Quality of life and efficacy of nebivolol in an open-label study in hypertensive patients. The QoLaN study

Abstract

Background. Nebivolol is a highly selective β₁-adrenoreceptor antagonist with vasodilating properties. This study investigated its effect on quality of life (QoL) and blood pressure (BP) in real life conditions. In total, 1468 patients were enrolled, 12% diabetics. Nebivolol was prescribed as monotherapy, add-on or switch medication. Methods. In this open-label, prospective study, the JNC-VII BP target values were used: <140/90 and <130/80 mmHg for diabetics. The responder rate and the QoL was determined at baseline and after 4 and 8 weeks. Results. After 4 weeks, 27% of subjects reached target BP, 45% after 8 weeks. The responder rates were 92, 90 and 83% for the monotherapy, add-on and switch groups. Compared with baseline, all showed statistical significance at 8 weeks. Similarly to results for the QoL after 8 weeks, the mean improvement in QoL for all three groups was 9–10 points (total range: 0–88). Conclusions. The study demonstrates that nebivolol in mild to moderate hypertension is associated with overall improvements in QoL, with a marked BP-lowering effect, in mono-therapy, add-on or switch, irrespective of the glucose tolerance status. It may be hypothesized that its dual mode of action explains its BP-lowering effect as well as the tolerability

Keywords::

• Hypertension
• Nebivolol
• Quality of Life
• β-blocker diabetes

Introduction

All therapeutically applied β-adrenoreceptor blocking agents are known to block β₁-adrenoreceptors, by which they slow the heart rate and therefore reduce blood pressure (BP). Various beta-blockers, however, also substantially block β₂-adrenoreceptors, leading to adverse effects, such as broncho- and/or vasoconstriction. The ESH/ESC 2007 Guidelines, as well as the Fourth Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice, no longer recommend beta-blockers as first choice BP-lowering drugs because of their diabetogenic and dysmetabolic effects in subjects with the metabolic syndrome phenotype [1,2]. As stated in these updated guidelines, these effects seem, however, less pronounced or absent in beta-blockers with intrinsic vasodilating properties such as carvedilol and nebivolol [1,2].

Endothelial-derived factors modulate the contractile activity of smooth muscle cells in the vascular wall, and nitric oxide (NO) [3,4], produced and released from the endothelial cells, induces vessel wall relaxation and reduces vascular resistance [5,6]. Nebivolol is a highly selective b -blocking agent that combines beta-blocking and vasodilating properties [4,7]. The haemodynamic profile of nebivolol allows effective control of BP at a low degree of beta-blockade, while maintaining left ventricular function [8].

Subjects with mild to moderate hypertension are in general without complaints [9]. Since antihypertensive drugs have to be taken for many years, it is extremely important that BP-lowering therapies minimally interfere with subject's quality of life (QoL) so that drug compliance in the long run remains high [10]. Among beta-blockers, nebivolol's efficacy, safety and tolerability were ranked high in several studies [11–15], whose size and design, however, were not specifically aimed at assessing the drug's effects on a subject's QoL. The goal of this study was therefore to assess, in a population-based cohort of subjects in real life conditions, with mild to moderate hypertension, the QoL and efficacy of nebivolol at different intervention levels, according to the Seventh report of the Joint National committee (JNC-VII) on Prevention, Detection, Evolution and Treatment of High Blood Pressure [16].

Subjects and methods

This was an open-label, prospective, multicentre study designed to test the hypothesis that preservation of QoL can be maintained at a significantly higher level by the use of nebivolol, alone or in combination with other treatment(s), compared with other therapeutic options, with similar anti-hypertensive effect. One hundred and thirty-three GPs in Belgium enrolled 1468 patients (>18 years old) with essential hypertension and unsatisfactory control of BP at inclusion [seated diastolic BP (DBP) ≥95 and <115 mmHg] or complaining of intolerable adverse events during prior treatment.

Exclusion criteria included secondary hypertension, severe hypertension [systolic BP (SBP) >200 and/or DBP ≥115 mmHg], prior nebivolol therapy, hypersensitivity or contra-indication to beta-blockers, and major concomitant illnesses. The study was conducted in compliance with the Helsinki Declaration of 1975 (as revised in 1983) and approved by the Ethics Committee of the Clinique St-Etienne, Brussels. All patients provided a written informed consent prior to enrolment.

The study protocol included three visits. At the screening visit (V1), anthropometric data, BP, including hypertension duration and complications (stroke, transient ischaemic attack, angina, myocar-dial infarction, cardiac insufficiency, left ventricular hypertrophy) and heart rate were collected. Also, creatininaemia, associated conventional cardiovascular risk factors, dietary habits, and the practitioner's decision regarding high BP therapy (addition of, or switch to nebivolol (or other drug) for drug-naïve subjects or for subjects already receiving hypotensive drug(s)). Visits 2 and 3 (V2 and V3) were scheduled 4 and 8 weeks after V1. At these follow-up visits, the following data were collected: BP, heart rate, type and dose of hypotensive drug(s). Office systolic and diastolic BPs were measured after 5 min in sitting position, always on the same arm.

The study aim was to improve BP levels using a pharmacological intervention in order to reach JNC-VII recommended values for BP control (<140/90 mmHg for non-diabetic subjects, and <130/80 mmHg for diabetic subjects). The physician could freely decide between several alternatives: (i) to administer nebivolol to patients who were not taking any BP medication at the time (monotherapy group), (ii) to add nebivolol to existing BP-lowering agent(s) (add-on group), or (iii) to replace one of the anti-hypertensive drug(s) with nebivolol (switch group). Only one anti-hypertensive medication could be changed at V1, thereafter, the chosen treatment remained throughout the study period. The medication was prescribed by the physician at visit 1 and purchased by the subjects. The BP-lowering efficacy of nebivolol was ascertained from the proportion of controlled subjects, i.e. reaching JNC-VII recommended values for BP in non-diabetic (140–90 mmHg) and diabetic (130–80 mmHg) subjects prior to and following nebivolol treatment, as well as the proportion of responders. Responders were defined as subjects in whom systolic BP values decreased by ≥10 mmHg and diastolic BP decreased by ≥5 mmHg while on nebivolol, irrespective of JNC-VII target thresholds attainment, and/or those who considered as BP controlled at V2 and V3.

All participants filled out the QoLaN questionnaire at each visit (Table I). This questionnaire was designed for self-completion and consisted of 22 items, each with five possible answers pertaining to the previous month's subjective assessment of wellness as well as of items related to high BP symptoms and/or of frequently reported side-effects of commonly used BP-lowering drugs [17,18].

Table I. Questionnaire.

Over the last month, did you experience any of the following?	Over the last month, did you feel?	Does your current health status limit your daily activities?
Tiredness	Anxious	Climbing a flight of stairs
Dizziness	Satisfied with your personal life	Walking around the block several times
Facial redness	Depressed	Being satisfied with your sexual life
Cold hands and/or feet	Satisfied with your family life
Coughing	Satisfied performing daily activities
Tinnitus	Satisfied with your professional life
Breathing difficulty
Palpitations
Headache
Swollen legs and/or feet
□ never	□ never	□ no, not at all
□ once to twice	□ once to twice	□ no, not really
□ once to twice a week	□ once to twice a week	□ rather not
□ almost every day	□ almost every day	□ rather yes
□ at least once a day	□ at least once a day	□ yes, completely
Did you have to take leave from work for medical reasons over the previous month?	Are you satisfied with your current hypertension treatment?	Did you have to give up your usual leisure time activites?
□ no	□ no, not at all	□ no
□ one or two day(s)	□ no, not really	□ no, but I feel constrained
□ one week	□ rather not	□ yes, once or twice
□ two weeks	□ rather yes	□ yes, often
□ more than two weeks	□ yes, completely	□ yes, all the time
Do you feel better than one month ago? □ Yes □ No

Statistical analysis

Both quantitative and qualitative aspects of the observed changes in the QoL questionnaire were analysed in order to assess the significance of changes. The differences between means (V3 and V1) for each of the 22 QoL items were first analysed using paired Student's t-test within each group. One-way analysis of variance was used to compare V3 and V1 means, as well as differences between the three groups. Statistical significance was also inferred from longitudinal changes in the absolute and relative distribution of answers to the QoLaN questionnaire, using symmetry distribution analysis.

For comparisons between V3 and V1, only patients for whom both data points were available were included. Results were considered significant at the 5% critical level. Calculations were carried out using the SAS (version 9.1 for Windows) statistical package.

Results

The total number of subjects included in the study was 1468, with 587 subjects in the monotherapy group (nebivolol as sole BP-lowering agent), 460 subjects in the add-on group (nebivolol added to existing BP-lowering agent(s)) and 421 subjects in the switch group (a previous BP-lowering agent switched to nebivolol) (Table II). In all three groups, a high proportion of subjects was overweight and had truncal fat distribution as reflected by enlarged waist circumference. At baseline, mean systolic BP values were well above the JNC-VII recommended cut-off values for BP control.

Table II. Baseline characteristics.

	Nebivolol
	Monotherapy	Add-on	Switch
n	587	460	421
Age (years)	56.7±13.3	63.7±11.9	63.5±12.4
Sex ratio (M:F) (%)	52:48	48:52	45:55
BMI (kg/m^2)	26.9±4.5	28.6±5.3	27.6±4.7
Waist circumference (cm)	95±13	99±16	96±15
Within normal JNC-VII* BP levels (%)	1	1	15
Age at hypertension diagnosis (years)	55.6±13.2	57.3±12.0	56.5±11.8
Systolic BP** (mmHg)	161±14	162±15	152±17
Diastolic BP (mmHg)	98±7	96±8	89±10
Pulse pressure (mmHg)	63±14	66±15	63±15
Mean arterial pressure (mmHg)	119±8	118±9	110±11
Heart rate (bpm)	80±10	79±10	72±13
Diabetes mellitus (%)	5	20	12

Results are expressed as means±1 SD or as proportions (%).

M, Male; F, Female;

*Normal JNC-VII levels defined according to glucose tolerance status (see Methods);

** BP, Blood pressure.

The group of BP-lowering drug-naïve subjects given nebivolol as monotherapy were more recently diagnosed with high BP than those in the add-on (n=460) or switch (n=421) groups (1 vs. 7 years). The sex ratio was well balanced in each group. Systolic and diastolic BP values were similar in the monotherapy and the add-on groups, and lower (by a mean 10 and 7 mmHg) in the switch group. In the latter group, 15% of subjects were within normal JNC-VII target at inclusion, vs. 1% in the drug-naïve and add-on groups. Mean arterial pressure was also lower (±10 mmHg) in the switch group. Known diabetes prevalence was 5% (monotherapy), 20% (add-on) and 12% (switch).

The commonest reason for switching or introducing nebivolol was inadequate BP control; this was mentioned for 73, 64 and 26% of cases in the monotherapy, add-on and switch groups, respectively. In the monotherapy and add-on groups, side-effects, tiredness and headache were mentioned for 9–5% of cases. For the switch group, side-effects came close to unsatisfactory BP control (24 vs. 26%), followed by tiredness, cold-extremities and headache (12, 11 and 5%, respectively). The responder and JNC-VII goal achievement rates are described in Figure 1. At V3, an overall 45% of subjects under nebivolol therapy were adequately controlled (vs 5% at inclusion). This incremental 40% was achieved through a 27% increase at V2 followed by a further 13% increase of controlled subjects at V3. In each group, similar trends were observed between V2 and V3 with respect to the proportions of subjects deemed adequately controlled.

Figure 1. Proportion (%) of controlled subjects and responders under nebivolol in each treatment category (monotherapy, add-on, switch) at visits 2 and 3: proportion of JNC-VII goal achievers (dark column), proportion of subjects with SBP/DBP decreased by more than 10/5 mmHg (white column), and proportion of responders defined by SBP/DBP decreased by more than 10/5 mmHg irrespective of JNC-VII target thresholds attainment and/or those who were considered as BP controlled (grey column)

The results of the QoLaN questionnaire were analysed both quantitatively and qualitatively (Tables III and IV). The analyses were performed for total scoring and also for subscores representing series of items that were grouped according to: (i) the physical aspects (tiredness; dizziness; facial redness; cold hands and/or feet; coughing; tinnitus; breathing difficulty; palpitations; headache; and swollen legs and/or feet), (ii) the subjective feelings (anxiety; satisfaction with one's personal life; depression; satisfaction with one's family life; satisfaction in performing one's daily activities; satisfaction with one's professional life) and (iii) the symptomatic status (climbing a flight of stairs; walking around the block several times; giving up one's usual leisure time activities; having to take leave from work for medical reasons over the previous month; being satisfied with one's sex life and satisfaction with one's current hyper-tension treatment), as assessed by the questionnaire. For the qualitative component of the analysis, the outcome between V3 and V1 was categorized as status quo, worsening or improvement. Another way to qualitatively assess the changes was to compute, for each subject, the total number of items improved, which ranges between 0 (no item improved) and 22 (all items improved), and to compare these numbers between the three treatment groups.

Table III. Quantitative changes in Quality of life items.

Item		Monotherapy	Add-on	Switch	p
1	n	282	245	226
	v1	1.8±1.3	1.9±1.2	1.9±1.4	NS
	v3	0.91±1.0	1.0±1.1	1.1±1.2	NS
	D	–0.93±1.3*	–0.86±1.2*	–0.79±1.4*	NS
2	n	282	246	226
	v1	0.97±1.1	0.95±1.1	0.97±1.2	NS
	v3	0.37±0.67	0.37±0.72	0.42±0.76	NS
	D	–0.60±1.1*	–0.58±1.2*	–0.55±1.1*	NS
3	n	280	246	224
	v1	0.75±1.2	0.80±1.2	0.79±1.2	NS
	v3	0.32±0.67	0.30±0.65	0.33±0.79	NS
	D	–0.44±1.1*	–0.50±1.1*	–0.45±1.0*	NS
4	n	281	246	226
	v1	0.71±1.1	0.78±1.2	1.3±1.5	<0.0001
	v3	0.35±0.74	0.42±0.82	0.47±0.89	NS
	D	–0.36±0.99*	–0.37±0.98*	–0.85±1.5*	<0.0001
5	n	281	243	225
	v1	0.63±1.1	0.74±1.1	0.76±1.2	NS
	v3	0.39±0.83	0.42±0.86	0.44±0.94	NS
	D	–0.25±0.94*	–0.33±0.93*	–0.32±1.1*	NS
6	n	280	242	225
	v1	0.65±1.0	0.66±1.1	0.53±0.96	NS
	v3	0.23±0.68	0.21±0.55	0.25±0.70	NS
	D	–0.43±0.97*	–0.44±1.0*	–0.28±0.83*	NS
7	n	279	244	226
	v1	0.68±1.1	0.75±1.09	0.73±1.2	NS
	v3	0.39±0.77	0.49±0.88	0.45±0.90	NS
	D	–0.29±0.93*	–0.26±0.90*	–0.28±0.90*	NS
8	n	281	244	226
	v1	1.1±1.2	0.89±1.0	0.77±1.1	0.013
	v3	0.37±0.64	0.24±0.56	0.35±0.72	NS
	D	–0.69±1.1*	–0.65±1.0*	0.42±0.95*	0.0088
9	n	281	244	226
	v1	1.3±1.2	0.94±1.1	1.1±1.3	0.0043
	v3	0.54±0.84	0.51±0.77	0.57±0.84	NS
	D	–0.73±1.2*	–0.43±1.1*	–0.50±1.3*	0.0089
10	n	280	242	224
	v1	0.45±0.89	0.62±1.0	0.72±1.2	0.013
	v3	0.26±0.68	0.39±0.83	0.34±0.79	NS
	D	–0.19±0.91**	–0.22±0.93**	–0.38±1.3*	NS
11	n	280	245	225
	v1	1.3±1.4	1.2±1.3	1.1±1.3	NS
	v3	0.69±0.96	0.76±1.1	0.80±1.1	NS
	D	–0.61±1.2*	–0.44±1.1*	–0.32±1.0*
	n	280	245	225
	vl	1.3±1.4	1.2±1.3	1.1 ± 1.3	NS
	v3	0.69±0.96	0.76±1.1	0.80±1.1	NS
	D	–0.61±1.2^*	–0.44±1.1^*	–0.32±1.0^*	0.0095
12	n	280	244	222
	vl	2.6±1.2	2.5±1.1	2.6±1.1	NS
	v3	2.8±1.1	2.7±1.1	2.9±1.1	NS
	D	0.18±1.2**	0.25 ±1.3**	0.24±1.1**	NS
13	n	280	245	225
	vl	1.0±1.2	1.1 ± 1.2	1.0±1.3	NS
	v3	0.63±0.91	0.64±0.57	0.65 ±1.0	NS
	D	–0.40±1.2^*	–0.43±1.0^*	–0.36±1.2^*	NS
14	n	279	243	224
	vl	2.7±1.1	2.6±1.1	2.7±1.1	NS
	v3	2.8±1.1	2.8±1.1	2.9±1.1	NS
	D	0.17±1.1**	0.25±1.1**	0.15±1.1***	NS
15	n	280	243	221
	vl	2.5±1.2	2.5±1.0	2.5±1.2	NS
	v3	2.9±1.1	2.7±1.1	2.7±1.2	NS
	D	0.36±1.1^*	0.19±1.1**	0.19 ±1.2***	NS
16	n	252	191	178
	vl	2.3±1.3	2.3 ±1.2	2.3 ±1.3	NS
	v3	2.8±1.2	2.6±1.2	2.8±1.2	NS
	D	0.45 ±1.2^*	0.29±1.3**	0.50±1.3^*	NS
17	n	281	245	225
	vl	1.2±1.3	1.5±1.3	1.5±1.4	0.028
	v3	0.72±1.1	1.0±1.3	1.0±1.2	0.0035
	D	–0.52±1.2^*	–0.47±1.2^*	–0.52±1.0^*	NS
18	n	280	245	223
	vl	1.1 ± 1.3	1.5±1.3	1.4±1.4	0.0048
	v3	0.74±1.1	1.0±1.3	0.99±1.3	0.012
	D	–0.36±1.1^*	–0.42±1.3^*	–0.41±1.3^*	NS
19	n	269	238	219
	vl	0.75±1.1	0.94±1.3	0.86±1.2	NS
	v3	0.36±0.88	0.58±1.1	0.50±1.0	0.045
	D	–0.39±1.1^*	–0.36±1.1^*	–0.36 ±1.2^*	NS
20	n	259	206	184
	vl	0.53±1.1	0.56±1.2	0.66±1.3	NS
	v3	0.28±0.94	0.26±0.89	0.30±0.97	NS
	D	–0.25±1.1**	–30±1.1^*	–0.36±1.2^*	NS
21	n	264	215	188
	vl	2.5±1.2	2.1±1.4	2.3±1.4	0.0087
	v3	2.7±1.1	2.3±1.3	2.5±1.3	0.0008
	D	0.23 ±1.0**	0.16±1.3	0.27±1.1**	NS
22	n	236	244	222
	vl	2.3 ±1.4	2.3±1.1	2.1±1.1	NS
	v3	3.2±0.96	3.1±0.99	3.1±1.0	NS
	D	0.92±1.6^*	0.77±1.4^*	1.0±1.3^*	NS
Total	N	277	243	222
	vl	24.1 ±14.4	25.5±13.5	25.4±13.4	NS
	v3	14.4±11.2	16.3±10.5	15.9±10.3	NS
	D	–9.67±12.1^*	–9.15±12.2^*	–9.52±10.7^*	NS

Items are: 1, Tiredness; 2, Dizziness; 3, Facial redness; 4, Cold hands and/or feet; 5, Coughing; 6, Tinnitus; 7, Breathing difficulty; 8, Palpitations; 9, Headache; 10, Swollen legs and/or feet; 11, Anxiety; 12, Satisfaction with personal life, 13, Depression; 14, Satisfaction with family life; 15, Satisfaction in performing daily activities; 16, Satisfaction with professional life; 17, Climbing a flight of stairs; 18, Walking around the block several times; 19, Having to give up usual leisure time activites; 20, Having to take leave from work for medical reasons over the previous month; 21, Being satisfied with one's sexual life; 22, Satisfaction with current hypertension treatment. “D”, Difference in quality of life items between V3 and V1 in the three groups receiving nebivolol. A negative value is indicative of improvement, except for items 12, 14, 15, 16, 21 and 22, for which a positive value means improvement.

*p<0.0001;

**p≥0.0001 and p< 0.01;

***p≥0.01 and p<0.05.

Table IV. Qualitative changes in Quality of life (QoL) items.

Item		Monotherapy	Add-on	Switch	p
1	n	282	245	226	NS
	worsening	6.4%	7.4%	11.1%
	no change	33.3%	35.0%	34.9%
	improvement	60.3%	57.6%	54.0%
2	n	282	246	226	NS
	worsening	5.7%	9.4%	5.3%
	no change	52.8%	49.5%	57.1%
	improvement	41.5%	41.1%	37.6%
3	n	280	246	224	NS
	worsening	7.5%	5.7%	4.0%
	no change	61.8%	61.0%	67.8%
	improvement	30.7%	33.3%	28.2%
4	n	281	246	226	<0.0001
	worsening	6.8%	6.1%	8.3%
	no change	66.9%	66.7%	46.2%
	improvement	26.3%	27.2%	45.5%
5	n	281	243	225	NS
	worsening	7.5%	6.6%	9.3%
	no change	69.7%	68.7%	64.9%
	improvement	22.8%	24.7%	25.8%
6	n	280	242	225	NS
	worsening	5.4%	4.6%	4.9%
	no change	66.4%	65.6%	71.5%
	improvement	28.2%	29.8%	23.6%
7	n	279	244	226	NS
	worsening	7.2%	8.2%	7.1%
	no change	69.5%	67.2%	69.4%
	improvement	23.3%	24.6%	23.5%
8	n	281	244	226	NS
	worsening	5.0%	3.3%	5.8%
	no change	52.3%	54.1%	61.0%
	improvement	42.7%	42.6%	33.2%
9	n	281	244	226	0.007
	worsening	9.3%	9.8%	12.0%
	no change	39.1%	50.4%	51.7%
	improvement	51.6%	39.8%	36.3%
10	n	280	242	224	NS
	worsening	7.9%	8.7%	9.4%
	no change	73.2%	70.2%	66.0%
	improvement	18.9%	21.1%	24.6%
11	n	280	245	225	0.0023
	worsening	8.2%	10.2%	9.8%
	no change	49.3%	51.8%	61.8%
	improvement	42.5%	38.0%	28.4%
12	n	280	244	222	NS
	worsening	18.6%	15.6%	14.0%
	no change	52.5%	52.4%	56.7%
	improvement	28.9%	32.0%	29.3%
13	n	280	245	225	NS
	worsening	11.8%	9.4%	9.7%
	no change	54.6%	55.9%	59.8%
	improvement	33.6%	34.7%	30.5%
14	n	279	243	224	NS
	worsening	16.1%	16.5%	18.3%
	no change	59.5%	51.4%	56.2%
	improvement	24.4%	32.1%	25.5%
15	n	280	243	221	0.029
	worsening	10.0%	18.5%	18.6%
	no change	58.2%	50.6%	48.8%
	improvement	31.8%	30.9%	32.6%
16	n	252	191	178	NS
	worsening	11.5%	15.2%	9.0%
	no change	54.0%	52.3%	54.5%
	improvement	34.5%	32.5%	36.5%
17	n	281	245	225	NS
	worsening	7.1%	9.8%	5.8%
	no change	56.2%	53.1%	59.1%
	improvement	36.7%	37.1%	35.1%
18	n	280	245	223	NS
	worsening	8.6%	11.8%	10.3%
	no change	59.6%	47.8%	54.3%
	improvement	31.8%	40.4%	35.4%
19	n	269	238	219	NS
	worsening	4.8%	8.8%	7.8%
	no change	65.5%	63.9%	63.0%
	improvement	29.7%	27.3%	29.2%
20	n	259	206	184	NS
	worsening	5.0%	3.9%	4.4%
	no change	76.5%	76.2%	78.2%
	improvement	18.5%	19.9%	17.4%
21	n	264	215	188	NS
	worsening	15.5%	13.5%	16.0%
	no change	56.1%	58.1%	54.2%
	improvement	28.4%	28.4%	29.8%
22	n	236	244	222	NS
	worsening	12.3%	12.3%	9.0%
	no change	34.3%	30.7%	28.8%
	improvement	53.4%	57.0%	62.2%

Items are: 1, Tiredness; 2, Dizziness; 3, Facial redness; 4, Cold hands and/or feet; 5, Coughing; 6, Tinnitus; 7, Breathing difficulty; 8, Palpitations; 9, Headache; 10, Swollen legs and/or feet; 11, Anxiety; 12, Satisfaction with personal life; 13, Depression; 14, Satisfaction with family life; 15, Satisfaction in performing daily activities; 16, Satisfaction with professional life; 17, Climbing a flight of stairs; 18, Walking around the block several times; 19, Having to give up usual leisure time activites; 20, Having to take leave from work for medical reasons over the previous month; 21, Being satisfied with one's sexual life; 22, Satisfaction with current hypertension treatment. Changes in quality of life items between V1 and V3 in the the three groups receiving nebivolol. In cross-classification and symmetry analyses, all items were significantly improved at V3, except for items 10, 12, 14 (monotherapy), and for items 15, 20 and 21 (switch).

At baseline, the mean (±SD) total score of the 22 questionnaire items (range 0–88) was 24.1±14.4 (monotherapy), 25.5±13.5 (add-on), and 25.4±13.4 (switch). The mean total difference in Table III (at the bottom of the right column) was calculated by attributing a negative value to all improved values; in doing so, the differences between V3 and V1 for items 12, 14, 15, 16, 21 and 22, for which a positive value means improvement (because of the manner in which the original questions were formulated), were converted to a negative value. This results in mean improvements of –9.67, –9.15 and –9.52 in the three groups. The scores dropped markedly and significantly in each group (p<0.0001), with no differences between groups (Table III). The number of items improved per patient was not statistically different between the three groups (7.2, 7.3 and 7.0; p=0.74) (Table IV).

Scoring at inclusion significantly differed between groups with respect to the following QoL items: cold hands and/or feet; palpitations; headache; swollen legs and/or feet; climbing a flight of stairs; walking around the block several times; and satisfaction with one's sex life. These differences were in line with the expected rationale(s) for introducing (or switching to) nebivolol, and/or with drug-related side-effects in the already treated group. For the following items, scoring at final visit (V3; after 2 months on nebivolol) significantly differed between groups: climbing a flight of stairs; walking around the block several times; giving up one's usual leisure time activities; and being satisfied with one's sex life. With respect to the magnitude of changes in QoL scoring between inclusion and termination, the following items significantly differed between groups: cold hands and/or feet; palpitations; headache; and anxiety. The latter effects were in keeping with nebivolol's dual pharmacological properties (Table III). The three specific subscores (physical aspects, subjective feelings, and symptomatic status) also dropped significantly within each group (p<0.0001; not shown).

The qualitative changes between V3 and V1 within each nebivolol group (monotherapy, add-on and switch) are detailed in Table IV. The table lists the proportions of subjects reporting improvement, worsening or lack of change for each QoLaN questionnaire component between V3 and V1. These items relate either to QoL or clinically relevant items, as potential rationale(s) for introducing/ switching BP-lowering drug(s) and/or as side-effects associated with common classes of BP-lowering drugs. All groups showed harmonious drifts toward improvement, except for items 4 (cold hands and/or feet), 9 (headache), 11 (anxiety) and 15 (satisfaction in performing daily activities), for which the changes were different between groups. At V3, all items showed ample shifts in the sliding scale distribution toward improvement of QoL, lesser side-effects or both. These shifts were obvious in the different groups (monotherapy, add-on and switch), with the most marked differences observed for tiredness, palpitations, headache, and cold extremities.

The questionnaire's items that shifted most were those with the largest absolute difference in improvement vs. worsening (such as tiredness, headache, palpitations, satisfaction with current therapy), i.e. items for which the proportion of subjects reporting “no change” between V3 and V1 was the lowest. While absenteeism only modestly shifted toward improvement in the overall cohort and in the monotherapy and switch groups, there was a slight shift toward increased absenteeism in the add-on group. As a whole, the scale shifts in the overall cohort were paralleled in the groups, both in magnitude and directionality. Regarding cold extremities, however, the improvement-to-worsening ratio was more pronounced in the switch group (Table IV).

Discussion

The QoLaN study assessed, in a population-based cohort of subjects with mild to moderate hypertension, the QoL and efficacy of nebivolol at different intervention levels of the JNC-VII hypertension treatment algorithm. With respect to JNC-VII BP thresholds for diabetic and non-diabetic subjects, nebivolol use was highly effective as monotherapy, as add-on or as switch agent, as indicated by the percentages of goal-achieving subjects during and at the end of the study. In order to enumerate the responders, we applied strict criteria, namely a combined systolic/diastolic decrement of ≥10/5 mmHg. Not withstanding the level of intervention (monotherapy, add-on, switch), nebivolol use entailed that the majority of subjects reached the criteria to be categorized as belonging to the responder category at study completion, irrespective of glucose tolerance status. Furthermore, the results of this study are in line with the concept evoked in the ESH/ESC 2007 Guidelines regarding specificities within the beta-blockers class [1,2].

The design of the QoLaN questionnaire aimed at documenting wellness while being specifically adapted to capture the magnitude of both common hypertension symptoms and/or commonly reported side-effects of the usual BP-lowering drugs in a population-based study. As reported by Van Bortel et al. [14], nebivolol use is particularly neutral with respect to overall tolerance to various levels of exercise, and this may account for part of the benefits reported. Thus, the improvements in questionnaire's items were related not only to the named side-effects or to conditions commonly observed following the use of first-generation beta-blockers, but also to more holistic matters pertaining to personal, family of professional life, as well as satisfaction with current therapy.

The QoLaN population included a high proportion of subjects with a known diagnosis of diabetes mellitus, in whom strict BP control is essential to prevent micro- and macrovascular complications. The finding of high diabetes prevalence was not unexpected, since insulin resistance and the metabolic syndrome phenotype are common underlying conditions and co-morbidities in subjects with essential hypertension and/or type 2 diabetes, the common form of diabetes mellitus. The ample BP-lowering efficacy of nebivolol reported in this study was observed both in non-diabetic and diabetic subjects, despite the latter having to reach more ambitious BP goals to qualify as responders. The uniform results observed in non-diabetic and diabetic subjects suggest that nebivolol may be a well-tolerated means of decreasing BP through beta-blockade regardless of glucose homeostasis status. This may be of particular interest in those diabetic subjects requiring beta-blockade while suffering of lower limbs arterial macroangiopathy.

This study has obvious limitations, including its open design as an open phase IV study (where any change in treatment may result in subjective improvement) with substantial and unsurprising dropout rate. However, the baseline characteristics of non-completers were not different from completers (not shown). Another potential limitation is the use of a specifically designed, though unvalidated, questionnaire to assess the effects of nebivolol. On the other hand, the chosen questions were designed to capture any relevant changes in physical aspects, subjective feelings and symptomatic status, which altogether may significantly impact on first-line management of high BP in daily life. A potential confounder of the QoLaN questionnaire resides in its lack of allowance for current employment (vs. retirement) status. Considering the average age of the study population (61 years), one may reasonably assume that a large proportion of subjects who reported no change were actually retired. The open study design also has inherent limitations. On the other hand, the real-life setting and the magnitude of the cohort size contribute to relevance of the observed changes. Furthermore, no previous large-scale study addressed the QoL issue with respect to using a dual-effect beta-blocker such as nebivolol in primary care as BP-lowering agent.

As a class, beta-blockers are highly effective BP-lowering drugs, albeit with a higher degree of class-related side-effects compared with newer renin– angiotensin blocking agents. Yet, in a double-blind, randomized, parallel group study evaluating nebivolol and angiotensin receptor blocker losartan on QoL and BP-lowering, Van Bortel et al. [19] found similar decrease in SBP, a larger decrease in DBP with nebivolol and no difference in overall QoL assessing physical well-being. The QoLaN study questionnaire addressed not only aspects of physical well-being, but also subjective feelings as well as the impact of current health status on daily activities.

In conclusion, the QoLaN study found in a population-based cohort with mild to moderate hypertension that nebivolol markedly improves both BP and QoL at different intervention levels of the JNC-VII hypertension treatment algorithm. These improvements were of similar magnitude whenever nebivolol was introduced as a monotherapy, add-on or switch treatment modality in a mixed non-diabetic and diabetic population in a primary care setting.

Acknowledgement

This study was funded by a grant of Menarini Benelux SA/NV.

Disclosure: Prof. Dr. M. Hermans has received speaker's fees, advisory honoraria and/or scientific or travel grants from: AstraZeneca, Aventis, Bayer, Covance, Danone, E. Lilly, Solvay Pharma, GSK, LifeScan, Lipha, Medtronic-Minimed, Menarini Benelux, Menarini Diagnostics, Menarini International, MSD, MSH, NovoNordisk, Nycomed, Pfizer, Roche, Sanofi-Aventis, Servier Benelux, Solvay Pharma. Prof. Dr. A. Albert and L. Seidel carried out the statistical analysis and their department was paid by Menarini Benelux for the work done. Prof. Dr. P. van de Borne: no conflicts of interest to report. Dr. O. De Coster has received speaker's fees, advisory honorary and travel grants from: Boston Scientific, Biotronik, Medtronic, Solvay Pharma, Novartis, AstraZeneca, Menarini Benelux and Servier Benelux.