Journal of Human Hypertension (2000) 14, 205–212  2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Bisoprolol and nifedipine retard in elderly hypertensive patients: effect on quality of life

CJ Bulpitt1, M Connor1, M Schulte2 AE Fletcher3 on behalf of the European Bisoprolol Trial Investigators 1Section of Care of the Elderly, Imperial College School of Medicine, Hammersmith Hospital, London, UK; 2Merck KgaA, Darmstadt, Germany; 3Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK

Subjects over the age 60 with sustained sitting diastolic quality of life, there were no statistically significant dif- pressures of 95–115 mm Hg were randomised to a ferences between the two groups after 8 weeks. How- or nifedipine ever, when analysing the results of the last available (368 ؍ regime based on bisoprolol (n for 24 weeks. The goal diastolic press- assessment (usually at 24 weeks) there were significant (379 ؍ retard (n ure was р90 mm Hg and to achieve this, double-blind (P Ͻ 0.05) improvements in tension/anxiety, anger/ medication could be doubled (5/10 mg bisoprolol, hostility, vigour/activity, and confusion/bewilderment, 40/80 mg nifedipine retard) or hydrochlorothiazide assessed by the Profile of Mood States (POMS) in 25 mg (unblinded) could be added to the higher dose. In patients receiving bisoprolol in comparison to those an intention-to-treat analysis, 309 subjects in both the receiving nifedipine retard. The Sickness Impact Profile bisoprolol and nifedipine retard treated group provided and objective tests of cognitive function did not differ at least a baseline and a second quality of life assess- statistically between the two groups. Quality of life was ment (82%). An excess of symptoms was observed in maintained at a good level on both treatments with the nifedipine group for oedema of the legs, nocturia, advantages for bisoprolol in certain areas. Journal of constipation, racing heart and heart thumping. Fewer Human Hypertension (2000) 14, 205–212. patients reported wheeze in the nifedipine group. For

Keywords: quality of life; anxiety; cognitive functioning; elderly; bisoprolol; nifedipine

Introduction treat analysis. In the second trial 540 patients were randomised to 6 months treatment with either nifed- The quality of life (QOL) of patients on antihyper- ipine retard, atenolol or cilazapril.3 Symptomatic tensive treatment is important in many ways. complaints and withdrawals increased with nifedip- Firstly, measures of quality of life reflect physical ine retard but fatigue was lessened by this drug. and psychological well-being and activity and these Finally a small cross-over trial of 61 patients are of premium importance to the patient. Second, received 8 weeks of bisoprolol and 8 weeks of nifed- quality of life is affected by the nature of the treat- ipine retard.4 There was no difference between the ment and is closely related to default from treatment drugs in the QOL outcome although the ‘on-treat- and non-compliance with the treatment regime.1 Nifedipine retard and bisoprolol are both widely ment’ analysis suggested a trend in favour of nifedi- prescribed representatives of the dihydropyridine pine in a Health Status Index (HSI). Individual calcium channel blockers and selective beta-block- symptoms were not reported in this trial but the overall complaint rate was incorporated in the ers respectively. Although these drug groups have 4,5 been compared in quality of life trials2–4 the out- HSI. However the relative merits of the two drugs come has not been clear. The first trial compared have not been established and we report the results nifedipine gastrointestinal therapeutic system of a large trial performed by the European Bisoprolol (GITS) with atenolol.2 Withdrawal rates on nifedip- Trial Investigators to compare bisoprolol with nifed- ine tended to be high but there was an advantage for ipine retard.6 nifedipine GITS in the 60% of patients remaining on It is also widely believed that beta-blockers may the drug. This was not confirmed in the intention-to- have additional benefits in reducing anxiety and tension. Thus several trials have assessed anxiety with beta-blocker treatment using the Symptom Rat- Correspondence: Professor CJ Bulpitt, Section of Care of the ing Test (SRT) or Profile of Mood States (POMS). Elderly, Imperial College School of Medicine, Du Cane Road, London W12 0NN, UK This aspect of beta-blocker therapy is also assessed Received 14 September 1999; revised 20 November 1999; in the present trial. accepted 23 November 1999 Bisoprolol and nifedipine retard: effect on QOL CJ Bulpitt et al 206 Patients and methods ish and back-translated by someone who had not seen the original English version. The translation Male or female patients over 60 years of age suffer- and back-translation was repeated until an accept- ing from essential hypertension (sitting diastolic able match was obtained to the original. The trans- у blood pressure on placebo at baseline 95 mm Hg lations were tested with patients to ensure that they р and 115 mm Hg) were eligible for inclusion. Pre- were acceptable to, and understood by, the average vious antihypertensive medication was washed out person. during 14 days prior to the first administration of The interviewers were all trained by the investi- active study medication. Informed consent was gators in dedicated sessions. In the trial the QOL obtained from all patients prior to any study-related questionnaire was administered by the trained inter- procedures. During the second week of wash-out on viewers in a quiet location prior to having blood no treatment a placebo was given. The randomised pressure or other measurements made. The ques- double-blind active-treatment period lasted for 6 tionnaire consisted of the following sections. months and started with low-dose therapy (bisoprolol 5 mg o.d., or nifedipine retard 20 mg b.d.) for 4 weeks. Matching placebos were employed (a) Following sections of the Sickness Impact so that all subjects took the same number of tablets. Profile (SIP)7 After 4 weeks, they remained on low-dose treatment р Social Interaction: describes the effects of poor if diastolic blood pressure had been reduced to 90 health on relationships with family and friends, and mm Hg or they were titrated to the higher doses of enjoyment of social activities. study medication (bisoprolol 10 mg o.d., nifedipine Homework: describes the effects of poor health on retard 40 mg b.d.). After another 4 weeks, patients housework, and other primarily physical activities on high-dose treatment whose diastolic blood press- Ͼ related to looking after the home. ure continued to be 90 mm Hg were given un- Sleep and Rest: describes the effect of poor health blinded 25 mg of hydrochlorothiazide (HCT), in on daytime and night-time rest. addition. Each section includes a set of statements which Blood pressure measurements (sitting after 5, 6 are individually read to the patient. They respond if and 7 min of rest, standing 2, 3 and 4 min after they agree with the statement, and also if it is due rising) were performed at baseline as well as after 4, to their health. High scores indicate worse quality 8 and 24 weeks of active treatment. of life. All measurements were carried out at approxi- mately the same time of day (in the morning prior to the morning dose) using a standard sphygmo- (b) Digit symbol substitution from the Wechsler manometer. Systolic blood pressure was taken as Adult Intelligence Scale (WAIS)8 Korotkoff phase I and diastolic blood pressure as Korotkoff phase V sounds. The patients are asked to write different symbols Adverse events which were volunteered by sub- next to numbers 1 to 9. The number of correct jects or observed by the investigators were recorded, responses are counted over 90 sec. This is a test of regardless of whether or not a causal relationship cognitive functioning, namely psychomotor per- with the study medication was assumed. Adverse formance, attention and integration. events were also assessed as to their intensity (mild, moderate or severe). Safety laboratory parameters (c) Symbol copying (haemoglobin, leucocytes, differential white cell count, ASAT ALAT, ␥-GT, glucose, total cholesterol, This was adopted from the Digit Symbol Substi- triglycerides, creatinine, electrolytes) and standard tution Test. The patients are asked to copy as many 12-lead ECG recordings at rest were performed at the of a random series of 240 symbols for a period of beginning and at the end of the study. Furthermore, 90 sec. The number of correct copies informs more investigators and patients were asked about the tol- on motor speed than cognitive functioning. erability of the study medication. All study medi- cation (placebo, bisoprolol, nifedipine retard) was (d) Brief memory and concentration assessment provided as capsules of identical size, colour and [Cognitive Failures Questionnaire 1] shape. Investigators were based in Austria, Italy, Ger- Seven questions on memory, thinking clearly, mind many, Netherlands, Poland, Spain, Switzerland and wandering, concentration, forgetting, being dis- the UK. The study was conducted in accordance tracted and having poor attention scored on a 4- with the Declaration of Helsinki as amended in point scale. A high score indicates less good cog- Tokyo, Venice and Hong Kong and good clinical nition. practice (GCP) guidelines. The trial protocol was approved by independent ethics committees of each 9 participating country. (e) Cognitive failures questionnaire [Cognitive Failures Questionnaire 2]

Quality of life measurement This assesses the performance of everyday memory tasks as reported by the subject. Twenty-five items The English version of the questionnaire was trans- were scored on a 5-point scale. A high score indi- lated into Dutch, German, Italian, Polish and Span- cates less good memory.

Journal of Human Hypertension Bisoprolol and nifedipine retard: effect on QOL CJ Bulpitt et al 207 (f) Profile of Mood States (POMS)10 change in a particular variable, divided by the pooled standard deviation at baseline.12 This is a 65-item scale consisting of six subscales: tension/anxiety, depression/dejection, anger/ hostility, vigour/activity, fatigue/inertia and Results confusion/bewilderment. Patients rate each item on A total of 771 patients were enrolled into the study. a five-point scale. A high score indicates a worse During the prephrase 24 patients were withdrawn, quality of life except for vigour/activity. 747 patients were randomised by 60 trial centres in eight European countries. The study was completed (g) Symptom assessment5 by 614 patients. Dropouts from active treatment for occurrence of adverse events refer to 74 patients Thirty-four symptoms were assessed including (bisoprolol: n = 23; nifedipine: n = 51). All 747 those associated with hypertension and those occur- patients randomised took at least one dose of active ring as side effects of treatment. Thirty-four were medication and were included in the analysis of assessed in men and 32 in women. The patients safety (bisoprolol: n = 368; nifedipine: n = 379). rated their symptoms on a five-point scale according Patient characteristics and previous antihyperten- to how much the symptom had bothered them in sive medication were very similar in the two treat- the past week, namely not at all, a little, moderately, ment groups.6 Blood pressure averaged 167/101 and quite a bit and extremely. Symptoms were also cat- 169/102 mm Hg in the bisoprolol and nifedipine egorised as present (bothered them moderately, groups at baseline. After 24 weeks the blood press- quite a bit or extremely) or absent (present, not at ures were 149/86 and 148/86 mm Hg respectively.6 all or a little). The latter categories were employed In the intention-to-treat analysis of 721 patients, 490 to provide a complaint rate giving the percentage of patients were on treatment with low dose symptoms reported. (bisoprolol: n = 229/64.1%; nifedipine: n = 261/71.7%), 145 with high dose (bisoprolol: n = 75/21.0%; nifedipine: n = 70/19.2%) and 86 with (h) Health Status Index (HSI) high dose plus hydrochlorothiazide (bisoprolol: n = = This varies between a theoretical high of 1.0 (when 53/14.9%; nifedipine: n 33/9.1%) at their individ- perfectly well) to zero when dead. The HSI is com- ual study end. puted from answers to the SIP and other questions and modified according to the symptom complaint Adverse events rate.5,11 Seventy-four adverse drug reactions led to with- drawal, 51 in the nifedipine group (13.5%) and 23 in Quality control of the questionnaires was performed the bisoprolol group (6.3%, P Ͻ 0.001). As expected centrally by the Epidemiology Research Unit based nifedipine treatment led to oedema (14 subjects), at the Hammersmith Hospital Campus. One centre flushing (10) and headache (5). The corresponding was removed from the study as the questionnaires results for bisoprolol were three, one and one were given to the patients to complete and the infor- respectively. Bisoprolol reduced palpitations (zero mation was not collected by an interviewer. compared with four) and was not associated with any serious asthmatic reactions, although change Statistical methods was reported by two patients (compared to none). Efficacy variables were primarily analysed using the Baseline characteristics of patients providing two intention-to-treat (ITT) approach. Additionally, a or more assessments of quality of life supportive per-protocol analysis was carried out. Differences between medications regarding with- Eighty-four percent of patients receiving bisoprolol drawal rates were assessed by Fisher’s exact test. (309) and 82% of those receiving nifedipine (309) When assessing changes between two time points, completed two or more quality of life interviews. data in excess of 3 standard deviations in either Table 1 gives the baseline characteristics for these direction were excluded. patients. Average age was 68 years with a range of Changes in QOL measures were determined 59–90 years. There were no statistically significant between baseline (0) and 8 weeks, between baseline differences at baseline between the two random- and 24 weeks and between baseline and the last ised groups. available questionnaire. The analyses to be Table 2 gives the changes in the quality of life presented include the 0 to 8-week intention to treat scores between 0 and 8 weeks and between the base- analysis and the 0 – last available analysis. The lat- line and the last available questionnaire following ter was very similar to the 0 to 24-week analysis but randomisation. The second analysis allows the cap- included data from withdrawing patients. The ture of information on those who withdrew. How- change in QOL summary statistics were compared ever, these results are almost identical to those for using an unpaired t-test with logarithmic transform- the change between 0 and 24 weeks as 281 on biso- ation as required. The change in symptoms was prolol completed a 24-week questionnaire and 273 assessed by chi-squared tests. on nifedipine. All analyses were intention-to-treat. The effect size was calculated for certain vari- Between baseline and 8 weeks the complaint rate ables. This is the difference between the drugs in the fell on both bisoprolol and nifedipine. The two

Journal of Human Hypertension Bisoprolol and nifedipine retard: effect on QOL CJ Bulpitt et al 208 Table 1 Baseline characteristics of the patients involved in the intention-to-treat analysis with two or more interviews completed

Bisoprolol s.d. Nifedipine s.d.

(n) Mean Range (n) Mean Range

Complaint rate (%) 309 17.7 0–74 12.5 309 18.61 0–79 12.3

Sickness impact profile Home Management 309 15.4 0–72 14.8 309 15.8 0–78 16.7 Social Interaction 309 16.7 0–92 15.3 309 17.1 0–76 14.4 Sleep and Rest 309 17.3 0–100 16.6 309 16.9 0–76 14.4 Total 309 16.5 0–68 12.9 309 16.7 0–61 11.6

Profile of Mood States Tension-Anxiety 309 9.3 1–35 5.7 309 9.2 0–30 5.8 Depression-Dejection 309 7.0 0–51 8.4 309 7.3 0–36 8.0 Anger-Hostility 309 5.6 0–43 6.2 309 5.7 0–31 6.0 Vigour 309 14.2 0–31 6.2 309 15.1 0–30 6.3 Fatigue 309 5.7 0–22 4.8 309 5.7 0–27 4.9 Confusion 309 5.6 0–18 3.5 309 5.6 0–20 3.6

Digit Symbol Substitution Correct Responses 304 28.5 0–73 11.9 305 29.5 0–90 12.2

Symbol Copying Correct Responses 303 64.2 0–140 26.8 305 66.1 0–140 25.5

Cognitive Failures 1 309 3.7 0–14 3.4 308 3.6 0–17 3.3 2 308 24.8 0–62 13.0 309 24.2 0–81 13.0

Health Status Index 309 0.75 0.5–0.98 0.17 309 0.75 0.5–0.98 0.17

Age 309 67.9 59–90 6.4 309 68.5 59–86 5.9

Table 2 Changes in overall quality of life scores. Intention-to-treat analysis

Bisoprolol Nifedipine R P Bisoprolol Nifedipine R P Change (s.e.m.) Change (s.e.m.) 0–8 Change (s.e.m.) Change (s.e.m.) 0–LA 0–8 wks 0–8 wks 0–LA 0–LA

Complaint rate (⌬ %) −1.45 (0.37) −0.87 (0.44) 0.554 −2.27 (0.51) −1.02 (0.57) 0.101

Sickness Impact Profile Social Interactiona −3.25 (0.51) −3.19 (0.53) 0.928 −4.47 (0.54) −4.55 (0.64) 0.920 Home Managementa −2.63 (0.58) −2.24 (0.61) 0.647 −4.04 (0.69) −2.93 (0.64) 0.237 Sleep & Resta −2.35 (0.62) −2.75 (0.67) 0.664 −3.97 (0.76) −3.17 (0.80) 0.466 Totala −2.93 (0.37) −2.82 (0.41) 0.999 −4.03 (0.46) −3.96 (0.49) 0.919

Profile of Mood States Tension/Anxietya −1.11 (0.25) −0.79 (0.26) 0.370 −2.04 (0.26) −0.69 (0.28) Ͻ0.001 Depression/Dejectiona −0.75 (0.26) −1.18 (0.29) 0.271 −1.42 (0.27) −1.68 (0.33) 0.546 Anger/Hostilitya −0.90 (0.22) −0.70 (0.21) 0.501 −1.29 (0.24) −0.52 (0.27) 0.032 Vigour/Activity 0.57 (0.23) −0.27 (0.23) 0.344 0.83 (0.25) −0.24 (0.25) 0.002 Fatigue/Inertiaa −0.25 (0.20) −0.81 (0.21) 0.055 −0.74 (0.22) −0.64 (0.23) 0.754 Confusion/Bewildermenta −0.33 (0.14) −0.34 (0.16) 0.969 −0.79 (0.15) −0.35 (0.17) 0.050

Digit Symbol Substitution Correct Responses 3.02 (0.35) 3.39 (0.37) 0.474 4.86 (0.45) 3.81 (0.45) 0.101

Symbol Copying Correct Responses 3.95 (0.66) 5.03 (0.67) 0.249 6.55 (0.84) 6.59 (0.75) 0.970

Cognitive Failures 1a −0.34 (0.14) −0.49 (0.14) 0.452 −0.69 (0.15) −0.38 (0.16) 0.140 Cognitive Failures 2a −1.91 (0.43) −1.57 (1.11) 0.877 −3.03 (0.53) −1.97 (0.54) 0.160

Health Status Index 0.041 (0.010) 0.031 (0.010) 0.465 0.039 (0.010) 0.046 (0.010) 0.531

0–8, 0 to 8 weeks; 0-LA, 0 to last available; s.e.m., standard error of mean. aNegative score equals improvement, otherwise positive score equals improvement. P, Probability referring to comparison of change on bisoprolol will change on nifedipine retard; R, Retard.

Journal of Human Hypertension Bisoprolol and nifedipine retard: effect on QOL CJ Bulpitt et al 209 groups also improved in Sickness Impact Scores, of oedema, constipation, and nocturia and, compat- Profile of Mood States measures, measures of cogni- ible with the known action of beta adrenoceptor tive functioning and the Health Status Index. The blocking drugs, bisoprolol tended to reduce (P Ͻ improvements did not differ between the two ran- 0.05) heart thumping and racing heart and to be domised groups, however for ‘last available’ assess- associated with wheezing. ments in the POMS, the following were statisti- cally different: Discussion (1) reduced tension-anxiety with bisoprolol (−2.04 The present trial studied over 600 patients followed units on bisoprolol vs −0.69 units on nifedipine, for 24 weeks and is broadly in agreement with a trial P Ͻ 0.001); that compared 182 patients on atenolol with 179 on (2) reduced anger-hostility with bisoprolol (−1.29 nifedipine retard for a 6-month period.3 units on bisoprolol vs −0.52 units, P = 0.032); Both trials showed an excess of symptomatic com- (3) increased vigour with bisoprolol (+0.83 units vs plaints on nifedipine retard leading to a higher dis- −0.24 units, P = 0.002); continuation rate on nifedipine. However, most (4) a greater reduction in confusion-bewilderment importantly, in the smaller trial atenolol did not with bisoprolol (−0.79 against −0.35, P = 0.0501). influence psychological well-being although the The intention-to-treat changes between 0 and 24 POMS was also employed in assessment. Bisoprolol weeks confirmed the changes between baseline and is more lipophilic than atenolol13 and therefore last available questionnaire in tension-anxiety (P = could be expected to enter the central nervous sys- 0.001), anger/hostility (P = 0.018), vigour (P = 0.003) tem (CNS) more effectively. However, propranolol but not confusion (P = 0.125). A per protocol 0 to is even more lipophilic and produces an excess of 24-week analysis also confirmed these results. The symptoms,14,15 supposedly due to CNS penetration. ␤ 13 changes in total complaint rate were not statistically Bisoprolol is notable for its 1 selectivity and this significantly different, either in the O-LA analysis may provide a clue as to how it reduces tension, (Table 2) nor the 0 to 24-week intention-to-treat anxiety, anger and confusion. It has been stated that analysis (a 3.09 unit reduction with bisoprolol com- ‘alterations in mood and thought appear to be pared with a 2.02 unit reduction with nifedipine, P caused more often by other beta-blockers than by = 0.151). bisoprolol’.13 This observation may have arisen from Table 3 gives the changes in symptoms that beneficial effects of bisoprolol on anxiety, tension covered the adverse drug reactions leading to with- and confusion. In randomised quality of life studies drawal, namely oedema, flushing, headache, palpi- atenolol has produced results equivalent to angio- tations, itching and wheezing; and two other symp- tensin-converting enzyme (ACE) inhibitors, verapa- toms, statistically significant at the 1% level, mil, and a diuretic.1 In a study comparing atenolol constipation, and nocturia. Nifedipine was associa- with the nifedipine gastrointestinal therapeutic sys- ted (P Ͻ 0.01) with a statistically significant excess tem (GITS); where release of drug is more gradual

Table 3 Symptoms reported on the questionnaire for adverse reactions (oedema, flushing, headaches, palpitations, itching and wheezing) and other symptoms that were statistically significant at the 1% level. The percentage improving and worsening are recorded at 8 weeks and at the last available result (usually 24 weeks)

Symptom Last available Bisoprolol Nifedipine R P (LA) or 8 weeks Improve (%) Worse (%) Improved (%) Worse (%)

Oedema 8 16 10 13 30 Ͻ0.001 LA 17 16 16 34 Ͻ0.001 Flushing 8 16 11 12 19 0.056 LA 17 10 18 15 0.529 Headache 8 34 13 31 16 0.719 LA 38 12 36 16 0.207 Heart thumps and misses beat 8 26 10 19 13 0.428 LA 25 8 22 17 0.039 Racing heart 8 30 9 26 15 0.198 LA 35 8 30 19 0.027 Itching 8 7 10 12 13 0.014 LA 10 12 12 17 0.233 Wheezing 8 10 10 14 9 0.328 LA 10 8 17 12 0.039 Constipation 8 23 9 15 20 0.003 LA 19 8 17 23 Ͻ0.001 Nocturia 8 23 15 21 26 0.023 LA 29 16 25 29 0.002

P values assess between drug differences; R, Retard.

Journal of Human Hypertension Bisoprolol and nifedipine retard: effect on QOL CJ Bulpitt et al 210 Table 4 Effect sizes in 11 trials that have assessed either anxiety measured by the Symptom Rating Test (SRT) or tension/anxiety assessed by the Profile of Mood States (POMS). Also given are the effect sizes for cognitive functioning using the SRT or confusion/bewilderment using the POMS

Trial reference Best performing Comparator Effect size drug Anxiety/tension Cognition/confusion SRT POMS SRT POMS

21 Verapamil Nifedipine R 0.15 0.36 15 Verapamil Propranolol 0.32 0.14 22 Pinacidil Nifedipine R 0.11 0.18 23 Rilmenidine Methyldopa 0.00 0.32 24 Atenolol Captopril 0.17 0.04 4 Bisoprolol Nifedipine R 0.02 0.09 18 Bisoprolol Bendrofluazide 0.04 0.19 25 Atenolol Captopril 0.03 0.09 0.05 0.00 3 Atenolol Cilazapril – 0.02 – 0.00 3 Atenolol Nifedipine R – 0.02 – 0.00 19 Dilevalol Bendrofluazide – 0.21 – 0.13 Present trial Bisoprolol Nifedipine R – 0.23 – 0.13

R, Retard.

and 24-h action is provided with one dose, a per ide, found no differences, but only studied patients protocol analysis suggested an advantage from for 8 weeks. nifedipine GITS but the intention-to-treat analysis In a trial comparing dilevalol with bendrofluazide did not confirm this.2 The difference between the in the elderly hypertensive over 6 months19 the Pro- two analyses is assumed to be due to the exclusion file of Mood States was employed as in the present of withdrawals from the per protocol analysis. trial. The falls in tension-anxiety and depression- Nevertheless it is probable that long-acting formu- dejection on dilevalol were 1.06 and 1.31 units lations of nifedipine smooth out the peak and trough respectively with significance levels of 0.12 and 0.09 plasma concentrations and have an advantage over when compared with bendrofluazide. These changes nifedipine retard. However, a recent comparison of are similar to those observed in the present study nifedipine GITS with the longer acting dihydropyri- and may be due to the fact that dilevalol is also a dine calcium channel blocker, amlodipine, sug- beta-blocker. However, dilevalol is a non-specific gested advantages in the overall measures of QOL beta-blocker with some alpha-blocking activity and and vitality for nifedipine GITS, albeit with more beta-adrenergic peripheral vasodilating capacity. positive effects on cognitive functioning in the The drug has been withdrawn owing to hepatotoxic- amlodipine group.16 A randomised QOL trial is ity.20 required comparing bisoprolol, atenolol and long- Table 4 gives the effect sizes for nine trials in acting nifedipine. Owing to differential withdrawal hypertensive patients where anxiety has been meas- the present analysis relies mainly on the comparison ured using the Symptom Rating Test (SRT) or of baseline with the last available information in an tension/anxiety using the Profile of Mood States intention-to-treat analysis. (POMS). The effect size allows a direct comparison The randomised cross-over trial of de Hoon and of the results in different trials. One trial had a small colleagues4 was similar in certain respects to the effect size of 0.32 and suggested that propranolol did present trial but only obtained QOL results in 61 not reduce anxiety.15 Three trials compared atenolol patients studied for 8 weeks. The present trial dem- with an ACE inhibitor and, although atenolol always onstrates that the benefits of bisoprolol were not tended to reduce anxiety more than the ACE inhibi- apparent at 8 weeks. De Hoon et al4 employed the tors (effect sizes 0.02 to 0.17), no effect size was sub- Bulpitt and Fletcher questionnaire5 and the Symp- stantial. Similarly the effect size for dilevalol com- tom Rating Test (SRT)17 as a measure of psychologi- pared to bendrofluazide (0.21) was small. In the cal well-being and failed to determine a reduction present study the effect size for anxiety in favour of in anxiety with bisoprolol. They did not report the bisoprolol was of a similar order of magnitude (0.23) individual symptoms incorporated in the Bulpitt to that observed in the comparison of dilevalol with and Fletcher questionnaire but listed 17 adverse bendrofluazide and suggests a real but small benefit events on bisoprolol against 10 on nifedipine retard. in favour of these beta-blockers. As pointed out The latter did not include oedema, flushing or head- above, these benefits were not apparent after 8 ache. Three patients dropped out whilst on nifedip- weeks of treatment. ine retard and three on bisoprolol. The disagreement Confusion/bewilderment POMS scores did not between the result of the two trials may be due to differ in the dilevalol/bendrofluazide trial,18 nor in the relatively small numbers being followed for 8 the atenolol/cilazapril/nifedipine trial.3 Neverthe- weeks in the de Hoon study. Similarly the random- less dilevalol treatment was significantly better than ised cross-over trial of Vanmolkot et al18 employed bendrofluazide when assessed by the objective Digit the Bulpitt and Fletcher questionnaire and the SRT. Symbol Substitution and Symbol Copying tests. In The authors compared bisoprolol with bendrofluaz- the present trial objective tests of cognitive func-

Journal of Human Hypertension Bisoprolol and nifedipine retard: effect on QOL CJ Bulpitt et al 211 tioning did not reveal any differences between biso- 2 Testa MA, Hollenberg NK, Anderson RB, Williams GH. prolol and nifedipine retard nor did subjective Assessment of quality of life by patient and spouse evaluation of memory and attention. However there during antihypertensive therapy with atenolol and was some evidence for a greater improvement in nifedipine gastrointestinal therapeutic system. Am J confusion/bewilderment on bisoprolol compared to Hypertens 1991; 4: 363–373. nifedipine retard. Although of borderline signifi- 3 Fletcher AE et al. Quality of life with three antihyper- = tensive treatments cilazapril, atenolol, nifedipine. cance (P 0.04) two other trials have reported a sub- Hypertension 1992; 19: 499–507. jective cognitive problem with nifedipine retard. 4 de Hoon JN, Vanmolkot FH, van de Ven LL, Van-Bortel These trials assessed cognitive function with the LM. Quality of life comparison between bisoprolol and 21,22 Symptom Rating Test. One revealed a deterior- nifedipine retard in hypertension. Cardiovasc Drugs & ation with nifedipine retard in comparison with pin- Ther 1997; 11: 465–471. acidil, a potassium channel opener, and the second 5 Bulpitt CJ, Fletcher AE. The measurement of quality of revealed a deterioration with nifedipine retard in life in hypertensive patients: a practical approach. Br comparison with verapamil. Table 4 gives the effect J Clin Pharmacol 1990; 30: 353–364. sizes. Small effects (effect sizes 0.32–0.36) were seen 6 European Bisoprolol Trial Investigators. European when verapamil was compared with nifedipine study in elderly hypertensive patients – comparison of retard and rilmenidine was compared with methyl- bisoprolol and nifedipine retard on efficacy, safety and dopa. Very small effect sizes were observed when on quality of life. (In preparation.) verapamil was compared to propranolol (0.14), pina- 7 Bergner M, Bobbit RA, Carter WB, Gilson BS. The sick- ness impact profile: development and final revision of cidil to nifedipine retard (0.18), dilevalol to bendro- a health status measure. Med Care 1981; 19: 787–805. fluazide (0.13), and bisoprolol to nifedipine retard 8 Wechsler D. The Measurement and Appraisal of Adult (0.09–0.13). Atenolol did not differ from captopril, Intelligence Scale. Psychological Corporation: New cilazapril or nifedipine retard with respect to cogni- York, 1955. tive functioning. These data are difficult to interpret 9 Broadbent DE, Cooper PF, Fitzgerald P, Parkes KR. The but the possibility remains that methyldopa and cognitive failures questionnaire (CFQ) and its corre- nifedipine have subtle adverse effects on cognitive lates. Br J Clin Psych 1982; 21: 1–16. function with methyldopa having the greatest 10 McNair DM, Lorr M, Doppleman LF. Manual for the impact. This may also be true for propranolol,15 ben- Profile of Mood States. San Diego Educational and drofluazide18–19 and nifedipine GITS.16 Industrial Testing Service: San Diego, California, 1971. A recent observational study revealed increased 11 Bulpitt CJ et al on behalf of the Cilazapril-Captopril white matter changes in patients treated with cal- Multicentre Group. Quality of life in chronic heart fail- ure: cilazapril and captopril versus placebo. Heart cium channel blockers.26 However a large random- 1998; 79: 593–598. ised trial of active treatment against placebo in the 12 Fletcher A et al. Quality of life measures in health care management of isolated systolic hypertension (the II: design, analysis and interpretation. BMJ 1992; 305: Syst-Eur trial), revealed that treatment with a cal- 1145–1148. cium blocker, nitrendipine, did not impair cognitive 13 Dollery CT (ed). Therapeutic Drugs. Second Edition. function and tended to reduce the incidence of Editorial Board: Boobis A, Rawlins M, Thomas S, Wil- dementia.27 In addition, objective measures of cogni- kins M. Vol 1 Churchill Livingstone: Edinburgh, 1991, tive functioning in one randomised trial did not pp B91–B96, reveal any difference between nifedipine retard, 14 Croog SH et al. The effects of antihypertensive therapy atenolol and cilazapril.3 on quality of life. N Engl J Med 1986; 314: 1657–1664. Whether or not nifedipine retard produces a real 15 Fletcher AE et al. The effects of verapamil and decline in cognitive function compared to other propranolol on quality of life in hypertension. J Hum treatments is unknown, but treatment with a similar Hypertens 1989; 3: 125–130. 16 Testa MA et al and the nifedipine GITS Study Group. dihydropyridine drug, nitrendipine, is better than 28 Quality of life and calcium channel blockade with placebo in cardiovascular terms and it is probable nifedipine GITS versus amlodipine in hypertensive that the reported subjective effects are reversible on patients in Spain. J Hypertens 1998; 16: 1938–1847. stopping the drug. 17 Kellner R, Sheffield BF. A self rating scale of distress. We conclude that, in quality of life terms, bisopro- Psychol Med 1973; 3: 88–100. lol had advantages over nifedipine retard in sympto- 18 Vanmolkot FHM, de Hoon JNJM, van de Ven LLM, Van matic and psychological well-being. It remains to be Bortel LMAB. Impact of antihypertensive treatment on determined whether or not bisoprolol has advan- quality of life: comparison between bisoprolol and tages over other beta-blockers or long-acting prep- bendrofluazide. J Hum Hypertens 1999; 13: 559–563. arations of nifedipine. 19 Slovick DI et al. Quality of life and cognitive function with a diuretic compared with a beta blocker: a ran- domised controlled trial of bendrofluazide versus dile- Acknowledgements valol in elderly hypertensive patients. Cardiology in the Elderly 1995; 3: 139–145. The trial was supported by Merck KGaA, Darmstadt’ 20 Harvengt C. Labetalol hepatotoxicity. Ann Intern Med the manufacturers of bisoprolol. 1991; 114: 341. 21 Palmer A et al. A comparison of verapamil and nifedi- References pine on quality of life. Br J Clin Pharmac 1990; 30: 365–370. 1 Bulpitt CJ, Fletcher AE. Quality of life evaluation of 22 Fletcher AE et al. Quality of life on antihypertensive antihypertensive drugs. PharmacoEconomics 1992; 1: therapy: a double blind trial comparing quality of life 95–102. on pinacidil and nifedipine in combination with a

Journal of Human Hypertension Bisoprolol and nifedipine retard: effect on QOL CJ Bulpitt et al 212 thiazide diuretic. J Cardiovasc Pharmacol 1992; 20: Clinical centres 108–114. Dr von Behren, Wiesbaden-Biebtich; W de Leur, 23 Fletcher AE et al. The effect of two centrally-acting Nieuwkerken-Waas; R D’Hollander, De Klinge;H anti-hypertensive drugs on the quality of life. Eur J Merckx, Beveren; M van den Brandon, St Niklaas; Clin Pharmacol 1991; 41: 397–400. L van Goethem, Kieldrecht; P Peeters, Meerdonk;G 24 Fletcher AE et al. Quality of life on antihypertensive therapy: a randomized double-blind controlled trial of Abate, Chieti; A Bossini, Roma; R Fogari, Pavia;C captopril and atenolol. J Hypertens 1990; 8: 463–466. Pasotti, Voghera; A Pirrelli, Bari; F Rengo, Napoli; 25 Palmer AJ et al. Quality of life in hypertensives treated PEH Kromdijk, Maassluis; LAJ Kroot, Dongen; RJM with atenolol or captopril: a double-blind crossover van de Kimmenade, Mierlo; J Visser, Middelburg; trial. J Hypertens 1992; 10: 1409–1416. AGJM Roos, Brunssum;WMu¨ llauer, Innsbruck;B 26 Heckbert SR et al. The association of antihypertensive Rittler, Innsbruck; K Larcher, Innsbruck; G Sevig- agents with MRI white matter findings and with Modi- nani, Innsbruck; G Ullmann, Wien; R Hammer, fied Mini-Mental State Examination in older adults. Wien; H-P Appel, Wien; H Nef, Zurich; P Willimann, J Am Geriatr Soc 1997; 45: 1423–1433. Zurich; J Llibre, Barcelona; J Plana, Barcelona;JL 27 Forette F et al, on behalf of the Syst-Eur Investigators. Palma, Madrid; J Bueno, Zaragoza; K Baumgartl, Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe Pfungstadt; W Donadon, Pordenone; A Vaccarella, (Syst-Eur) trial. Lancet 1998; 352: 1347–1351. Casatenovo-Como; Prof Mazzola, Casatenovo-Como; 28 Staessen JA et al. for the SYST-EUR trial investigators. L Mos, Udine; M Santonastaso, Conegliano-Treviso; Randomised double-blind comparison of placebo and LA Sechi, Udine; A Cieslinski, Poznan; M Sznajder- active treatment for older patients with isolated sys- man, Warsaw; G Swiatecka, Gdansk; E Czestochow- tolic hypertension. Lancet 1997; 350: 757–764. ska, Gdynia; E Nartowicz, Bydgoszcz; W Modrzejew- ski, Bialystok; Z Kornacewicz-Jach, Szczecin;L Hirnle, Wroclaw; D Liszewska-Pfeifer, Warszawa;M Markiewicz, Lublin; R Gehrlein, Offenbach; J Ger- hardt, Wendelsheim; P Krupp, Bad Zwischenahn;A Massing, Offenbach; C Raddatz, Gau-Algesheim;I Appendix Senftleber, Messkirch; A Schmidt, Offenbach;U Pflaum, Wiesbaden; GJ Herrmann, Frankfurt; R Will, Participating Institutions and Personnel for the Frankfurt;BLu¨ hrs, Wiesbaden; S Berger, Wies- European Bisoprolol Trial baden; SH Taylor, Leeds.

Principal investigator for efficacy and safety Co-ordination W Vetter, Zurich M Schulte, Darmstradt, R van der Does, Mannheim

Principal investigator for quality of life Data management and quality control CJ Bulpitt, London J Grove, London

Journal of Human Hypertension