A Dose-Response Trial of Nebivolol in Essential Hypertension

A dose-response trial of nebivolol in essential hypertension

L Van Nueten, AG Dupont, C Vertommen, H Goyvaerts and JIS Robertson International Clinical R&D, Janssen Research Foundation, Beerse, Belgium

A double-blind placebo-controlled dose-response trial clear inferiority of efﬁcacy in black patients. A single of nebivolol, a cardioselective beta-blocking drug which daily dose of 5 mg was appropriate, with no evident also induces endothelium-dependent dilatation via nitric advantage at 10 mg. The drug was well tolerated, even oxide, has been performed. Nebivolol reduced blood at 10 mg daily. BP control was achieved largely in the pressure (BP) in a dose dependent way, and was shown absence of typical side effects of beta-blockade. The to be effective given once daily, without appreciable dif- combination of properties of nebivolol renders it an ferences between peak and trough drug levels. There attractive addition to the antihypertensive repertoire. was no postural component to the BP fall. There was no

Keywords: hypertension therapeutic trials; ␤-blockers; vasodilation; nitric oxide; black patients; side effects

Introduction All were required to have a fifth phase diastolic pressure of at least 95 mm Hg at the end of a 1 month Nebivolol is a highly cardioselective beta-adrenergic placebo ‘run-in’ period. Patients previously either blocking agent, devoid of intrinsic sympathomi- treated or untreated could be recruited. Exclusion 1,2 metic activity. It has been shown to control blood criteria are listed in Table 1. 3–7 pressure (BP) over 24 h with dosage once daily. The protocol of the trial is summarized in Table Nebivolol induces endothelium-dependent 2. After initial assessment, qualifying patients were arterial and venous dilatation via the l-arginine- nitric oxide pathway.8–10 At similar antihypertensive doses to established beta-blockers such as aten- Table 1 Exclusion criteria olol, nebivolol causes less beta-1 blockade, as • assessed by the reduction of exercise-induced tachy- age less than 18 and more than 70 years; • cardia.11 During both acute and chronic treatment secondary hypertension, or malignant hypertension (retinal haemorrhage, exudates or papillary oedema); with nebivolol, left ventricular function is well- • maintained; in trials in patients with left ventricular asthma or chronic obstructive airway disease; • Ͻ dysfunction nebivolol was well tolerated, and bradycardia ( 60 beats per minute at rest); atrial 12–14 fibrillation or recurrent tachyarrhythmia requiring anti- enhanced left ventricular performance. Nebivo- arrhythmic therapy; lol has also been shown to improve both left ven- • sick sinus syndrome or AV-block greater than first degree; tricular diastolic function and compliance in large • insulin dependent diabetes; arteries.12,15 • The properties of nebivolol are thus attractive for history of sensitivity or significant adverse reaction to betablockers; the treatment of essential hypertension, especially • myocardial infarction or cerebrovascular accident within when this is accompanied by left ventricular dys- the past 6 months; function. The present study was designed to deter- • heart failure requirent treatment, valvular disease of a mine the optimal antihypertensive dose, as well as haemodynamic significance; the duration of effect. The acceptability of the drug • significant renal or hepatic disease (urine protein Ͼ trace, in relation to age and race was also assessed. creatinine Ͼ 2.2 mg/dl or Ͼ 200 ␮mol/l, SGOT and/or SGPT greater than twice the upper limit of normal); Patients and methods • (possible) pregnancy or nursing; • any concurrent condition that may, according to the The trial was a double-blind, randomized, placebo- investigator, jeopardize participant adherence to the controlled, parallel-group dose-finding study which protocol or ability to complete the trial (eg, alcohol or was conducted among 509 patients with essential drug abuse, disabling or terminal illness, personality or mental disorders, etc); hypertension recruited from 40 centers in Europe • concomitant therapy with medications that may affect BP; and the USA. All subjects gave informed consent. • 50% over ideal weight range, based on body mass index (actual weight/square of height, ie kg/m2, normal values: 20–25 kg/m2), or based on Metropolitan Life Insurance Correspondence: Dr L Van Nueten, Janssen Research Foundation, Company’s 1983 Height and Weight Table; International Clinical R&D, Turnhoutseweg 30, 2340 Beerse, • investigational drug treatment within the past 30 days; Belgium • Received 10 September 1996; revised 4 December 1996; accepted predictable lack of cooperation. 9 December 1996 Nebivolol dose-response trial L Van Nueten et al 140 Table 2 Protocol summary

Assessments Placebo run-in Randomization Double-blind treatment

visit 1 visit 2 visit 3 visit 4 visit 5 (week 4) (week 2) (baseline) (week 2) (week 4)

Efﬁcacy Blood pressure:trough x x x x x peak x x x Positive experiences x x x x Symptom questionnaire x x Safety Heart rate x x x x x ECG x x Body weight x x x x x Adverse events x x x x Haematology, biochemistry, urinalysis x x

instructed to stop any antihypertensive medication Thus from randomization to the end of double- during the next 2 weeks. They were then given sin- blind treatment, assessments were made at trough gle-blind once-daily placebo for 4 weeks. Those drug level, 23–25 h from dosing, and also at peak qualifying were then, by a computer-generated ran- drug level 2 h from dosing. All BP measurements on domization procedure constructed in blocks of six, each patient were made by the same investigator, in assigned double-blind to placebo, or to nebivolol the same room, at the same time of day, using a stan- 0.5, 1.0, 2.5, 5 or 10 mg once daily, to be continued dard mercury sphygmomanometer. The cuff bladder for 1 month. All tablets were identical in appearance was required to be at least 30 cm long and 13 cm and taste, and were to be taken each morning at wide; an appropriately large cuff was used if the arm breakfast, except on the occasion of clinic visits (see circumference was more than 34 cm. At the first below). Drugs which could affect the antihyperten- visit, BP was assessed in both arms; if a difference sive action of nebivolol (eg, tricyclic antidepress- of more than 5 mm Hg was found, the arm with the ants, monoamine oxidase inhibitors or cortico- higher value was taken, otherwise the right arm was steroids) were not allowed. used. The same arm was subsequently employed for Other medications needed for the treatment of BP measurement in each patient throughout the concurrent disease were permitted provided they trial. remained unchanged throughout the trial. Major At each visit heart rate was counted supine and dietary modifications, as for weight reduction or salt standing, and body weight was measured. Twelve- restriction, were not allowed. During double-blind lead electrocardiography (ECG) was recorded at the therapy, visits were scheduled at 2 and 4 weeks. end of the placebo run-in period and at the end of Patients were permitted to withdraw voluntarily double-blind therapy. at any time for any reason; they were also with- Blood samples for routine haematology and bio- drawn if a serious adverse event occurred, if the chemistry, and urine samples for routine testing double-blind code was broken prematurely, if the were obtained at the end of the placebo run-in and supine diastolic pressure was 120 mm Hg or more, double-blind treatment periods. or for any other relevant reason at the discretion of At each visit subjects were asked the questions: the investigator. If the supine diastolic pressure was ‘Did you experience any benefit from treatment?’; at least 115 mm Hg and at most 119 mm Hg, the and ‘Has treatment upset you in any way?’ patient was seen again within 48 h; if the diastolic At the end of the placebo run-in period and at the pressure remained at least 115 mm Hg the patient end of the double-blind treatment period, patients was then withdrawn. Compliance with treatment was assessed by tablet rated (on a standard symptom questionnaire) how much they were distressed: (1 = not at all; 2 = a little counts at the end of the placebo run-in period and = = at the end of double-blind treatment. Smoking hab- bit; 3 moderately; 4 severely) by the following 35 its and alcohol consumption were recorded. symptoms associated with antihypertensive drugs: Supine and standing systolic (SBP) and diastolic abdominal pain, thirst, inability to concentrate, BPs (DBP) were measured at all scheduled clinic nightmares, skin rash, impotence (men only), gen- visits, using respectively Korotkoff phases I and V. eral weakness, rapid heart beat, cold fingers and Supine pressure was taken after the patient had toes, vomiting, swelling of feed or ankles, feeling rested for 5 min, the last of three consecutive read- depressed, confusion, coughing, itchy skin, blurred ings being used for analysis. Standing pressure was vision, flushing, dry mouth, constipation, muscle measured once after 2 min upright following the cramps, inability to fall asleep, abnormal mood supine recordings. At the clinic visits for BP swings, vertigo or dizziness, shortness of breath, measurement, patients were asked not to take their hair loss, dry eyes, slow heartbeat, nausea, heart- medication at breakfast; instead, BP was measured burn, diarrhoea, numbness or tingling in hands or on arrival at the clinic, tablets were then ingested, feet, decreased interest in sex, wheezing, loss of and BP recorded again 2 h later. taste, and increased frequency of urination. Nebivolol dose-response trial L Van Nueten et al 141 Statistical analysis (Figure 1, Table 3). There were significant falls in this value from baseline for all treatment groups The statistical analysis was performed according to including placebo. During active nebivolol therapy, the ‘intent-to-treat’ principle, ie, on all patients ran- the falls in pressure at the two lowest daily doses of domized, regardless of their compliance with the nebivolol (0.5 and 1.0 mg) did not differ from pla- protocol. All statistical tests reported are two-tailed р cebo, but at all three of the higher daily nebivolol and a P value 0.05 was considered significant, doses (2.5, 5.0 and 10.0 mg) diastolic pressure was unless specified otherwise. The end point evalu- significantly lower than with placebo. Comparison ation, ie, last available observation per patient, was of the outcomes at the different doses showed the considered as primary timepoint. The shift from 1.0 mg dose of nebivolol to be more effective than baseline (supine position) of DBP at trough drug 0.5 mg, and both 5.0 mg and 10.0 mg to be more level was defined as the primary measurement. For effective than 2.5 mg. The difference between 5.0 each continuous variable, a two-way analysis of and 10.0 mg was not significant. There was no variance (ANOVA) model with effects for treatment appreciable difference between the outcomes at 2 group and continent of origin (Europe or USA) was and 4 weeks of active therapy. As can be seen from used to detect an overall difference between the six Figure 1 and Table 3, the changes in supine systolic treatment groups. When a statistical overall differ- pressure at trough drug level paralleled those in ence was noted, Dunnett’s t-test, with placebo as ref- diastolic pressure. BP values at trough and peak erence group, was subsequently performed to drug level (supine and standing), at the 4th week of account for multiple comparisons when investigat- double-blind treatment, are shown in Table 3. It is ing efficacy in the nebivolol groups versus placebo. evident that similar dose-related falls in BP were Additional analyses were performed to characterize found at these measurements, and that only minor the within-group comparisons. To determine the variations occurred between peak and trough. The dose-response relationship, the Kodell-Chen closed 16 trough-to-peak ratio for supine diastolic pressure trend test procedure with one-tailed Jonckheere- with nebivolol 5 mg once daily was 0.894. There Terpstra trend test was performed at the 10% sig- was no appreciable postural component to the BP nificance level. reduction. Trough-to-peak ratio was calculated for the supine 17 Defining ‘response’ as an achieved supine dias- DBP as follows: tolic pressure at trough drug level as р90 mm Hg ⌬ − ⌬ trough = DBP, NEB, trough DBP, PLAC, trough and/or a fall in pressure from baseline of at least 10 peak ⌬DBP, NEB, peak − ⌬DBP, PLAC, peak mm Hg, the response rates were: placebo 32%; and ⌬ = at the respective doses of nebivolol, 31%, 38%, where DBP shift in DBP from baseline (ie, end 43%, 58% and 57%. BP reduction was unrelated point run-in) to the end of double-blind treatment. to age. The influence of sex, age and race on the shift In each treatment group, notably also including from baseline of trough diastolic pressure in supine those taking placebo, the decrease in supine dia- position was investigated by means of a two-way stolic pressure at trough drug level was greater in ANOVA with treatment and separately, each of the women, the mean difference at 5 mg nebivolol daily characteristics as main effects. In the case of a sig- being 1.1 mm Hg. Overall the difference between nificant effect, Dunnett’s t-test was used to investi- women and men in this respect was nominally sig- gate the difference of the nebivolol treatment groups nificant (P = 0.039), although the baseline values in from placebo in each stratum separately. the two sexes were similar. Nebivolol was no less effective in black than in Results non-black subjects. At the 5 mg dose, comparative falls in BP on average, black vs non-black, baseline Five hundred and nine patients were entered, the to end of study, were, at trough drug level 9.7/8.5 numbers in each treatment group being similar vs 9.0/9.4 mm Hg, and at peak 12.7/8.4 vs 12.6/11.9 (placebo n = 84; nebivolol groups respectively 0.5, mm Hg; while the respective response rates were 1.0, 2.5, 5, 10 mg: n = 83, n = 87, n = 85, n = 86, and 62% vs 57%. n = 84). Fifty-three per cent of the patients were Heart rate was slowed by nebivolol in a dose- men. The mean age of all patients at entry was 56 related fashion, with a maximum fall of some 10 years (range 24–70). Seventy per cent were Cauca- beats per minute, standing, at peak drug level, simi- sian, 22% were black, and 7% of Hispanic origin. A lar with 5 and 10 mg daily. ECG confirmed the above low salt diet was taken by 42% and alcohol by 47%, clinically assessed changes in heart rate, and while 23% were smokers. Twenty-two patients took additionally showed dose-related increases in QT a constant daily dose of aspirin, and 22 others a con- (with a maximum of 17.2 msec at nebivolol 10 mg), stant daily dose of other non-steroidal anti-inflam- with a decrease in QTc intervals (with a maximum matory drugs during the trial. of 6.3 msec at nebivolol 5 mg) , as is usual with other Compliance with therapy, as assessed by tablet beta-blockers.18 count, was more than 98% in all treatment groups. There were no consistent or clinically relevant Individual compliance of less than 80% was found changes in body weight, in biochemical or haemato- in one patient in the placebo group, and in the nebi- logical values or on urine testing. volol groups respectively 0, 3, 1, 2 and 1. Fifteen patients withdrew because of supposed The primary trial criterion was the achieved adverse effects of drug therapy during double-blind supine diastolic pressure at trough drug level treatment. Two of these were taking placebo, while Nebivolol dose-response trial L Van Nueten et al 142

Figure 1 Diastolic and systolic BP (mean + s.e.m.), trough drug level, supine position.

Table 3 BP at baseline and differences from baseline at the trial endpoint

Drug level Position Group Mean diastolic BP (mm Hg) Mean systolic BP (mm Hg)

Baseline Shift baseline Baseline Shift baseline to endpoint to endpoint

Trough Supine PLAC 101.3 −3.3 158.8 −3.1 NEB0.5 100.9 −4.0 157.7 −2.9 1 101.8 −6.0 160.9 −6.8 2.5 101.8 −7.1 161.2 −8.6 5 101.6 −9.2 160.3 −9.2 10 101.2 −10.2 157.9 −8.2 Standing PLAC 102.8 −2.6 155.7 −2.3 NEB0.5 102.4 −3.7 156.3 −3.2 1 102.2 −5.0 159.3 −8.5 2.5 103.3 −6.3 160.7 −9.5 5 103.1 −9.0 159.7 −9.2 10 102.9 −9.6 155.4 −7.9

Peak Supine PLAC 99.9 −4.4 158.0 −4.7 NEB0.5 100.4 −5.7 155.7 −4.3 1 100.6 −7.8 159.0 −8.5 2.5 100.3 −8.8 157.4 −9.2 5 100.1 −11.0 159.9 −12.6 10 99.3 −9.8 155.4 −9.4 Standing PLAC 101.7 −2.5 156.4 −3.8 NEB0.5 100.7 −3.8 153.2 −4.1 1 101.7 −5.8 157.1 −8.1 2.5 102.7 −8.0 157.3 −11.1 5 102.0 −10.3 158.1 −11.4 10 100.4 −8.6 153.8 −8.6

at the respective nebivolol doses there were 3, 2, 3, all, there were similar numbers of improvements 2 and 3 withdrawals. There was no clear pattern to and deteriorations reported. Table 4 shows the most these reported reactions, and none was evidently frequent adverse events reported spontaneously on drug-related. placebo and on the various doses of nebivolol dur- Over the month of double-blind treatment, the ing double-blind treatment. As can be seen, the type mean total symptom score did not worsen in any of and incidence of such events was similar on placebo the treatment groups, and there was no change in and active nebivolol, and was not in the latter case the mean score for any individual symptom. Over- dose-related. Nebivolol dose-response trial L Van Nueten et al 143 Table 4 Adverse experiences reported in at least three patients/group

Nebivolol

Placebo 0.5 mg 1 mg 2.5 mg 5 mg 10 mg (n = 83) (n = 83) (n = 87) (n = 84) (n = 86) (n = 84)

Headache 6 6 2 7 4 Rhinitis 12 5 2 2 1 3 Cough 5 5 1 Dizziness 2 3 2 5 3 Cold extremities 1 1 5 Fatigue 1 1 1 4 2 Bradycardia 1 1 3 3 Pruritus 3 2 1 1 Nausea 1 1 3 2 Abdominal pain 3 3 2 1 2 Chest pain 2 1 4 1 Percent of patients with adverse events 36 36 35 33 40 35

Discussion distinct, but not excessive, fall in heart rate. No age- related antihypertensive effect was discerned. The The present trial has confirmed that nebivolol is an drug was well tolerated, even in doses of 10 mg effective antihypertensive agent given once daily, daily. The pattern of reported adverse events without appreciable differences in BP level between double-blind did not differ between placebo and peak and trough drug levels. This is an important nebivolol, and was moreover not dose-related. These point, because efficacy is thereby achieved whilst findings are gratifying, whilst being subject to the avoiding high plasma concentrations of drug with unavoidable caveat that such assessments are neces- any consequent attendant potential problems. 19 sarily limited in sensitivity. At the recommended Lipicky has stated that if 50–75% of the peak effect definitive dose of 5 mg once daily, nebivolol of a dose is preserved at trough, issues concerning achieved an antihypertensive effect comparable to the proper dosing interval do not arise; the closer to that of standard beta-blocking drugs, but with few of no loss of effect throughout the dosing interval the the side effects usually accompanying such therapy. better. Nebivolol 5 mg once daily, with a figure of The combination of properties of nebivolol, notably 89%, clearly surpassed that standard. The duration its possession of beta-adrenergic blockade with of antihypertensive effect of different beta-blockers vasodilation and potentiation of nitric oxide effects 20 varies widely. It remains uncertain how long the on arterial and venous endothelium is especially effect of a dose of atenolol, a standard beta-blocker, attractive. Enhancement of vascular endothelial and will last, although a single daily dose is often con- smooth muscle nitric oxide has been proposed as 20 sidered to be satisfactory. It has been demonstrated beneficial not only in lowering high BP, but also in that active hydroxymetabolites can sustain the anti- moderating associated atherosclerosis.26,27 The 21 hypertensive effect of native nebivolol. A single present trial accords well with the former sugges- daily dose of 5 mg appears to be appropriate, with tion. Substantiation of the second proposal must no evident antihypertensive advantage at 10 mg. await further study. The similar efficacy of nebivolol in black as in Beta-adrenergic blocking drugs are now well- non-black patients is noteworthy and gratifying. It established as initial therapy in essential hyperten- has been emphasized that black Americans are often sion.18,22 Nebivolol, a long-acting, vasodilating beta- comparatively poorly responsive to standard beta- blocker which is highly cardioselective, has con- 22 blocking drugs. siderable potential in this context. The greater antihypertensive response in women than in men is unexplained. While it is tempting to ascribe this to some particular property of nebivolol, Participating physicians that it was also seen with placebo engenders cau- France: D De Treglode (Quimperle), P Wahl (Saint- tion. No such differential, either on active drug or Michel). placebo, was observed in earlier trials.23–25 This Germany: R Buck (Budelsdorf), E Homsy aspect merits attention in other trials employing (Ludwigshafen), G Kleinmanns (Du¨ sseldorf), H nebivolol, although it may well be simply a chance Mauersberger (Villingen-Schwenningen), I Naudts finding. No orthostatic component to the BP (Dudenhofen), G Preissler (Puchheim), K Winn reduction was seen. Absence of postural hypoten- (Hannover). sion is a feature of many beta-blockers, although it Italy: V Cagli (Rome), L Corea (Perugia), C Di Veroli can appear with beta-blockers also having a vaso- (Rome), C Lai (Cagliari). dilator action, especially if there is an alpha-block- The Netherlands: ER Coene (Zeist), CHL Klaassen ing component, such as with labetalol or carvedi- (Beverwijk), C Oldenbroek (Hoorn), AJ te Rijdt lol.18 The lack of postural hypotension with (Hengelo), MJ van der Horn (Ijmuiden), GJM van der nebivolol is thus noteworthy. Nebivolol caused a Linden (Dordrecht). Nebivolol dose-response trial L Van Nueten et al 144 Portugal: AN Diogo (Lisbon). vasculature: evidence for an l-arginine/NO-dependent UK: JM Beattie (Birmingham), DF Da Costa mechanism. J Pharmacol Exp Ther 1995; 274: 1067– (Newcastle), GA Ford (Newcastle), MK Harris 1071. (Birmingham), AC Hunt (Birmingham), WA Littler 10 Bowman AJ, Chen CPL, Ford GA. Nitric oxide- (Birmingham). mediated venodilator effects of nebivolol. Br J Clin Pharmacol 1994; 38: 199–204. USA: JE Angelo (New Orleans), WB Appelgate 11 Van Rooy P, Van Nueten L, De Creé J. Nebivolol: blood (Memphis), NR Cutler (Beverly Hills), L Hogan pressure reduction in relation to ␤-blockade in healthy (Wilmington), RH McDonald (Pittsburgh), FG volunteers. Drug Investigation 1991; 3 (Suppl 1): McMahon (New Orleans), A Mendez (Coral Gables), 174–175. JH Mersey (Baltimore), HM Perry (St. Louis), HL Phi- 12 Stoleru L et al. Effects of d-nebivolol and l-nebivolol lips (Columbiana), RB Rhoades (Augusta, Martinez), on the left ventricular systolic and diastolic function: HW Schnaper (Birmingham), LK Smith (Phoenix), comparison with d-l nebivolol and atenolol. J Cardio- HE Thomas (Boston), ML Tuck (Sepulveda). vasc Pharmacol 1993; 22: 183–190. 13 Goldstein M et al. Administration of nebivolol after coronary artery bypass graft in patients with altered left ventricular function. J Cardiovasc Pharmacol Acknowledgements 1993; 22: 253–258. We are indebted to Mr Walter De Roeck and Mrs 14 Rousseau MF et al. Medium term effects on beta-blockade on left ventricular mechanics: a double-blind, pla- Patricia Xhonneux for their constructive involve- cebo controlled comparison of nebivolol and atenolol ment in the data processing. We also would like to in patients with ischemic left ventricular dysfunction. thank the trial coordinators and trial monitors in the J Card Fail 1996; 2: 15–23. different countries. We are grateful to Mrs Ilse 15 Van Merode T et al. Verapamil and nebivolol improve Versmissen for her skillful secretarial assistance. carotid artery distensibility in hypertensive patients. J Hypertens 1989; 7 (Suppl 6): S262–S263. 16 Kodell RL, Chen JJ. 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