A Dose-Response Trial of Nebivolol in Essential Hypertension
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Journal of Human Hypertension (1997) 11, 139–144 1997 Stockton Press. All rights reserved 0950-9240/97 $12.00 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; b-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 antihyperten- sive 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; • , 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 . trace, in relation to age and race was also assessed. creatinine . 2.2 mg/dl or . 200 mmol/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.