a dose-response study of atenolol in mild to moderate hypertension in general practice
TRANSCRIPT
Current Medical Research and Opinion Vol. 5 , No. 2, 1977
A dose-response study of atenolol in mild to moderate hypertension in general practice
N. K. Gostick, M.B., Ch.B., S. R. Mayhew, M.B.,Ch.B., D.Obst.R.C.O.G., R. Million, M.B., B.Ch., M.R.C.G.P., D. Sagar, M.B., B.S., S. R. Suxena, M.B.,M.R.C.P., D. F. Ingram,* B.Sc., M.B., B.S.. D.Pharm.Med., and N. P. Barker, * B.Tech., F.R.S.S.
Rugby, Hiintingdon, Eccles, Nottingham and Newcastle, and *Stuart Pharmaceuticalr Ltd., Cheadle, England
Received: 27th J d y 1977 Curr. Med. Res. Opin., (1977), 5, 179.
Summary A double-blind, crossover, multicentre study of 98 previously untreated patients MYth mild to moderate essential hypertension ivas carried out in general practice to assess the effect of 50 mg, 100 mg, and 200 mg atenolol, given once daily, compared with thut of placebo over a period of 4 uveks each. At the end of the double-blind phase, all patients took 100 mg atenolol daily for a further 8 weeks. All three doses of atenolol produced statistically significant falls in systolic and diastolic pressure and pulse rate ( p < 0.001). The lowest pressures were achieved with 100 mg dailj.; u diflerence of 22/15 mmHg at the end of the double-blindphase, and a &#erenee of 25116 rnmHg ut the final observation. Body weight, blood urea, blood uric acid, and serum electroll-tcs remained within normal limits throughout the stu&. The incidence qf side-eflects with 50 mg and 100 mg atenolol MWS not signijicantlj, different from that causedby placebo, but the incidence of tiredness at the 200 mg dose level was greater than that caused l ? ~ > placebo and by the lower doses. The incidence of possible side-eflL>cts eficited b,. a questionnaire was low, the greatest number being volunteered bj, paticnts takiiig placebo. It is concluded that the optimal dose of atenololfor treatiizgpatients with mild to moderate hypertension in general practice is 100 nig daily.
Key words: Atenolol - antihypertensive agents - hypertension
Introduction Atenolol (‘Tenormin’ t ), 4-(2’hydroxy-3 ’-i sopropy laminopropox y)-phenylacetamide, is a new beta-adrenoceptor blocking agent. It has been shown to be cardioselective both in a n i m a l ~ ~ , ~ - l and in man.’ ,2,1 s 1 It has proved to be an effective anti- hypertensive agent in man,7,8,1 O J 2-14 with avery low level of side-effects1 Conway et ~ 2 1 . ~ reported that the plasma half-life of atenolol was between 6 and 9 hours, and
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A dose-response study of atenolol in mild to moderate hypertension in general practice
the agent has been shown to be therapeutically effective in hypertensive patients when given once a day.5.8.17
A review of the published papers on the use of atenolol in hypertension indicates that a wide range of doses has been used. Thus, Petrie et a1.14 used 200 mg to 400 mg/day, Myers et a1.13 used 75 mg to 900 mg/day, Harris et a1.8 100 mg to 400 mgiday, and Hansson et a1.7 100 mg to 800 mg/day. However, Myers et a1.’3 found no significant further falls in blood pressure on increasing the dose beyond 150 mg/day, Meekers et a1.72 found that increasing the dose from 75 mg/day to 300 mg/day increased the hypotensive effect but that increasing from 300 mg/day to 600 mg/day did not. Lehtonen’O thought the optimum dose was 100 mg to 200 mg/day, whilst Hansson et considered that it was200 mg/day. Furthermore, with one e~ception,~ all of the published studies involved hypertensive patients under hospital supervision. However, it has been noted by Haines6 that only 4 % of hypertensive patients are referred to hospital for management, and it is not unreasonable to suggest that this small percentage of referals may well represent a somewhat atypical group of patients. For these reasons, a dose-response study of atenolol in hypertension was carried out in newly-diagnosed hypertensive subjects treated in general practice.
Patients and methods Five general practitioners selected 98 patients with mild to moderate previously untreated essential hypertension for inclusion in the study, which was conducted on a multicentre basis, all participants working to the same protocol.
Patients with mild to moderate hypertension were defined as those with at least 2 out of 3 sitting diastolic blood pressures greater than 94 mmHg but less than 11 1 mmHg after 5 minutes’ rest. Patients had not received antihypertensive medication for at least 3 months prior to admission to the study. Patients who were under 18 years or over 65 years of age were excluded, as were those with cardiovascular disease (other than a raised blood pressure), asthma, a blood urea above 8 mmol/l, and pregnant women or women wishing to become so. Having been selected in this manner, the consent of the patient to taking part in the study was obtained.
The trial was a double-blind, randomized, 4-way crossover study comparing 4 x 4-week periods of treatment with placebo, 50 mg atenolol once a day, 100 mg atenolol once a day, and 200 mg atenolol once a day, given according to a Latin Square design. Matching tablets of atenolol and placebo were used in order to ensure blindness. At the end of the double-blind phase, all patients continued to take 100 mg atenolol daily and were reviewed after a further 8-weeks’ treatment.
On entry to the study the patient’s name, age, sex, and body weight were recorded. Initially, at the end of each 4-week period, and at the end of the 8-week open phase, blood pressure and pulse rate were measured in the sitting position after 5 minutes’ rest. Blood pressure was always measured by the same observer in the same arm for any particular patient and diastolic pressure was recorded at Phase N using a Hawksley Random Zero sphygmomanometer.
Blood urea, uric acid, and serum electrolytes were also measured initially, throughout the double-blind phase at 4-week intervals, and at the final visit, as were
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N. K. Gostick, S. R. Mayhew, R. Million, D. Sagar, S. R. Suxena, D. F. Tngram and N. P. Barker
enquiries for possible side-effects. Side-effects were assessed both by use of a standard open question (“Have you any other complaints?’) and also by application of a check list which asked about the presence of tiredness, cold extremities, depression, dizzi- ness, and impotence.
It was possible for the physician to withdraw a patient from the study at any time, at his discretion. Should this occur, the reason for withdrawal was to be categorized, as far as possible, into lack of effect, worsening of the patient’s state, intolerable side- effects, or patient’s non-compliance with the trial routine.
Results Of the 98 patients admitted to the study, 84 were available for analysis. There were 44 men and 40 women, and the mean age of the group was 50.1 years (range 28 years to 64years). Themeanbodyweight ofthegroupwas75.7 kgandtheaverageuntreated blood pressure was 165.6 mmHg systolic and 101.9 mmHg diastolic.
The reasons for drop-out of the 14 patients were as follows: 1 patient was with- drawn due to ‘lack of effect’ and 2 failed to attend for assessment. In 2 patients, data were missing and 1 other was admitted in error in that some basic admission criteria were not fulfilled. These 3 were withdrawn from analysis. Eight patients withdrew from the study due to possible side-effects. Of these 8,2 patients withdrew whilst on placebo (1 with a choking sensation, and 1 with excessive tiredness), 1 on the 100 mg atenolol dose (a case of dyspnoea with aching in the legs and diarrhoea), and 5 on the 200 mg atenolol dose (3 with tiredness or lethargy, 1 with dizziness, a tight feeling in the chest and visual disturbance, and 1 with visual disturbance). None of these problems was proved to be due to atenolol and, in particular, the 2 cases of visual disturbance were thoroughly investigated and no causal relationship to atenolol was shown.
Blood pressure and pulse rate were assessed using analysis of variance and the Student’s t-test. Table I shows the mean systolic and diastolic blood pressure and mean pulse rate (fS.E.M.) at the initial visit, at the end of each 4-week period in the double-blind phase, and at the final visit. Table I. Mean (1S.E.M.) blood pressure and pulse rate before and at the end of each treatment period: 84 patients
Measurement Initial Double-blind phase Final
Placebo 50mg 100mg 200mg atenolol/ atenolol/ atenolol/ day h Y h Y
Blood pressure (mmHg): Systolic 165.6 155.1 145.7 143.4 144.4 140.8
k2.0 k2.3 f2.4 k2.4 h2.5 f2.9
Diastolic 101.9 95.8 88.6 86.9 88.2 85.1 *0.75 k l . 0 1 1 . 3 f l . 0 f l . 0 1 1 . 3
Pulse rate 85.2 80.8 67.0 65.2 65.7 65.5 (beatslmin) rt1.6 41.4 11.4 k1.3 i 1 . 3 41.4
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A dose-response study of atenolol in mild to moderate hypertension in general practice
En the double-blind phase of the study, all three doses of atenolol produced highly significant falls in systolic and diastolic blood pressure and in pulse rate compared to placebo (p < 0.OOl). The lowest average blood pressures were achieved on the 100 mg per day regimen both in the double-blind phase of the study (143.4 mmHg systolic, 86.9 mmHg diastolic), and at the final observation (140.8 mmHg systolic, 85.7 mmHg diastolic). The average blood pressure on 100 mg daily in the double- blind phase of the study was not significantly lower than on the 50 mg or 200 mg regimen. However, the average final blood pressure on 100 mg daily was significantly lower than that on the 50 mg dose (p < 0.01), but was not significantly different from the 100 mg or 200 mg doses in the double-blind phase. The average systolic and diastolic blood pressure was significantly lower on placebo than on entry to the study (p < 0.001). This was also true of pulse rate (p < 0.01).
Table11 shows the mean values (+S.E.M.) for body weight and the various blood tests performed. It can be seen that these parameters remained within normal limits during the study.
Table 11. Mean values for body weight and various laboratory parameters before and at the end of each treatment period: 84 patients
Measurement Initial Double-blind phase Final
Placebo 50mg 100mg 200mg atenololl atenolol/ atenolo]/ day day day
Body weight (kg) 75.7 75.2 75.0 75.0 75.3 75.1 Blood urea (mmol/l) 5.9 5.7 5.8 5.4 6.0 5.6 Blood uric acid 0.35 0.36 0.37 0.37 0.37 0.31 ( m o l / l ) Serum sodium 140.2 140.3 140.2 140.7 140.3 140.5 (mmol/l) Serum potassium 4.3 4.2 4.2 4.3 4.2 4.2 (mmol/l) Serum chloride 101.8 101.6 101.6 102.2 102.5 102.5 (mmol/l) Serum bicarbonate 27.5 26.3 25.1 26.2 26.3 25.9 (mmol/l)
Side-effects The incidence of possible side-effects in the double-blind phase of this study, as elicited by the questionnaire, is shown in Table ILI.
The incidence of each side-effect on atenolol at 50 mg and 100 mg daily was not significantly different from that on placebo. However, the incidence of tiredness on the 200 mg dose level was statistically greater than on 100 mg (p<0.05). The incidence of possible side-effects elicited by the open question is shown in Table IV. It can be seen that there was a low level of additional complaints. The highest level was detected during the placebo period.
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N. K. Gostick, S. R. Mayhew, R. Million, D. Sagar, S. R. Suxena, D. F. Ingram and N. P. Barker
Table 111. Incidence of possible side-effects in the double-blind phase of the trial: elicited by questionnaire
Side-effect Placebo Atenolol 50 mg/day 100 mg/day 200 mg/day
Tiredness 5 7 7 16 Cold extremities 2 5 5 I Depression I 3 1 2 Dizziness 3 3 4 5 Impotence 1 1 1
7
Total 13 19 18 30
Table IV. elicited by open question
Side-effect Placebo Atenolol
Incidence of possible side-effects in the double-blind phase of the trial:
50 mg/day 100 mg/day 200 mg/day
Headache 2 2 1 Dyspepsia 1 1 Dyspnoea 2 1 Backache 1 Sleep disturbance 1 Joint pains I 1 1 Cramp 1 Chest pain 1
Total 7 2 4 5
7
Discussion The results of this study show that atenolol, given in daily doses of 50 mg, 100 mg, and 200 mg, produced a highly significant fall in blood pressure when compared to placebo of about 11 mmHg systolic and 9 mmHg diastolic in this group of mild to moderate previously untreated hypertensive patients in general practice.
The assessments in this study were made some 8 to 12 hours after the last tablet was taken. This is comparable with the situation that the average practitioner finds when he sees patients in the evening surgery, dosing being in the morning. Con- sequently, different results could be anticipated from those studies where special efforts were made to assess patients 24 hours after the last dose.' However, this was not the case.
The greatest fall in blood pressure was associated with the dosage of 100 mg daily, both in the double-blind phase of the study and also at the linal observation made after a further 8-weeks' treatment at this dose. The greatest reduction in pulse rate was also associated with the 100 mg dose regimen.
As far as possible side-effects (patient complaints) were concerned, there was little difference between the level on placebo and that on the 50 mg and 100 mg regimens. However, the incidence of withdrawals due to possible side-effects, and of side-effects elicited by questionnaire, was highest on the 200 mg regimen. The number of patients with side-effects was not significantly greater on the 50 mg and 100 mg dose ofatenolol
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A dose-response study of atenolol in mild to moderate hypertension in general pracrice
than on placebo, but tiredness was significantly increased on 200 mg per day. This confirms the observation of Petrie et a/.,14 Myers et af.,13 Hansson et d.,' and Douglas-Jones and Cruickshank,5 that treatment with atenolol is associated with a low level of patient complaints.
The evidence of this present study is that there was no improvement in control in this group of patients on moving to 200 mg daily of atenolol, and that this dose was associated with the highest level of patient complaints and withdrawals. It is concluded, therefore, that the optimal dose of atenolol for the treatment of mild to moderate cases of hypertension seen in general practice is 100 mg once a day, insofar as this dose has been shown to give the greatest reduction inbloodpressure with a minimal level of patient complaints.
References 1 . Astrom, H., (1975). Comparison of the effects on airway conductance of a new selective beta- adrenergic blocking drug, atenolol, and propranolol in asthmatic subjects. Scand. J. Resp. Dis.,
2. h t r o m , H., and Vallin, H., (1974). Effect of a new beta-adrenergic blocking agent, ICI 66,082, on exercise haemodynamics and airway resistance in angina pectoris. Br. Heart J., 36, 1194-1200. 3. Barrett, A. M., Carter, J., Fitzgerald, J. D., Hull, R., and Le Count, D., (1973). A new type of cardioselective adrenoceptive blocking drug. Br. J . Pharmacol., 48,340P. 4. Conway, F. J., Fitzgerald, J. D., McAinsh, J., Rowlands, D. J., and Simpson, W. T., (1976). Human pharmacokinetic and pharmacodynamic studies on atenolol (ICI 66,082), a new cardio- selective P-adrenoceptor blocking drug. Br. J . Clin. Pharmacol., 3,267-272. 5. Douglas-Jones, A. P., and Cruickshank, J. M., (1976). Once-daily dosing with atenolol in patients with mild or moderate hypertension. Br. Med. J. , 1,990-991. 6. Haines, A. P., (1976). Hypertension - its appearance and management in general practice. Update, 13,91-102. 7. Hansson, L., Aberg, H., Karlberg, B. E., and Westerlund, A., (1975). Controlled study of atenolol in treatment of hypertension. Br. Med. J., 2,367-370. 8. Harris, A. M., Woollard, K. V., and Tweed, J. A., (1976). A study of once daily Tenormin (atenolol) in hypertension: some implications in patient compliance. J. Znt. Med. Res., 4, 347-351. 9. Harry, J. D., Knapp, M. S., and Linden, R. J., (1973). The action of ICI 66,082 on the heart. Br. J. Pharmacol., 48,340P. 10. Lehtonen, A., (1976). Atenolol in hypertension. Acta Therap., 2,125-132. 11. Marlin, G. E., Kumana, C. R., Kaye, C. M., Smith, D. M., and Turner, P., (1975). An investi- gation into the cardiac and pulmonary P-adrenoceptor blocking activity of ICI 66,082 in man. Br. J. Clin. Pharmacol., 2,151-157. 12. Meekers, J., Missotten, A., Fagard, R., Demuynck, D., Harvengt, C., Pas, P., Billiet, L., and Amery, A., (1975). Predictive value of various parameters for the antihypertensive effect of the beta- blocker ICI 66,082. Arch. Znt. Pharmacodyn. Ther., 213,294-306. 13. Myers, M. G., Lewis, G. R. J., Steiner, J., and DoIlery, C. T., (1976). Atenolol in essential hypertension. Clin. Pharmacol. Ther., 19,502-507. 14. Petrie, J. C., Galloway, D. B., Webster, J., Simpson, W. T., and Lewis, J. A., (1975). Atenolol and bendrofluazide in hypertension. Br. Med. J., 4,133-135. 15. Singh, B. N., Nisbet, H. D., Harris, E. A., andwhitlock, R. M. L., (1975). Acomparison of the action of ICI 66,082 and propranolol on cardiac and peripheral p-adrenoceptors. Eur. J. Pharrnacol.,
16. Vilsvik, J. S., and Schaaning, J., (1976). Effect of atenolol on ventilatory and cardiac function in asthma. Br. Med. J., 2,453-455. 17. Woolfson, A. M. J., and Knapp, M. S., (1976). Once-daily treatment of hypertension. Br. Med. J., 2,235.
56,292-296.
34,75-86.
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