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Nebivolol Vs Enalapril in the Treatment of Essential Hypertension: a Double-Blind Randomised Trial

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Nebivolol Vs Enalapril in the Treatment of Essential Hypertension: a Double-Blind Randomised Trial Journal of Human Hypertension (1997) 11, 813–819 1997 Stockton Press. All rights reserved 0950-9240/97 $12.00 ORIGINAL ARTICLE Nebivolol vs enalapril in the treatment of essential hypertension: a double-blind randomised trial L Van Nueten1, A Schelling2, C Vertommen1, AG Dupont1 and JIS Robertson3 1Janssen Research Foundation, Beerse, Belgium; 2St Fransiscus Gasthuis, Rotterdam, The Netherlands; 3Glasgow, UK The efficacy and acceptability of nebivolol 5 mg and response rate (70% vs 55%; P 5 0.002). The trough-to- enalapril 10 mg, each given once daily, were compared peak sitting diastolic ratios also favoured nebivolol in essential hypertension in a multicentre, randomised, (84% vs 60%, P 5 0.002). Nebivolol, but not enalapril, double-blind trial over 3 months. For the index pre- slightly but significantly lowered heart rate. Both drugs declared variable, sitting diastolic pressure at trough were well-tolerated, although enalapril was drug level, nebivolol achieved greater falls in pressure accompanied by a significantly higher incidence of (212.3 vs 29.9 mm Hg; P 5 0.009) and a higher coughing. Keywords: vasodilating b-blockers; therapeutic trials; ACE inhibition; nitric oxide Introduction Patients eligible at screening were informed of the trial procedures, and those entering were required b Nebivolol is a highly cardioselective -blocker with to give informed consent. These subjects were then vasodilating properties; it acts in part via the L- given single-blind placebo for 1 month. Any pre- arginine/nitric oxide pathway; it is devoid of intrin- 1–9 sic sympathomimetic activity. Nebivolol has been Table 1 Exclusion criteria shown in human essential hypertension to control blood pressure (BP) effectively over 24 h in a dose of I secondary hypertension; 5 mg once daily; no additional effect was seen with I malignant hypertension (retinal haemorrhage, exudates or 10 mg.10–12 At similar antihypertensive doses to papillary oedema); b I asthma or chronic obstructive airway disease; established -blockers such as atenolol, nebivolol I , b bradycardia 60 beats/minute at rest; caused less -blockade as assessed by reduction of I atrial fibrillation or tachyarrhythmia requiring exercise-induced tachycardia.9,13 Nebivolol antiarrhythmic therapy; improved left ventricular function when given to I sick sinus syndrome or AV block greater than first degree; I heart failure requiring treatment; patients with cardiac impairment and was well tol- I 14–18 valvular disease of haemodynamic significance; erated in heart failure. The present study com- I myocardial infarction or cerebrovascular accident within the prises a double-blind randomised parallel-group last 6 months; comparison of nebivolol with the angiotensin- I insulin-dependent diabetes; converting enzyme (ACE) inhibitor enalapril in I sensitivity or significant adverse reaction to beta-blockers or essential hypertension. ACE-inhibitors; I significant renal (urine protein . trace, creatinine .2.2 mg/dl or .200 mmol/l) or hepatic (alamine-amino transferase and/or aspartate-amino transferase .2× the Patients and methods upper normal limit, total bilirubin .1.5× the upper normal The trial was conducted in 30 centres variously in limit) disease; I renal artery disease; Argentina, Brazil, Denmark, France, Italy, Mexico, I antecedents of auto-immune disease (leukopenia The Netherlands, South Africa, Sweden, and the ,3500/mm3 and/or neutropenia ,100 mm3); United Kingdom. Ambulatory patients, previously I pregnancy, nursing or childbearing potential; treated or untreated, with a fifth phase diastolic I any condition that could compromise the trial (alcohol or pressure over 94 mm Hg, and aged 18–74 years, were drug abuse, disabling illness, etc); I concomitant medication that could affect blood pressure (eg, recruited. Exclusion criteria are listed in Table 1. tricyclic antidepressants, monoamine oxidase inhibitors; corticosteroids; non-steroidal anti-inflammatory drugs); I 50% over ideal weight, based on Body Mass Index on Correspondence: Dr L Van Nueten, Janssen Research Foundation, Metropolitan Life Insurance Company’s 1983 Height and International Clinical R&D, Internal Medicine, Turnhoutseweg Weight Table; I 30, 2340 Beerse, Belgium investigational drug treatment within the past 30 days; I Received 20 January 1997; revised 19 July 1997; accepted 5 predictable lack of co-operation. August 1997 Nebivolol vs enalapril in hypertension L Van Nueten et al 814 vious antihypertensive drugs were either stopped with antihypertensive drugs (eg, thirst, cold fingers immediately, or were gradually withdrawn over a and toes, flushing, coughing etc). maximum of 2 weeks. Patients attended the clinic At week 2 of the run-in period, and at the end of at 2 and 4 weeks of the placebo period. Those with the double-blind comparison, routine urine testing a diastolic BP (DBP) above 114 mm Hg at 2 weeks was done, and blood samples were taken for routine were allocated to active double-blind therapy forth- haematological and biochemical tests; whilst in a with. Untreated patients whose diastolic was below subset of centres, from a total of 154 patients, a 95 mm Hg at the 4th week of placebo did not pro- further 10 ml of blood was collected for more ceed further. Trial subjects were randomly assigned detailed analysis of lipids (total cholesterol, high- in blocks of 12 to receive orally, once-daily and density and low-density lipoproteins (HDL and double-blind, either nebivolol 5 mg or enalapril LDL) and triglycerides). 10 mg. Visits during this comparison period were Twelve-lead electrocardiography was performed scheduled for weeks 2, 4, 8 and 12. After 3 months at week 2 of the run-in period, at the end of the of double-blind therapy the patients in both treat- double-blind comparison, and at the end of the run- ment groups were reallocated randomly to a ‘run- out period. out’ period of 1 month, double-blind on either pla- Patients were free to discontinue the trial at any cebo or a continuation of their existing nebivolol or time. They could also be withdrawn for any reason enalapril therapy. Visits were scheduled at weeks 2 at the discretion of the investigator. They were to be and 4 of the run-out period. withdrawn if the sitting diastolic pressure exceeded Medication comprised tablets identical in size, 119 mm Hg after 2 weeks, or 114 mm Hg after 4 colour, and taste, containing either placebo, nebivo- weeks of double-blind treatment, or if the treatment lol 5 mg, or enalapril 10 mg. Throughout, one tablet code was broken for any reason. The trial was was to be taken once daily at breakfast, except when approved by the ethical supervisory committee of the subjects attended for BP assessment, when medi- each participating centre. cation was omitted until this had been completed. At the randomisation (‘baseline’) and at the com- Statistics pletion of the 3 months comparison period, BP was also measured 2–3 h after drug ingestion, ie, at times The pre-declared index variable to be assessed was likely to be close to peak plasma levels.19–22 Com- sitting diastolic pressure at trough drug level. The pliance was assessed by tablet count at the end of shift from baseline of sitting DBP at trough level was the comparison period. Systolic and diastolic BPs defined as the primary measurement. Assuming a (respectively taking Korotkoff phases 1 and 5) were difference of at least 4 mm Hg with a standard devi- measured at all scheduled visits employing a stan- ation of 12 mm Hg in this measurement between the dard sphygmomanometer. The cuff was required to two drug groups, with 80% power and 5% two- be at least 30 cm long and 13 cm wide; if the arm tailed significance, at least 142 patients were needed circumference exceeded 34 cm, an appropriate per treatment group. Therefore a minimum of 320 larger cuff was used. In each patient such measure- patients, 160 per group, were planned to be entered. ments were made by the same investigator (or mem- The statistical analysis was performed according ber of the investigator’s staff) in the same room at to the intent-to-treat principle, ie, on all patient’s the same time of day. Three consecutive sitting randomised, regardless of their compliance with the pressures were taken after the patient had rested for protocol. All statistical tests reported are two-tailed at least 5 min; the last value was used for decision- and a P-value <0.05 was considered significant, making and for statistical analysis, except for sus- unless specified otherwise. If for any reason a pected protocol deviations, where all readings were patient failed to complete the trial as planned, the considered. BP was further measured once after the last available data were taken as ‘end-point’. The patient had stood for 2 min. At the first visit BP was end-point evaluation was considered as the primary determined in both arms; if a difference of more than time point. 4 mm Hg was found, the arm with the higher press- Response to treatment was defined as a decrease ure was subsequently always used, otherwise the in sitting trough DBP to 90 mm Hg or below, or a right arm was employed throughout. decrease in diastolic pressure of at least 10 mm Hg Heart rate was recorded immediately after the vs baseline, if the treated diastolic values remained measurement of both sitting and standing BP on all above 90 mm Hg. Odds ratios were calculated to occasions. Patients were weighed, partially clothed, compare the response rates of the nebivolol group at each visit. with the enalapril group; additionally, x2 tests were Any adverse events were recorded either if men- performed on the number of responders. Trough-to- tioned spontaneously by the patient or in response peak ratio was calculated for the sitting DBP as fol- to the standard question, ‘Has treatment upset you lows:19 in any way?’ Positive events were those recorded in trough/peak = D DBP trough/D DBP peak response to the further standard question, ‘Did you experience any beneficial effect from treatment?’ where D DBP = shift in DBP from baseline (ie, at Symptoms were additionally assessed at the end randomisation) to week 12 of the double-blind treat- of the run-in period, and at the end of the double- ment.
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