. Pasini AF, Garbin U, Nava MC, et al. Nebivolol decreases oxidative stress inessential hypertensive patients and increases nitric oxide by reducing its oxidativeinactivation. J Hypertens. 2005;23:589–96. [PubMed]31. Psaty BN, Smith NL, Siscovick DS, et al. Health outcomes associated withantihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997;277:139–745. [PubMed]32. Relling MV, Cherrie J, Schell MJ, et al. Lower prevalence of the debrisoquinoxidative poor metabolizer phenotype in American black versus white subjects.Clin Pharmacol Ther. 1991;50:308–13. [PubMed]33. Ritter JM. Nebivolol: endothelium-mediated vasodilating effect. J CardiovascPharmacol. 2001;38(Suppl 3):S13–16. [PubMed]34. Rosei EA, Rizzoni D, Comini S, et al. the Nebivolol-Lisinopril Study GroupEvaluation of the efficacy and tolerability of nebivolol versus lisinopril in thetreatment of essential arterial hypertension: A randomized, multicenter, doubleblind study. Blood Press. 2003;12(suppl 1):30–5. [PubMed]35. Rousseau MF, Chapelle F, van Eyll C, et al. Medium-term effects of beta-blockade on left ventricular mechanics: a double-blind, placebocontrolledcomparison of nebivolol and atenolol in patients with ischemic left ventriculardysfunction. J Cardiac Failure. 1996;2:15–23. [PubMed]36. Shaw AA, Liu S, Zachwieja LF, et al. Effects of varying degrees of renalimpairment on the pharmacokinetic disposition of nebivolol. Clin PharmacolTher. 2005;77:P38.37. Shaw AA, Liu S, Tu HC, et al. Effects of hepatic impairment on thepharmacokinetic disposition of nebivolol: A dual acting nitric oxidemodulating/cardioselective beta1-antagonist. Clin Pharmacol Ther. 2005;77:P41.38. Simon G, Johnson ML. Comparison of antihypertensive and B1-adrenoreceptorantagonist effect of nebivolol and atenolol in essential hypertension. Clin ExperHypertens. 1993;15:501–9. [PubMed]
  11. 11. 39. Stoleru L, Wijns W, van Eyll C, et al. Effects of d-nebivolol and lnebivolol on leftventricular systolic and diastolic function: comparison with d-l-nebivolol andatenolol. J Cardiovasc Pharmacol. 1993;22:183–90. [PubMed]40. Taylor AL, Ziesche S, Yancy C, et al. the African-American Heart Failure TrialInvestigators Combination of isosorbide dinitrate and hydralazine in blacks withheart failure. N Engl J Med. 2004;351:2049–57. [PubMed]41. Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunctionin essential hypertension. A randomized, double-blind, crossover study.Circulation. 2001;104:511–14. [PubMed]42. Uhlir O, Fejfusa M, Havranek K, et al. Nebivolol versus metoprolol in thetreatment of hypertension. Drug Invest. 1991;3(Suppl 1):107–10.43. Ulvenstam G. A single-blind dose-ranging study of the effect of nebivolol inpatients with angina pectoris. Drug Invest. 1991;3(Suppl 1):199–200.44. Van Bortel LM, Bulpitt C, Fici F. Quality of life and antihypertensive effect withnebivolol and losartan. Am J Hypertens. 2005;18:1060–6. [PubMed]45. Van Nueten L, Dupont AG, Vertommen C, et al. A dose-response trial ofnebivolol in essential hypertension. J Human Hypertens. 1997;11:139–44.[PubMed]46. Van Nueten L, De Cree J. Nebivolol: Comparison of the effects of dl-nebivolol,d-nebivolol, l-nebivolol, atenolol, and placebo on exercise-induced increases inheart rate and systolic blood pressure. Cardiovasc Drugs Therapy. 1998;12:339–44. [PubMed]47. Van Nueten L, Taylor FR, Robertson JI. Nebivolol vs atenolol and placebo inessential hypertension: a double-blind randomized trial. J Human Hypertens.1998;12:135–40. [PubMed]48. Van Peer A, Snoeck E, Woestenborghs R, et al. Clinical pharmacokinetics ofnebivolol: a review. Drug Invest. 1991;3(Suppl 1):25–30.49. Van Rooy P, Van Nueten L, De Cree J. Nebivolol blood pressure reduction inrelation to beta blockade in healthy volunteers. Drug Invest. 1991;3(Suppl1):174–76.50. Weber MA. The role of new β-blockers in treating cardiovascular disease. Am JHypertens. 2005;18:169S–175S. [PubMed]51. Weiss RJ, Weber MA, Carr AA, et al. Nebivolol in the treatment of patients withstage 1 and stage 2 hypertension: Results of a randomized, double-blind, placebo-controlled study. Am J Hypertension. 2005;18:A96.--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Differential Effects of Nebivolol andMetoprolol on Central Aortic Pressureand Left Ventricular Wall Thickness
  12. 12. 1. Priit Kampus,2. Martin Serg,3. Jaak Kals,4. Maksim Zagura,5. Piibe Muda,6. Külliki Karu,7. Mihkel Zilmer,8. Jaan Eha+ Author Affiliations1. From the Department of Cardiology (P.K., M.S., M.Za., P.M., J.E.) andDepartment of Biochemistry, Centre of Excellence for Translational Medicine(P.K., M.S., J.K., M.Za., M.Zi.), University of Tartu, Tartu, Estonia; Heart Clinic(P.K., P.M., K.K., J.E.) and Clinic of Vascular Surgery (J.K.), Tartu UniversityHospital, Tartu, Estonia.1. Correspondence to Priit Kampus, Department of Cardiology, University of Tartu, 8Puusepa St, Tartu 51014, Estonia. E-mail Priit.Kampus@kliinikum.eeNext SectionAbstractThe aim of this study was to investigate the effects of the vasodilating β-blockernebivolol and the cardioselective β-blocker metoprolol succinate on aortic blood pressureand left ventricular wall thickness. We conducted a randomized, double-blind study on 80hypertensive patients. The patients received either 5 mg of nebivolol or 50 to 100 mg ofmetoprolol succinate daily for 1 year. Their heart rate, central and brachial bloodpressures, mean arterial pressure, augmentation index, carotid-femoral pulse wavevelocity, and left ventricular wall thickness were measured at baseline and at the end ofthe study. Nebivolol and metoprolol significantly reduced heart rate, brachial bloodpressure, and mean arterial pressure to the same degree. However, reductions in centralsystolic and diastolic blood pressures, central pulse pressure, and left ventricular wallthickness were significant only in the nebivolol group. The change in left ventricularseptal wall thickness was significantly correlated with central systolic blood pressurechange (r=0.41; P=0.001) and with central pulse pressure change (r=0.32; P=0.01). Nosignificant changes in augmentation index or carotid-femoral pulse wave velocity weredetected in either treatment group. This proof-of-principle study provides evidence tosuggest that β-blockers with vasodilating properties may offer advantages overconventional β-blockers in antihypertensive therapy; however, this remains to be tested ina larger trial.Key Words:
  13. 13. antihypertensive therapycentral blood pressurepulse wave velocityβ-blockersleft ventricular massSee Editorial Commentary, pp 1047–1048Blood pressure (BP) varies throughout the arterial tree because of pulse waveamplification, a phenomenon of wave reflection and arterial stiffness.1Because of pulsewave amplification, reduction in brachial BP does not reflect changes in central BP,which may become a more important target in the treatment of hypertension. Recent datafrom the Strong Heart Study2confirm earlier results from smaller studies on high-riskpatients3,4that central pulse pressure is superior to brachial pulse pressure in theprediction of further cardiovascular events. Moreover, several studies have demonstratedthat brachial BP is not a good surrogate for the hemodynamic effects of drug therapies oncentral circulation. The recently published EXPLOR Study5and the Conduit ArteryFunction Evaluation Study6clearly demonstrated that angiotensin-converting enzymeinhibitors, angiotensin receptor blockers, and calcium channel blockers have a morepronounced effect on reducing central BP compared with the cardioselective β-blocker(BB) atenolol. Different effects of BB on central BP can explain the findings of a recentmeta-analysis published by Law et al,7which demonstrates a slight inferiority of BB inpreventing stroke. The detrimental effect of BB on central BP has generated criticismregarding its use as first line therapy for essential hypertension. Dhakam et al8questionedthe hypothesis that the inferiority of atenolol in reducing central BP is a class effect ofBB. They demonstrated that the novel vasodilating BB nebivolol (NEB) reduces centralBP significantly more than atenolol, despite their similar effects on brachial BP.However, in the above-mentioned and other studies, the BB as the investigatedcomparison drug was in most cases atenolol. No data are available about metoprolol(MET), which is a more widely used cardioselective BB in the Northern and EasternEuropean countries.The main aim of the present study was to investigate the effect of the BB NEB and METsuccinate on central hemodynamics, arterial stiffness, and left ventricular wall thicknessin patients with essential hypertension during 1-year follow-up.Previous SectionNext SectionMethodsStudy DesignThe study participants, aged 30 to 65 years, with never-treated mild-to-moderate essentialhypertension, were included in a randomized, double-blind, active controlled trial(NCT01248338). The trial was investigator initiated and was driven and supported by
  14. 14. Berlin-Chemie AG (please see Figure S1 in the online Data Supplement at total of 80 patients were randomly assigned into 2 treatment groups receiving eitherNEB (Nebilet, dL-nebivolol hydrochloride, Berlin-Chemie AG) or MET (Betaloc zoc,MET succinate, Astra Zeneca). The NEB-treated patients received 5 mg of the drug daily,and the MET-treated patients started with 50 mg of the drug daily with possible up-titration to 100 mg daily 2 weeks after randomization. If the target BP of <140/90 mm Hgwas not achieved, the investigator was free to add 12.5 to 25 mg of hydrochlorothiazide(Hypothiazid, Chinon Pharmaceuticals and Chemical Works Private Co Ltd) daily 4weeks after randomization. The duration of the study was 52 weeks plus the screeningperiod of 2 weeks. The patients attended follow-up visits at weeks 2, 4, 12, 24, 40, and52. After 15 minutes of rest, BP was measured at each visit; pulse wave analysis andcarotid-femoral pulse wave velocity (PWV) registration were performed at baseline andat weeks 24 and 52. Echocardiography was performed at baseline and at the end of thestudy (please see Figure S2).Mild or moderate hypertension was defined as systolic BP 140 to 179 mm Hg and/ordiastolic BP 90 to 109 mm Hg on ≥2 occasions separated by 1 month. Patients wereexcluded during the screening period in case they had diabetes mellitus; adiposity;ischemic heart disease; clinically relevant heart failure; chronic pulmonary disease; valvedisease; arrhythmias; secondary hypertension; clinically relevant atherosclerotic diseaseof the lower extremities; acute or chronic inflammatory disease; hypercholesterolemia;known hypersensitivity or allergic reaction to BB; pregnancy or breastfeeding; history ofhepatic, renal, metabolic, or endocrine diseases; heavy smoking; and excessive alcoholconsumption (please see the online Data Supplement at subjects were studied and the plasma samples were collected between 8:00 and 10:00am after an overnight fast and abstinence from tobacco, alcohol, tea, or coffee. The studywas approved by the local research ethics committee, and written informed consent wasgiven by all of the subjects before the study.Measurements of HemodynamicsBrachial BPBrachial BP was measured in a sitting position from the nondominant arm as a mean of 3consecutive measurements at 5-minute intervals using a validated oscillometric technique(OMRON M4-I; Omron Healthcare Europe BV). The mean of the 2 closest BP readingswas used in further analysis. Brachial pulse pressure was calculated as the differencebetween brachial systolic BP and diastolic BP.Central Pressure and Augmentation IndexRadial artery waveforms were recorded with a high-fidelity micromanometer(applanation tonometry) from the wrist of the dominant arm, and pulse wave analysis was
  15. 15. performed of the systolic portion (SphygmoCor, version 7.1, AtCor Medical) of the pulsecurve in accordance with established guidelines.9The corresponding ascending aorticwaveforms were then generated, using a validated transfer function,9,10from whichcentral systolic and diastolic BPs, central pulse pressure, and augmentation index (AIx)were calculated. The AIx, a composite measure of wave reflection and systemic arterialstiffness, was defined as the difference between the second and the first systolic peaks ofthe central arterial waveform, expressed as the percentage of central pulse pressure.9Because AIx depends on heart rate (HR), it was corrected for a HR of 75 bpm(AIxHR75). Mean arterial pressure was calculated from the integration of the radialartery waveform. The degree of pulse pressure amplification was calculated as brachialpulse pressure/central pulse pressure.Carotid-Femoral PWVCarotid-femoral PWV, a direct measure of aortic stiffness, was determined by sequentialacquisition of pressure waveforms from the carotid and femoral arteries using the sametonometer (SphygmoCor, version 7.1, AtCor Medical). The timing of these waveformswas compared with that of the R wave on a simultaneously recorded ECG. The PWV wasdetermined by calculation of the difference between the carotid and the femoral pathlengths divided by the difference in the R wave to waveform foot times. The differencebetween the carotid and the femoral path lengths was estimated from the distance of thesternal notch to the femoral pulse measured in a direct line.9The pulse wave analysis andPWV measurements were made in duplicate, and their mean values were used insubsequent analysis.EchocardiographyEchocardiographic examination was performed by 2 experienced sonographers, whowere blinded to patient characteristics, using a commercially available device(Sonos7500, Philips Medical Systems, Inc) with a 3.5-MHz transducer and digitalrecording capabilities. The images were stored digitally, coded with a random number,and read by 2 blinded observers. Using the 2D and the M-mode, long-axis measurementswere obtained at the level distal to the mitral valve leaflets. Left ventricular internaldimension and septal and posterior wall thicknesses were measured at the end of thediastole (subscript “d”) according to the recommendations of the American Society ofEchocardiography.11Left ventricular mass was calculated using the following formula:0.8{1.04 [(LVIDd+PWTd+SWTd)3−(LVIDd)3]}+0.6 g, where LVIDd indicates leftventricular internal dimension, PWTd indicates posterior wall thickness, and SWTdindicates septal wall thickness. Left ventricular mass was indexed for the power of itsallometric or growth relation to height (height in meters2.7)12; this method was used toadjust for differences in body size. Relative wall thickness was calculated using theformula (2×PWTd)/LVIDd.11
  16. 16. Biochemical AnalysisWhite blood cell and red blood cell counts, hematocrit, hemoglobin, and platelets wereestimated with a Sysmex XE 2100 autoanalyzer (Sysmex Corporation). Plasma glucose,total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol,triglycerides, creatinine, and high-sensitivity C-reactive protein were determined bystandard laboratory methods, using certified assays, in a local clinical laboratory.Statistical AnalysisThe statistics were performed using the Software SAS, version 9.1 (SAS Institute Inc),and R ( All of the analyses were performed on an intention-to-treatbasis. All of the data were tested for normality. Normally distributed data are presented asmean±SD; nonnormally distributed data are presented as the median with theinterquartile range. For categorical variables, contingency tables were composed and theχ2or Fisher exact test, was used to compare the distributions for the 2 randomizedgroups. For continuous variables, which were not normally distributed for ≥1 group, theWilcoxon rank-sum test was used to test the difference between the groups. In othercases, the t test was used to test for difference. Changes from the baseline to the end pointwere also tested for the difference from 0 using the t test or the signed-rank test. The 2-way ANOVA with repeated measures was used to test the interaction between time anddrug, as well as error (drug × time). Correlations between the variables were examinedusing univariate linear regression analysis. Multivariate regression analysis wasperformed using enter method to determine whether the change in baseline factorsinfluenced the change in hemodynamic parameters. Significance was defined as P<0.05.Previous SectionNext SectionResultsThe baseline characteristics of the untreated hypertensive subjects are presented in Table1. Before randomization there were no statistically significant differences in thedemographic and clinical characteristics between the treatment groups. A total of 40patients (50%) were enrolled in the NEB arm, and 40 (50%) were enrolled in the METarm. Of the 80 patients enrolled, 63 (79%) completed the study. Seventeen patients werewithdrawn from the study for various reasons (please see the online Data Supplement).View this table:In this windowIn a new windowTable 1.Baseline Characteristics
  17. 17. Up-titration of MET to 100 mg was performed for 13 patients (32%). During thetreatment period, 30.0% of the patients (12 subjects) in the NEB group and 22.5% of thepatients (9 subjects) in the MET group (P=0.5) received an additional 12.5 to 25 mg ofhydrochlorothiazide.The hemodynamic indices for each treatment group before and after 1 year of therapy arepresented in Table 2. Brachial and central systolic or diastolic BP were not different forthe groups at baseline. The AIx, AIxHR75, and central pulse pressure were significantlyhigher in the NEB group at baseline.View this table:In this windowIn a new windowTable 2.Hemodynamic Indices and Left Ventricular Wall Thickness Before and After the 1-YearTreatment PeriodBoth drugs significantly reduced HR, brachial systolic and diastolic BP, and mean arterialpressure (Table 2), without differences between the groups (Figure 1). However, only thepatients of the NEB treatment group showed significantly decreased brachial pulsepressure (P=0.02). The reduction in central systolic BP, central diastolic BP (Figure 2),and central pulse pressure was significant only in the NEB group. At the same time, theseparameters did not display significant changes in the MET group (Table 2). Meanreduction in central pulse pressure was 6.2 mm Hg in the NEB group and 0.3 mm Hg inthe MET group (P=0.01). Pulse pressure amplification did not change during thetreatment period in either treatment arm.View larger version:In this pageIn a new windowDownload as PowerPoint Slide
  18. 18. Figure 1.Mean reduction in brachial systolic and diastolic blood pressures measured during thestudy period. Both treatment groups display significantly reduced brachial systolic anddiastolic blood pressures (P<0.001) during 52 weeks of treatment, without differencebetween the treatment arms. ■ indicates nebivolol; -●-, metoprolol; S, screening period;BP, blood pressure.View larger version:In this pageIn a new windowDownload as PowerPoint SlideFigure 2.Mean reduction in central systolic and diastolic blood pressures measured at baseline andat weeks 24 and 52. Only the nebivolol group displays significantly reduced centralsystolic (P<0.001) and diastolic blood pressures (P=0.01) after 52 weeks of treatmentcompared with baseline values. ■ indicates nebivolol; -●-, metoprolol; BP, bloodpressure.The AIxHR75 (22.88±11.89% to 18.60±11.25%; P=0.02) and PWV (7.5±1.51 to6.80±1.17 m/s; P=0.03) were significantly decreased after 6 months of treatment only inthe NEB group. However, no significant change was detected in AIx, AIxHR75, or PWVafter the 1-year treatment period for either treatment group (Table 2). There was a trendfor correlation (not significant) between the HR change and the AIx change for the wholestudy group (r=−0.24; P=0.06). However, the correlation was significant only for theNEB treatment arm (r=−0.40; P=0.03).There occurred significant reduction in left ventricular posterior wall thickness and leftventricular relative wall thickness, as well as a trend for reduction in left ventricularseptal wall thickness and indexed left ventricular mass compared with the baseline valuesonly for the NEB group (Table 2). Moreover, changes in septal wall thickness were moresignificantly correlated with changes in central systolic BP (r=0.41; P=0.001) and with
  19. 19. changes in central pulse pressure (r=0.32; P=0.01; Figure 3) compared with changes inbrachial BP values (r=0.32, P=0.01 and r=0.26, P=0.04, respectively). Multipleregression analysis showed that only changes in central systolic BP (P=0.009) wereindependently correlated with changes in septal wall thickness as the dependent variablebut not with medication used, body mass index, changes in mean arterial pressure, orchanges in heart rate (R2for model=0.2; P<0.01). Finally, no correlation was revealedbetween changes in brachial systolic BP and changes in septal wall thickness afteradjustment for changes in mean arterial pressure in multiple regression analysis.View larger version:In this pageIn a new windowDownload as PowerPoint SlideFigure 3.A, Correlation between central systolic blood pressure change and IVS thickness change(r=0.41; P=0.001) for the whole study group. B, Correlation between central pulsepressure change and IVS thickness change (r=0.32; P=0.01) for the whole study group.IVS indicates interventricular septal thickness; BP, blood pressure.Previous SectionNext SectionDiscussionThe aim of the present study was to investigate the effects of NEB and MET on centralhemodynamics in patients with essential hypertension during a 1-year treatment period.The main findings were that both drugs reduced similarly brachial systolic and diastolicBP; however, only the patients receiving NEB showed a significant reduction in centralBP. The decrease in central BP was correlated with degree of reduction in left ventricularwall thickness. At the same time, neither drug had an effect on AIx, AIxHR75, or PWVafter the 1-year treatment period.
  20. 20. BB and Reduction in Central Aortic PressureThe results of the present study generally indicate that the novel third generation BBNEB significantly reduces central BP. However, it is the first attempt to explore theeffects of the cardioselective BB MET on central BP. The results of the study confirmthat BB without vasodilating properties have less impact on central BP. Two short-termstudies (4 to 5 weeks) reported that NEB had a significantly greater effect on centralpulse pressure compared with the cardioselective BB atenolol.8,13Dhakam et al8in theirstudy demonstrated that overall aortic pulse pressure was 4 mm Hg lower after NEBtherapy than after atenolol therapy.8Moreover, the results from the Conduit ArteryFunction Evaluation Study6indicate that even a 3-mm Hg reduction in central pulsepressure was associated with better cardiovascular outcome. In the present study, theeffect of BB was tested during a 1-year period. Overall central pulse pressure reductionwas 6.2 mm Hg in the NEB group and only 0.3 mm Hg in the MET group. The recentlypublished EXPLOR Study5demonstrated that treatment with the calcium channel blockeramlodipine combined with the cardioselective BB atenolol during 24 weeks had lessimpact on central BP than amlodipine combined with valsartan (the difference inreducing central systolic BP was also 4 mm Hg). The authors concluded that the additionof amlodipine to atenolol did not abolish the adverse effect of cardioselective BB oncentral BP through bradycardia and changes at reflection sites. In the present study bothtreatment arms similarly reduced HR and mean arterial pressure. It could be suggestedthat the main mechanism for the reduction in central BP in the nebivolol arm actedthrough vasodilation and structural remodeling of the small arteries, leading to thereduction in reflection site intensity. It has been demonstrated that nebivolol vasodilatesthe human forearm vasculature through the l-arginine pathway,14improves small arterydistensibility index, and increases endothelium-dependent cutaneous vasodilation.15Atthe same time, cardioselective BB do not reduce total peripheral resistance orsympathetic activity,16which may lead to small artery vasoconstriction and increasedmedia:lumen ratio.17The AIx and pulse pressure amplification are related to wave reflection depending on theamplitude and site of wave reflection and on the speed at which pressure waves travelalong the arterial tree. In the present study, AIx and pulse pressure amplification did notchange during the 1-year treatment period in either treatment arm. Previous data aboutthe effect of NEB on AIx and pulse pressure amplification have been conflicting. Inpatients with isolated systolic hypertension, Dhakam et al8showed a slight increase ofAIx and no effect on pulse pressure amplification after 5 weeks of treatment with NEB.On the contrary, Mahmud and Feely13demonstrated, after treatment with NEB, asignificant reduction in AIx and an increase in pulse pressure amplification in patientswith essential hypertension. In the above studies, pulse pressure amplification and AIxwere found to be very strongly correlated with HR change, which could explain thedescribed controversial results. The present study also revealed a trend for correlation,although not significant, between HR change and AIx change for the whole study group.Moreover, the correlation was significant only for the NEB treatment arm. No correlationwas detected between central pulse pressure change and HR change, which may suggestthat more intensive central BP reduction in the NEB-treated patients appeared to be a
  21. 21. concomitant effect of HR and AIx change and reduction in peripheral vascular resistancerather than PWV change. It should be noted that there was already a difference inbaseline AIx and that the reduction in HR was not sufficient to produce significant AIxchange after 1-year therapy.The PWV is considered a gold standard measure of arterial stiffness,9whichindependently predicts outcome in hypertensive patients.18In the present study, thereoccurred a significant reduction in PWV after 6 months of treatment in the NEB group.However, after the 1-year treatment period there was no significant difference in thechange in PWV, radial-carotid PWV (data not shown), or pulse wave transit timebetween the 2 treatment arms. Previous studies have demonstrated a significant reductionin PWV after treatment with NEB.8,13It has been suggested that the effect of BB on PWVmay be related to the concomitant effect of reduction in mean arterial pressure,sympathetic tone, and HR. Consequently, one possible explanation for the nonsignificantchange in PWV in the present study is also the significantly smaller reduction in HRduring the 1-year treatment period (≈6 bpm). It should be noted that previous studieswere of short duration, and long-term use of BB may not have such a significant effect onHR and sympathetic activity, which are considered important determinants of PWV. Thetime-dependent effect of BB on vascular stiffness was also suggested in a recent reviewby Protogerou et al.19Another possibility is that, in the present study, baseline meanPWV was in the normal range. Also, because of the very strict inclusion criteria of thepresent study, the patients were at low total cardiovascular risk, which may also explainthe weak effect of treatment on PWV.BB and Left Ventricular Mass ReductionThe present study provides the first long-term evidence that the reduction in centralsystolic BP in the NEB group was directly related to the reduction in left ventricularseptal and posterior wall thicknesses. It has been demonstrated previously that, comparedwith brachial BP, central BP is a stronger determinant for left ventricular hypertrophy.20Recent data from the Strong Heart Study also indicate that, in terms of reduction in leftventricular hypertrophy, it is more important to target central systolic than brachial BP.21Moreover, a recent study has shown that the BB atenolol was less effective than losartanto reduce left ventricular hypertrophy,22despite the fact that both drugs reduced brachialBP to a similar degree. In a small open study, NEB monotherapy ≤12 months resulted ina reduction in left ventricular wall thickness,23and NEB was as effective as telmisartan inreducing left ventricular mass after 3 months of treatment.24However, a recent meta-analysis provides evidence that BBs show less regression of left ventricular masscompared with other antihypertensive drugs.25Regrettably, the results of 20 of thereviewed 31 studies were obtained with atenolol, the results of 3 studies with MET, andthe results of only 1 study with NEB. One plausible explanation for the lesser regressionof left ventricular hypertrophy by BB in the above meta-analysis is that central BP maynot be reduced as effectively as brachial BP, which ensures less afterload reduction witha cardioselective BB without vasodilating properties. Moreover, the failure to reducecentral BP with conventional BB was probably also the main reason for the inferiority ofBB in preventing stroke in a recent meta-analysis by Law et al.7Regarding the
  22. 22. diabetogenic role of BB and diuretics,26there was no change in fasting plasma glucoseafter the 1-year treatment period in either group, because we excluded patientspredisposed to diabetes mellitus (eg, those with metabolic syndrome or with increasedfasting glucose level).LimitationsThe current study has several limitations. The number of patients recruited in the studywas small. When this study was designed in 2005, there were no studies of appropriatesize providing the data about the effect of antihypertensive drugs on aortic pressurederived from applanation tonometry to undertake formal power calculation; larger studiesare therefore needed to confirm our results. Also, 17 of the 80 study patients werewithdrawn, which is quite a high proportion. The main reason for poor treatmentcompliance was that the study patients were relatively young, with newly diagnosedmild-to-moderate hypertension, who did not have any symptoms or complaints attributedto high BP. In the case of mild adverse events after the initiation of treatment, they tendedto withdraw their consent.Also, the inclusion criteria of the study were very strict, and the patients were at lowcardiovascular risk, which may explain the relatively normal mean values of centralhemodynamics and account for the disparity between several studied parameters andthose used in other studies. Although both study groups were comparable with regard tobrachial pressure, there occurred a shift in central hemodynamics (AIx and central PP) atbaseline.We cannot exclude an additional effect of the thiazide diuretic on the results. It has beenproposed that diuretics have a neutral or minimal beneficial effect on central BP, aorticstiffness, and pressure wave reflection.19,27PerspectivesOur study expands earlier observations of BB and shows that, despite the similar effect ofboth drugs on brachial BP and arterial stiffness, NEB has a more significant impact oncentral BP and left ventricular wall thickness than MET. This proof-of-principle studyprovides evidence to suggest that BB with vasodilating properties may offer advantagesover conventional BB in reduction of target organ damage in antihypertensive therapy;however, this remains to be tested in a larger trial. Moreover, noninvasive assessment ofcentral BP change might become a good surrogate for estimating reduction in leftventricular wall thickness in the future.Previous SectionNext SectionSources of Funding
  23. 23. This study is an independent, investigator-initiated trial supported by the Berlin-ChemieAG Menarini Group, by the Estonian Scientific Foundation (grants 7480 and 8273), andby target financing grants 0180105s08 and SF0180001s07.Previous SectionNext SectionDisclosuresNone.Previous SectionNext SectionAcknowledgmentsWe acknowledge the invaluable support of the physicians who conducted the clinical trial(Drs Kristina Lotamõis and Ingmar Lindström), the study nurse (Eva-Brit Mölder), andthe statistician (Mart Kals) for their important contributions. Also, we thank all of thepatients who participated in the study.Previous SectionNext SectionFootnotesContinuing medical education (CME) credit is available for this article. Go to to take the quiz.Received April 30, 2010.Revision received May 22, 2010.Accepted April 7, 2011.© 2011 American Heart Association, Inc.Previous SectionReferences1. 1.↵1. NicholsWW,2. ORourkeMF. McDonalds Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles. 5thed.London, United Kingdom: Arnold; 2005.
  24. 24. Search Google Scholar2. 2.↵1. RomanMJ,2. DevereuxRB,3. KizerJR,4. OkinPM,5. LeeET,6. WangW,7. UmansJG,8. CalhounD,9. HowardBV. High central pulse pressure is independently associated with adverse cardiovascularoutcome the Strong Heart Study. J Am Coll Cardiol. 2009; 54: 1730– 1734.Abstract/FREE Full Text3. 3.↵1. SafarME,2. BlacherJ,3. PannierB,4. GuerinAP,5. MarchaisSJ,6. GuyonvarchPM,7. LondonGM. Central pulse pressure and mortality in end-stage renal disease. Hypertension. 2002;39: 735– 738.Abstract/FREE Full Text4. 4.↵1. ChirinosJA,2. ZambranoJP,3. ChakkoS,4. VeeraniA,5. SchobA,6. PerezG,7. Mendez. Relation between ascending aortic pressures and outcomes in patients withangiographically demonstrated coronary artery disease. Am J Cardiol. 2005; 96: 645–648.CrossRefMedline
  25. 25. 5. 5.↵1. BoutouyrieP,2. AchoubaA,3. TrunetP,4. LaurentS. Amlodipine-valsartan combination decreases central systolic blood pressure moreeffectively than the amlodipine-atenolol combination: the EXPLOR Study. Hypertension.2010; 55: 1314– 1322.Abstract/FREE Full Text6. 6.↵1. WilliamsB,2. LacyPS,3. ThomSM,4. CruickshankK,5. StantonA,6. CollierD,7. HughesAD,8. ThurstonH,9. ORourkeM. Differential impact of blood pressure-lowering drugs on central aortic pressure andclinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE)Study. Circulation. 2006; 113: 1213– 1225.Abstract/FREE Full Text7. 7.↵1. LawMR,2. MorrisJK,3. WaldNJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospectiveepidemiological studies. BMJ. 2009; 338: 1665– 1683.CrossRef8. 8.↵1. DhakamZ,2. Yasmin,3. McEnieryCM,4. BurtonT,5. BrownMJ,
  26. 26. 6. WilkinsonIB. A comparison of atenolol and nebivolol in isolated systolic hypertension. J Hypertens.2008; 26: 351– 356.CrossRefMedline9. 9.↵1. LaurentS,2. CockcroftJ,3. Van BortelL,4. BoutouyrieP,5. GiannattasioC,6. HayozD,7. PannierB,8. VlachopoulosC,9. WilkinsonI,10. Struijker-BoudierH. Expert consensus document on arterial stiffness: methodological issues and clinicalapplications. Eur Heart J. 2006; 27: 2588– 2605.Abstract/FREE Full Text10. 10.↵1. PaucaAL,2. ORourkeMF,3. KonND. Prospective evaluation of a method for estimating ascending aortic pressure from theradial artery pressure waveform. Hypertension. 2001; 38: 932– 937.Abstract/FREE Full Text11. 11.↵1. LangRM,2. BierigM,3. DevereuxRB,4. FlachskampfFA,5. FosterE,6. PellikkaPA,7. PicardMH,8. RomanMJ,9. SewardJ,10. ShanewiseJS,11. SolomonSD,
  27. 27. 12. SpencerKT,13. SuttonMS,14. StewartWJ. Recommendations for chamber quantification: a report from the American Society ofEchocardiographys Guidelines and Standards Committee and the ChamberQuantification Writing Group, developed in conjunction with the European Association ofEchocardiography, a branch of the European Society of Cardiology. J Am SocEchocardiog. 2005; 18: 1440– 1463.CrossRefMedline12. 12.↵1. de SimoneG,2. DanielsSR,3. DevereuxRB,4. MeyerRA,5. RomanMJ,6. de DivitiisO,7. AldermanMH. Left ventricular mass and body size in normotensive children and adults: assessment ofallometric relations and impact of overweight. J Am Coll Cardiol. 1992; 20: 1251– 1260.Abstract13. 13.↵1. MahmudA,2. FeelyJ. β-Blockers reduce aortic stiffness in hypertension but nebivolol, not atenolol, reduceswave reflection. Am J Hypertens. 2008; 21: 663– 667.CrossRefMedline14. 14.↵1. CockcroftJR,2. ChowienczykPJ,3. BrettSE,4. ChenCP,5. DupontAG,6. Van NuetenL,7. WoodingSJ,8. RitterJM
  28. 28. . Nebivolol vasodilates human forearm vasculature: evidence for an l-arginine/NO-dependent mechanism. J Pharmacol Exp Ther. 1995; 274: 1067– 1071.Abstract/FREE Full Text15. 15.↵1. ArosioE,2. De MarchiS,3. PriorM,4. ZannoniM,5. LechiA. Effects of nebivolol and atenolol on small arteries and microcirculatory endothelium-dependent dilation in hypertensive patients undergoing isometric stress. J Hypertens.2002; 20: 1793– 1797.CrossRefMedline16. 16.↵1. BurnsJ,2. MaryDA,3. MackintoshAF,4. BallSG,5. GreenwoodJP. Arterial pressure lowering effect of chronic atenolol therapy in hypertension andvasoconstrictor sympathetic drive. Hypertension. 2004; 44: 454– 458.Abstract/FREE Full Text17. 17.↵1. SchiffrinEL. Remodeling of resistance arteries in essential hypertension and effects ofantihypertensive treatment. Am J Hypertens. 2004; 17: 1192– 1200.CrossRefMedline18. 18.↵1. BoutouyrieP,2. TropeanoAI,3. AsmarR,4. GautierI,5. BenetosA,6. LacolleyP,
  29. 29. 7. LaurentS. Aortic stiffness is an independent predictor of primary coronary events in hypertensivepatients: a longitudinal study. Hypertension. 2002; 39: 10– 15.Abstract/FREE Full Text19. 19.↵1. ProtogerouAD,2. StergiouGS,3. VlachopoulosC,4. BlacherJ,5. AchimastosA. The effect of antihypertensive drugs on central blood pressure beyond peripheral bloodpressure: part II–evidence for specific class-effects of antihypertensive drugs on pressureamplification. Curr Pharm Des. 2009; 15: 272– 289.CrossRefMedline20. 20.↵1. RomanMJ,2. DevereuxRB,3. KizerJR,4. LeeET,5. GallowayJM,6. AliT,7. UmansJG,8. HowardBV. Central pressure more strongly relates to vascular disease and outcome than doesbrachial pressure: the Strong Heart Study. Hypertension. 2007; 50: 197– 203.Abstract/FREE Full Text21. 21.↵1. RomanMJ,2. OkinPM,3. KizerJR,4. LeeET,5. HowardBV,6. DevereuxRB. Relations of central and brachial blood pressure to left ventricular hypertrophy andgeometry: the Strong Heart Study. J Hypertens. 2010; 28: 384– 388.
  30. 30. CrossRefMedline22. 22.↵1. DevereuxRB,2. DahlöfB,3. GerdtsE,4. BomanK,5. NieminenMS,6. PapademetriouV,7. RokkedalJ,8. HarrisKE,9. EdelmanJM,10. WachtellK. Regression of hypertensive left ventricular hypertrophy by losartan compared withatenolol: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Trial.Circulation. 2004; 110: 1456– 1462.Abstract/FREE Full Text23. 23.↵1. LiuGS,2. WangLY,3. NuetenLV,4. OomsLA,5. BorgersM,6. JanssenPA. The effect of nebivolol on left ventricular hypertrophy in hypertension. Cardiovasc DrugsTher. 1999; 13: 549– 551.CrossRefMedline24. 24.↵1. FountoulakiK,2. DimopoulosV,3. GiannakoulisJ,4. ZintzarasE,5. TriposkiadisF. Left ventricular mass and mechanics in mild-to-moderate hypertension: effect ofnebivolol versus telmisartan. Am J Hypertens. 2005; 18: 171– 177.CrossRefMedline25. 25.↵
  31. 31. 1. FagardRH,2. CelisH,3. ThijsL,4. WoutersS. Regression of left ventricular mass by antihypertensive treatment: a meta-analysis ofrandomized comparative studies. Hypertension. 2009; 54: 1084– 1091.Abstract/FREE Full Text26. 26.↵1. ElliottWJ,2. MeyerPM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis.Lancet. 2007; 369: 201– 207.CrossRefMedline27. 27.↵1. MatsuiY,2. EguchiK,3. ORourkeMF,4. IshikawaJ,5. MiyashitaH,6. ShimadaK,7. KarioK. Differential effects between a calcium channel blocker and a diuretic when used incombination with angiotensin II receptor blocker on central aortic pressure inhypertensive patients. Hypertension. 2009; 54: 716– 723.Abstract/FREE Full TextCiteULikeDeliciousDiggFacebookGoogle+MendeleyRedditStumbleUponTwitterWhats this?
  32. 32. Related ArticlesRate-Limiting Step: Can Different Effects of Antihypertensives on Central Blood PressureBe Translated Into Outcomes?o Laurie A. Tomlinson,o Viknesh Selvarajah,o and Ian B. WilkinsonHypertension.2011;57:1047-1048, published online before print May 2 2011,doi:10.1161/HYPERTENSIONAHA.111.172908o Extracto Freeo Full Texto PDFArticles citing this articleThe Effects of Acute Beta-Adrenergic Blockade on Aortic Wave Reflection inPostmenopausal Women Am J Hypertens.2013;0:hps074v1-hps074,o Abstracto Full Texto PDFAcute {beta}-Adrenergic Blockade Increases Aortic Wave Reflection in Young Men andWomen: Differing Mechanisms Between Sexes Hypertension.2012;59:145-150,o Abstracto Full Texto PDFRate-Limiting Step: Can Different Effects of Antihypertensives on Central Blood PressureBe Translated Into Outcomes? Hypertension.2011;57:1047-1048,o Full Texto PDFComparison of the Effects of Nebivololand Bisoprolol on Systemic VascularResistance in Patients with EssentialHypertension: -Blockade andHaemodynamics in Hypertension
  33. 33. Authors: Brett S.1; Forte P.2; Chowienczyk P.1; Benjamin N.2; Ritter J.1Source:Clinical Drug Investigation, Volume 22, Number 6, 1 June 2002 , pp. 355-359(5)Publisher: Adis International< previous article|view table of contents|next article >Buy & download fulltext article:ORPrice: $62.95 plus tax (Refund Policy)Abstract:Objective: To compare the haemodynamic effects of nebivolol, a highly selective antagonist of-adrenergic receptors with additional actions caused via the L-arginine/nitric oxide pathway,with those of bisoprolol, another selective -adrenergic receptor antagonist.Patients and methods: The study had a double-blind, randomised, crossover design, and wasperformed in an outpatient setting. Study participants comprised 15 patients (11 men, fourwomen, aged 29 to 69 years) with uncomplicated mild essential hypertension. Patients wererandomised to receive nebivolol (5mg orally daily) or bisoprolol (10mg orally daily) for 2 weeks,followed by a 2-week washout and 2 weeks of the other treatment. Measurements (by mercurysphygmomanometer and bioimpedance) were made at the end of each baseline and each activetreatment period.Results: Mean heart rate fell during active treatment (from 65 ± 2 to 53 ± 3 beats/min duringbisoprolol, p < 0.05, and from 64 ± 3 to 59 ± 3 beats/min during nebivolol). Systolic/diastolicblood pressure fell during active treatments to a similar extent with each treatment (bisoprolol:143 ± 3/90 ± 2mm Hg to 127 ± 3/80 ± 2mm Hg; nebivolol: 144 ± 4/92 ± 2mm Hg to 131 ± 4/83 ±
  34. 34. 3mm Hg; each p < 0.01). In contrast, the systemic vascular resistance index fell during nebivolol(from 2854 ± 201 to 2646 ± 186 dyn•sec•cm5•m, p < 0.05), but did not change significantlyduring bisoprolol treatment (baseline 2848 ± 177, with treatment 2787 ± 159 dyn•sec•cm5•m).Conclusion: The fall in systemic vascular resistance index during nebivolol (but not bisoprolol)treatment can be explained on the basis of a systemic vasodilator action of nebivolol. Theclinical importance of this action requires further investigation.Keywords:Antihypertensives, pharmacodynamics; Bisoprolol, pharmacodynamics;Nebivolol, pharmacodynamicsDocument Type: Original articleAffiliations:1: Department of Clinical Pharmacology, Centre for Cardiovascular Biologyand Medicine,St Thomass Hospital, London, UK 2: Department of ClinicalPharmacology, St Bartholomews Hospital, London, UKPublication date: 2002-06-01Comparison of the new cardioselectivebeta-blocker nebivolol with bisoprolol inhypertension: the Nebivolol, BisoprololMulticenter Study (NEBIS).Czuriga I, Riecansky I, Bodnar J, Fulop T, Kruzsicz V, Kristof E, Edes I; NEBIS Investigators; NEBISInvestigators Group.SourceDepartment of Cardiology, University of Debrecen, Hungary.AbstractOBJECTIVES:The aim of the present study was to evaluate the antihypertensive efficacy of the highlybeta(1)-selective adrenergic antagonist nebivolol in comparison with bisoprolol in thetreatment of mild to moderate essential hypertension.
  35. 35. METHODS:This multicenter, single-blind, randomized, parallel-group 16-week study involved a 4-week placebo run-in, followed by a 12-week treatment period (5 mg nebivolol or 5 mgbisoprolol). Patients (n = 273) eligible for the study had a sitting diastolic blood pressure(DBP) between 95 and 110 mm Hg and a systolic blood pressure (SBP) </=180 mm Hgat the end of the placebo run-in period. The primary endpoint of the study was thepercentage of responders achieving DBP normalization (</=90 mm Hg) or a DBPreduction of at least 10 mm Hg.RESULTS:The baseline SBP and DBP were similar in the two groups. Both SBP and DBP decreasedgradually and significantly upon treatment. The two treatments had similar effects on themean change from the baseline for both DBP (nebivolol -15.7 +/- 6.4 mm Hg vs.bisoprolol -16.0 +/- 6.8 mm Hg) and SBP. A high proportion of responders was noted inboth groups (nebivolol 92.0% vs. bisoprolol 89.6%) and there was no significantdifference between the treatments. The overall number and incidence of spontaneouslyreported adverse events were slightly, but not significantly lower for nebivolol (8 events;5.8%) than for bisoprolol (12 events; 8.9%).CONCLUSIONS:The findings of the present trial indicate that 5 mg nebivolol once daily is an effectiveantihypertensive agent. It can therefore be recommended as a useful alternative first-linetreatment option for the management of patients with mild to moderate essentialhypertension.PMID:14574084[PubMed - indexed for MEDLINE]Nebivolol Versus Metoprolol:Comparative Effects on Fatigue andQuality of LifeThis study has been completed.Sponsor:Weill Medical College of Cornell UniversityCollaborator:Forest Laboratories
  36. 36. Information provided by:Weill Medical College of Cornell Identifier:NCT00999102First received: October 20, 2009Last updated: March 16, 2012Last verified: March 2012History of ChangesFull Text ViewTabular ViewNo Study Results PostedDisclaimerHow to Read a Study RecordPurposeBeta-blockers are prescribed to millions of people for treatment of hypertension. Fatigueis a recognized and common side effect of beta-blockers that can have significant effectson quality of life. Worse, many people taking a beta-blocker for years are not even awareof the reduction of energy with which they are living.A new vasodilating beta-blocker, nebivolol, which is approved by the FDA for treatmentof hypertension, appears to be far less associated with fatigue than are most currentlyavailable beta-blockers. The purpose of this study is to compare nebivolol with thecurrent best-selling beta-blocker, metoprolol, and determine whether there is a significantdifference in side effects including fatigue, reduced exertion tolerance, and reducedquality of life.In this study, 30 subjects will take each of the 2 study drugs for 8 weeks, consisting of 4weeks at a lower dose, and 4 weeks ata higher dose. All dosages are FDA-approved fortreatment of hypertension. Subjects and investigators will not know which drug is beingadministered until completion of the study. Subjects will undergo a treadmill stress testand will complete fatigue and quality of life questionnaires after each 4 weeks oftreatment. An echocardiogram and non-invasive measurement of aortic blood pressurewill be performed after 8 weeks on each drug. Also, blood will be drawn and stored forpossible measurement of drug levels, after 4 and 8 weeks on each drug. Results on eachdrug will then be compared. If nebivolol is found to cause significantly less fatigue, itwould be of substantial importance to the many millions of people who are on life-longbeta-blocker therapy, and are living with reduced energy.Condition Intervention PhaseHypertension Drug: MetoprololDrug: NebivololPhase 4
  37. 37. Study Type: InterventionalStudyDesign:Allocation: RandomizedEndpoint Classification: Pharmacodynamics StudyIntervention Model: Crossover AssignmentMasking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)Primary Purpose: Supportive CareOfficialTitle:Nebivolol Vs. Metoprolol: Comparative Effects on Fatigue and Qualityof LifeResource links provided by NLM:MedlinePlus related topics: Blood Pressure MedicinesFatigueHigh Blood PressureDrug Information available for:Succinic acidMetoprololMetoprolol tartrateMetoprolol succinateNebivololMetoprolol fumarateNebivolol HydrochlorideU.S. FDA ResourcesFurther study details as provided by Weill Medical College of Cornell University:Primary Outcome Measures:To determine whether fatigue scores differ during treatment with nebivolol versusmetoprolol succinate [ Time Frame: Baseline, 4 weeks, 8 weeks, 12 weeks, 16weeks ] [ Designated as safety issue: No ]To determine whether treadmill exercise time differs during treatment withnebivolol versus metoprolol succinate [ Time Frame: Baseline, 4 weeks, 8 weeks,12 weeks, 16 weeks ] [ Designated as safety issue: No ]Enrollment: 37Study Start Date: October 2009Study Completion Date: January 2011Primary Completion Date: January 2011 (Final data collection date for primaryoutcome measure)Arms Assigned Interventions
  38. 38. Active Comparator: Nebivolol thenMetoprololNebivolol will be given at a dose of 5 mgand 10mg daily. After 8 weeks,participants will then be given metoprololsuccinate will be given at a dose of 50 mgdaily for 4 weeks, then 100 mg daily for 4weeks.Identical-appearing pills will begiven, and the drugs will be given inrandomized order without a placebo run-in. At the end of each 4-week treatmentperiod on each drug, subjects will undergoa treadmill stress test (using the standardCornell protocol), complete Quality ofLife and fatigue questionnaires, and haveblood drawn and frozen for later analysisfor drug levels.At the end of 8 weeks of treatment on eachdrug, subjects will undergoechocardiography and applanationtonometry (non-invasive measurement ofaortic blood pressure) to assess heartfunction.Drug: MetoprololComparison of Metoprolol and Nebivolol.Metoprolol succinate will be given at a doseof 50 mg daily for 4 weeks, then 100 mgdaily for 4 weeks. For nebivolol, dosage willbe 5 mg and 10mg daily. Identical-appearingpills will be given, and the drugs will begiven in randomized order without a placeborun-in.Other Names:LopressorToprol-XLDrug: NebivololComparison of Metoprolol and Nebivolol.Metoprolol succinate will be given at a doseof 50 mg daily for 4 weeks, then 100 mgdaily for 4 weeks. For nebivolol, dosage willbe 5 mg and 10mg daily. Identical-appearingpills will be given, and the drugs will begiven in randomized order without a placeborun-in.Other Name: BystolicActive Comparator: Metoprolol thenNebivololMetoprolol succinate will be given at adose of 50 mg daily for 4 weeks, then 100mg daily for 4 weeks. After 8 weeks, theparticipants will take nebivolol, dosagewill be 5 mg and 10mg daily. Identical-appearing pills will be given, and thedrugs will be given in randomized orderwithout a placebo run-in. At the end ofeach 4-week treatment period on eachdrug, subjects will undergo a treadmillstress test (using the standard Cornellprotocol), complete Quality of Life andfatigue questionnaires, and have blooddrawn and frozen for later analysis fordrug levels.At the end of 8 weeks of treatment on eachdrug, subjects will undergoechocardiography and applanationtonometry (non-invasive measurement ofDrug: MetoprololComparison of Metoprolol and Nebivolol.Metoprolol succinate will be given at a doseof 50 mg daily for 4 weeks, then 100 mgdaily for 4 weeks. For nebivolol, dosage willbe 5 mg and 10mg daily. Identical-appearingpills will be given, and the drugs will begiven in randomized order without a placeborun-in.Other Names:LopressorToprol-XLDrug: NebivololComparison of Metoprolol and Nebivolol.Metoprolol succinate will be given at a doseof 50 mg daily for 4 weeks, then 100 mgdaily for 4 weeks. For nebivolol, dosage willbe 5 mg and 10mg daily. Identical-appearingpills will be given, and the drugs will be
  39. 39. aortic blood pressure) to assess heartfunction.given in randomized order without a placeborun-in.Other Name: BystolicDetailed Description:Hypothesis: the beta-blocker nebivolol is associated with less fatigue thanmetoprolol, the most widely-prescribed beta-blockerMethods: a double-blinded crossover trial comparing nebivolol with metoprolol.Experimental procedures: Subjects will undergo electrocardiogram and routineblood testing, unless such tests have been performed within 6 months and areavailable for review. Subjects entered into the study will receive each of the 2study drug for 8 weeks. Metoprolol succinate will be given at a dose of 50 mgdaily for 4 weeks, then 100 mg daily for 4 weeks. For nebivolol, dosage will be 5mg and 10mg daily. Identical-appearing pills will be given, and the drugs will begiven in randomized order without a placebo run-in.At the end of each 4-week treatment period on each drug, subjects will undergo atreadmill stress test (using the standard Cornell protocol), complete Quality of Life andfatigue questionnaires, and have blood drawn and frozen for later analysis for drug levels.At the end of 8 weeks of treatment on each drug, subjects will undergo echocardiographyand applanation tonometry (non-invasive measurement of aortic blood pressure) to assessheart function.At the end of the study, the blinded subjects will be asked which of the 2 study drugs theyprefer, and the extent to which their energy differed between the 2 drugs.-Rationale: Millions of hypertensive patients are on life-long beta-blocker therapy. Inmany, it reduces cardiac output and increases peripheral resistance to blood flow (1). It iswell-established that beta-blockers cause fatigue in many patients and reduce exertiontolerance. Every physician knows this, and tacitly accepts that many patients are livingwith this unwelcome side effect.A new beta-blocker, nebivolol, has the standard beta-blocking effects, but also producesblood vessel relaxation (vasodilation), probably through increased secretion of thevasodilator nitric oxide. Studies indicate that nebivolol, unlike most beta-blockers, doesnot cause constriction of peripheral blood vessels, and is associated with improved heartfunction (2). Studies suggest that it is also less likely to cause fatigue (3).Personal experience is consistent with this, as I have observed marked improvement inenergy in patients in whom I have prescribed nebivolol in place of a different beta-blocker. The possibility of placebo effect of course cannot be excluded. Nevertheless, theknown hemodynamic differences between nebivolol and other beta-blockers, and thepositive clinical experience, warrant formal study to determine whether nebivolol iskinder than other beta-blockers in terms of the important side effect of fatigue.Eligibility
  40. 40. Ages Eligible for Study: 21 Years to 80 YearsGenders Eligible for Study: BothAccepts Healthy Volunteers: NoCriteriaInclusion Criteria:Individuals who are taking, or are about to begin taking, a beta-blocker, and whohave the approved indication of hypertensionExclusion Criteria:Orthopedic ailments that would interfere with performance of treadmill testingStroke or heart attack within the previous 1 yearSymptomatic coronary disease within the past year (angina, shortness of breath)Clinically significant pulmonary disease (e.g. emphysema or asthma).Poorly controlled hypertension (blood pressure above 160 systolic or 100diastolic)Patients with contra-indications to taking a beta-blocker (asthma orbradyarrhythmia)History of tachyarrhythmia (abnormal rapid heart rate)Contacts and LocationsPlease refer to this study by its identifier: NCT00999102LocationsUnited States, New YorkWeill Cornell Medical CollegeNew York, New York, United States, 10065Sponsors and CollaboratorsWeill Medical College of Cornell UniversityForest LaboratoriesInvestigatorsPrincipalInvestigator:Samuel J Mann,MDWeill Medical College of CornellUniversityMore InformationNo publications providedResponsible Party: Samuel Mann, MD, Weill Cornell Medical Identifier: NCT00999102 History of Changes
  41. 41. Other Study ID Numbers: 0901010162Study First Received: October 20, 2009Last Updated: March 16, 2012Health Authority: United States: Institutional Review BoardKeywords provided by Weill Medical College of Cornell University:hypertensionbeta blockersMetoprololblood pressure, highantihypertensive agentsvascular resistanceadrenergic beta-receptor blockadersbeta-Adrenergic blockersbeta-Adrenergic Blocking Agentsbeta-Adrenergic Receptor Blockadersbeta-Blockers, AdrenergicBystolicNebivololNebivololumNebivololum [Latin]R65,824Beloc- ZokH 93/26 succinateMetoprolol succinateSeloken ZOCSelozokSpesicor DosToprol XLToprol-XLUNII-TH25PD4CCBAdditional relevant MeSH terms:HypertensionVascular DiseasesCardiovascular DiseasesAdrenergic beta-AntagonistsMetoprololMetoprolol succinateNebivololAntihypertensive AgentsAdrenergic AntagonistsAdrenergic AgentsNeurotransmitter AgentsMolecular Mechanisms ofPharmacological ActionPharmacologic ActionsPhysiological Effects of DrugsCardiovascular AgentsTherapeutic UsesAnti-Arrhythmia AgentsSympatholyticsAutonomic AgentsPeripheral Nervous System AgentsAdrenergic beta-1 Receptor AntagonistsVasodilator processed this record on May 12, 2013Nebivolol (Bystolic), a Novel Beta Blockerfor HypertensionOlga Hilas, PharmD, BCPS, CGP and Danielle Ezzo, PharmD, BCPS, CGPAuthor information ►Copyright and License information ►
  42. 42. Go to:INTRODUCTIONHypertension is an asymptomatic condition of persistently elevated blood pressure (BP)that affects approximately 50 million Americans and one billion people worldwide.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control1,The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control2It has been associated with other diseases and events such as myocardialinfarction (MI), heart failure, stroke, and kidney disease.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control1Although hypertension the most common primary care diagnosis in theU.S., most patients are undertreated (fewer than 60% of patients receive any treatment),The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control1,The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control3–The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control6and only about 31% have BP that is adequately controlled.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control3The management of hypertension involves lifestyle modifications, pharmacologicaltreatment, or both. Weight reduction for overweight or obese patients, adherence to theDietary Approaches to Stop Hypertension (DASH) diet, moderate consumption ofalcohol, and physical activity are all essential to decreasing BP and enhancing theefficacy of pharmacotherapeutic regimens.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.
  43. 43. Destroy user interface control1Pharmacological treatment includes management with one or more agents belonging tothe following drug classes: thiazide diuretics, beta blockers, calcium-channel blockers,angiotensin-converting enzyme (ACE)–inhibitors, and angiotensin receptor blockers(ARBs). These medications can reduce BP as well as the complications of hypertension.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control1,The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control2,The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control7Although thiazide diuretics are recommended as the first-line therapy for most patientswith hypertension, beta blockers have a compelling indication for use in patients withhigh-risk conditions such as heart failure, MI, coronary disease, and diabetes.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control1,The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control8Beta blockers exert antihypertensive effects by reducing myocardialcontractility, heart rate, and cardiac output.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control9,The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control10Central inhibition of sympathetic nervous system outflow, inhibition of therenin–angiotensin system by reducing renin release from the juxtaglomerular apparatus, andresetting or altered sensitivity of baroreceptors may also contribute to the BP-lowering effectsof this drug class.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.
  44. 44. Destroy user interface control9–The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control11Beta blockers differ in many of their pharmacological properties, including beta1- andbeta2-adrenergic receptor selectivity and vasodilatory capabilities. Currently, all availablebeta blockers can be categorized into one of four principal groups based on their receptoraffinity and hemodynamic properties:noncardioselective, nonvasodilatorycardioselective, nonvasodilatorynoncardioselective, vasodilatorycardioselective, vasodilatoryA fifth category includes nonselective beta blockade with intrinsic sympatho-mimeticactivity; however, this group of agents is not favored for use because of datademonstrating their potential to increase peripheral vascular resistance and to attenuatedecreases in heart rate and cardiac output that may negate any benefits in cardiovasculardisease.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control10Nebivolol (Bystolic, Forest Laboratories), a third-generation beta blocker, is approved bythe FDA for the treatment of hypertension.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control12The medication’s unique chemical structure is composed of a racemicmixture of d-nebivolol and l-nebivolol (Figure (Figure11).The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control13Nebivolol exerts nitric oxide (NO)–mediated vasodilation in addition toconventional beta-blocking effects.Figure 1Chemical structure of nebivolol.
  45. 45. Go to:PHARMACOLOGY AND MECHANISM OF ACTIONThe following popper user interface control may not be accessible. Tab to the nextbutton to revert the control to an accessible version.Destroy user interface control13–The following popper user interface control may not be accessible. Tab to the nextbutton to revert the control to an accessible version.Destroy user interface control17Beta blockers are typically categorized as selective or nonselective to beta receptors.Nebivolol may be considered both, depending on the drug’s concentration in the body. Atlow concentrations, typically achieved in extensive metabolizers (the majority of thepopulation), and at doses of 10 mg and below, nebivolol is beta1-selective. However, athigher concentrations, in poor metabolizers and at higher doses, nebivolol loses itsselectivity and blocks both beta1 and beta2 receptors.Nebivolol also possesses novel vasoactive factors. It provides vasodilation by releasingendothelial nitric oxide. The vasodilation properties result in an overall positivehemodynamic side-effect profile, including cold extremities and a reduction in exerciseintolerance.Go to:PHARMACOKINETICS ANDPHARMACODYNAMICSThe following popper user interface control may not be accessible. Tab to the nextbutton to revert the control to an accessible version.Destroy user interface control13–The following popper user interface control may not be accessible. Tab to the nextbutton to revert the control to an accessible version.
  46. 46. Destroy user interface control16,The following popper user interface control may not be accessible. Tab to the nextbutton to revert the control to an accessible version.Destroy user interface control18The pharmacokinetic features of nebivolol vary according to the phenotype of themetabolizer. After a 15-mg dose, peak plasma concentrations were reached at 0.5 to 2hours in extensive metabolizers and in 3 to 6 hours in poor metabolizers. Absorption ofnebivolol is very similar to that of an oral solution. The presence or absence of food doesnot alter the drug’s kinetic profile; therefore, nebivolol may be taken without regard tomeals.Nebivolol is highly protein-bound, mostly to albumin at 98%, independent of itsconcentrations. The half-life of nebivolol varies as well: 10.3 hours in extensivemetabolizers and 31.9 hours in poor metabolizers.Nebivolol undergoes extensive first-pass metabolism through the cytochrome P450 2D6enzyme system. There is a great difference in bioavailability (12% for extensivemetabolizers and 96% for poor metabolizers). However, the lower concentration ofunchanged drug in extensive metabolizers is balanced by the formation of activehydroxyl metabolites, yielding insignificant clinical differences in therapeutic endpoints.Metabolism pathways differ according to the phenotype. The predominant metabolicpathway in extensive metabolizers is aromatic hydroxylation, whereby glucuronidationand alicyclic hydroxylation are secondary; N-dealkylation is less important. Thepredominant metabolic pathway in poor metabolizers is glucuronidation and alicyclichydroxylation; both N-dealkylation and aromatic hydroxylation are less important.Nebivolol is excreted mostly as metabolites (38% urine and 44% feces in extensivemetabolizers vs. 67% urine and 13% feces in poor metabolizers).Go to:CLINICAL EFFICACYThe FDA’s approval of nebivolol was based on its antihypertensive effectiveness in thetwo pivotal randomized, double-blind, multicenter, placebo-controlled trials conducted inthe U.S. Both studies concluded that nebivolol was safe, well tolerated, and effective forpatients with mild-to-moderate hypertension.