Journal of Human Hypertension (1998) 12, 135–140 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00 ORIGINAL ARTICLE Nebivolol vs atenolol and placebo in essential hypertension: a double-blind randomised trial L Van Nueten1, FR Taylor2 and JIS Robertson1 1Janssen Research Foundation, Beerse, Belgium; 2The Surgery, Hexton Road, Barton le Clay, Bedfordshire, UK A double-blind, randomised, parallel-group trial was cant falls in heart rate. Both active drugs were well toler- conducted in patients with essential hypertension in ated, nebivolol marginally more so. Nebivolol, a long- British general practices, of nebivolol 5 mg, atenolol acting, cardioselective, vasodilating beta-blocker which 50 mg, and placebo each given once daily. Both active acts partly via the l-arginine/nitric oxide mechanism, drugs, in comparison with placebo, caused highly sig- appears potentially valuable for the treatment of hyper- nificant and similar reductions in systolic and diastolic tension. pressures without orthostatic effect, and small signifi- Keywords: nitric oxide; quality of life; side effects Introduction daily were begun. After 4 weeks of this single-blind placebo run-in, those with a sitting diastolic press- Nebivolol is a highly cardioselective beta-blocking ure of at least 95 mm Hg and at most 115 mm Hg agent devoid of intrinsic sympathomimetic activity, could enter the trial proper. A previous dose- with vasodilating properties and a prolonged action; response trial of nebivolol had shown that 5 mg it acts in part via the l-arginine/nitric oxide path- once daily in hypertensive patients controlled blood way. At similar anti-hypertensive doses, nebivolol pressure (BP) over 24 h; no additional effect was has been found to exert less beta-1 blockade than do seen with 10 mg.10 Likewise, atenolol 50 mg once standard beta-blockers, as judged by the extent of daily had earlier been found to be as effective as reduction of exercise-induced tachycardia.1–9 This 100 mg.11 Thus the doses of active drugs used were paper reports a double-blind randomised trial of once-daily nebivolol compared with once-daily nebivolol 5 mg and atenolol 50 mg. Patients were atenolol, a well established cardioselective beta- randomised via a computer-generated list to receive, blocker and placebo, in essential hypertension. double-blind, once-daily placebo, or nebivolol 5 mg, or atenolol 50 mg, for the trial duration of 1 month, further visits being scheduled at 2 weeks and at the Patients and methods end of this time. If after 2 weeks of the double-blind Ͼ The trial was conducted in patients under primary treatment the diastolic pressure was 120 mm Hg, Ͼ medical care (general practice) in Britain. Male and or the systolic 220 mm Hg, patients were with- female ambulatory subjects, between the ages of 18 drawn and considered as non-responders. Patients and 71 years, with mild-to-moderate essential could also withdraw at any time should they wish; hypertension, were eligible; those previously or for any reason at the discretion of the investigator, untreated, or who had responded poorly or were or if a serious adverse event occurred. intolerant of previous treatment, could be recruited. All trial medication consisted of tablets identical Exclusion criteria are listed in Table 1. Those in appearance and taste. Patients were instructed to entering were required to give informed consent. At take one tablet once daily at breakfast, except on the the screening visit, initial assessments were perfor- occasion of clinic visits, when medication was omit- med, candidate patients were asked to discontinue ted until after BP had been taken. Thus the BP any current anti-hypertensive drugs within the next values reported (Figures 1–4) are those obtained 23– 2 weeks, while single-blind placebo tablets once 25 h after dosing. Drugs that might interfere with the anti-hypertensive effect of the trial medication were not allowed (see Table 1). Other medications were Correspondence: Dr L Van Nueten, Janssen Research Foundation, permitted as needed provided they remained International Clinical R&D, Internal Medicine, Turnhoutseweg unchanged during the trial; short-term treatment of 30, 2340 Beerse, Belgium Received 20 June 1997; revised 1 October 1997; accepted 10 intercurrent illness was also allowed. Compliance October 1997 was assessed by tablet count at the end of the Nebivolol and atenolol in essential hypertension L Van Nueten et al 136 Table 1 Exclusion criteria ț secondary hypertension, or malignant hypertension (retinal haemorrhage, exudates or papillary oedema) ț asthma or chronic obstructive airway disease ț bradycardia (less than 60 beats per minute at rest) ț atrial fibrillation or recurrent tachyarrhythmia requiring antiarrhythmic therapy ț insulin dependent diabetes ț history of sensitivity or severe adverse reaction to beta-blockers ț myocardial infarction or cerebrovascular accident within the last 6 months ț heart failure requiring treatment, or valvular disease of haemodynamic significance ț severe renal or hepatic disease (urine protein Ͼ trace, creatinine Ͼ 2.2 mg/dl or Ͼ 200 Tmol/l, ASAT and/or ALAT greater than twice the upper normal limit) ț (possible) pregnancy or nursing ț any concurrent condition that could, according to the investigator, jeopardise participant adherence to the protocol or ability to complete the trial (eg, alcohol or drug abuse, disabling or terminal illness, personality or mental disorders) ț concurrent therapy with medications that could affect blood pressure (therapy with tricyclic antidepressants drugs or MAO inhibitors; corticosteroids or non-steroidal anti-inflammatory drugs, if used regularly; hormonal contraceptives) ț investigational drug treatment within the past 120 days ț predictable lack of co-operation Figure 1 Diastolic blood pressure, sitting: (means ± s.e.m.). W = Week of trial. The number of patients contributing to each value is given. (– – –) placebo; (-------) atenolol; (——) nebivolol. double-blind trial period. Major dietary changes, eg, taneously, or if recalled in response to the standard for weight reduction or salt restriction, were not per- question, ‘Has treatment upset you in any way?’. mitted during the trial. Positive experiences were recorded if reported spon- Systolic and diastolic pressures were recorded, taneously, or in response to the standard question, using a random-zero sphygmomanometer, taking ‘Did you experience any beneficial effect from treat- Korotkoff phases 1 and 5, respectively. In each ment?’. A quality of life questionnaire comprising patient, measurements were made by the same 91 questions was completed by a subset of patients investigator or member of the investigator’s staff, in at the end of the 4-week double-blind period. A 12- the same room and at the same time of day, prefer- lead electrocardiogram was recorded at screening, at ably in the morning. At the first visit BP was determ- the end of the placebo run-in, and at the end of the ined in both arms; if a difference of Ͼ4 mm Hg was double-blind treatment period. Routine haematolog- found, the arm with the higher pressure was used ical, biochemical, and urine tests were performed at throughout, otherwise the right arm was always screening, at the end of the placebo run-in, and at employed. The sphygmomanometer cuff was at least the end of the double-blind treatment period. 30 cm long and 13 cm wide; if the arm circumfer- On the assumption that a difference in supine ence exceeded 34 cm, an appropriately larger cuff diastolic pressure by a mean ± s.d. of 5 mm Hg ± was used. Sitting BP was taken after the patient had 11.5 would occur between placebo and at least one rested for 5 min; standing pressure after 2 min of of the other treatment groups, it was calculated that standing. Heart rate was counted sitting and stand- a total of 414 patients (138 per treatment group) ing. At each visit patients were weighed partially would be needed to detect the difference with a 5% clothed. two-tailed significance and 95% power. Adverse events were noted if mentioned spon- The primary pre-declared index variable was sit- Nebivolol and atenolol in essential hypertension L Van Nueten et al 137 Figure 2 Diastolic blood pressure, standing: (means ± s.e.m.). W = Week of trial. The number of patients contributing to each value is given. (– – –) placebo; (--------) atenolol; (——) nebivolol. Figure 3 Systolic blood pressure, sitting: (means ± s.e.m.). W = Week of trial. The number of patients contributing to each value is given. (– – –) placebo; (--------) atenolol; (——) nebivolol. ting diastolic pressure at ‘trough’ drug level, 23–25 h decrease in sitting diastolic pressure at trough drug from the previous intake of medication, using the level to 90 mm Hg or below. The ␹2 test was used to last available reading in each patient (end-point), detect between-group differences for the percentages whether or not that patient completed the intended of responders. The quality of life questionnaire was full trial duration. An ‘intent to treat’ analysis was evaluated descriptively and by non-parametric test performed, that is, all randomised patients, regard- (Wilcoxon–Mann–Whitney U-test). less of their compliance with the protocol, were included. Treatment effects were evaluated at a two- Results tailed 5% significance level by means of a one-way analysis of variance. If the overall comparison was A total of 366 patients entered the run-in period, ie, significant, multiple comparisons were made by slightly fewer than were intended from the above Dunnett’s t-test to assess differences between nebiv- statistical considerations. Of these, two dropped out olol and placebo and between nebivolol and ateno- before randomisation. Of the remainder, 119 were lol. Response rate (normalisation) was defined as a allocated to nebivolol, 121 to atenolol and 124 to Nebivolol and atenolol in essential hypertension L Van Nueten et al 138 Figure 4 Systolic blood pressure, standing: (means ± s.e.m.).