British HeartJournal, I97I, 33, 6oi-6o6. Br Heart J: first published as 10.1136/hrt.33.4.601 on 1 July 1971. Downloaded from Double-blind three-dose trial of oral alprenolol in angina pectoris

E. Sowton' and C. Smithen With the technical assistance of J. Woods From the Institute of Cardiology and National Heart Hospital, London W.i

Seventeen patients with typical angina pectoris have been given alprenolol in a randomized double-blind cross-over trial. The drug was given twice daily in a total dosage of 200 mg/day, 400 mg/day, and 800 mg/day over 2-week periods, so that the total trial (excluding the run-in period) covered 3 months. Statistically significant increases in the total work performed on a bicycle ergometer before the onset ofanginalpain were achieved during the treatment periods of 200 mg/day and 400 mg/day, the increases being approximately 20 per cent. Heart rate was statistically significantly reduced both at rest and on effort, and on work loads up to and including the onset of anginal pain. Electrocardiograms recorded on each work load show statistically significantly less ST segment depression at all levels up to the onset of pain. The ST segment depression at the onset ofanginalpain was also significantly less during alpreno- lol treatment than during placebo treatment over the 2oo mg and 800 mg/day periods. Despite the increase in effort tolerance and the reduction in electrocardiographic evidence of ischaemia, there was no significant reduction in consumption of nitroglycerin tablets, and this is attributed to patients taking tablets prophylactically. http://heart.bmj.com/ No clinically significant side effects occurred and laboratory tests were unchanged during the 3-month period.

An increasing number of beta-adrenergic re- present study we have attempted to assess the ceptor blocking drugs are being introduced effectiveness of oral alprenolol (Aptin, Betap- into clinical practice for the treatment of tin, H56/28, I-(o-allylphenoxy)-3-isopropyl- patients with angina pectoris with different amino-2-propanol) in the prophylactic treat- on September 28, 2021 by guest. Protected copyright. *degrees of positive sympathomimetic action ment of patients with angina pectoris and also and of 'quinidine-like' action. We have to obtain information concerning the dose shown elsewhere in studies of normal volun- levels likely to be most effective. This drug teers (J. Hoy and E. Sowton, I970, un- possesses some degree of positive sympatho- published data), in relatively normal subjects mimetic action and has a 'quinidine-like' during exercise (Gibson, Hoy, and Sowton, effect in addition to its beta-adrenergic recep- 1970), and in patients with angina pectoris tor blocking action (Ablad, Brogird, and Ek, (R. Balcon, I970, personal communication) 1967; Forsberg and Johnsson, I967). or other cardiac diagnoses (J. Hoy and E. The importance of dose levels in treatment Sowton, 1970, unpublished data) that the of angina pectoris is well recognized, and it is relative potency of different beta-blocking frequently suggested that during the run-in drugs depends upon the method used for period of an angina trial the dose should be measurement and that for any given parameter increased to the optimum level for each indi- the effective clinical potency is related to the vidual patient. In our view this prejudges the exercise level and to the doses of drugs used. issue and tends to invalidate the trial, since It is apparent that clinical results achieved it is obviously impossible to determine an with one beta-blocking drug do not necessarily optimum dose for a drug without assuming apply to any other drug and, in particular, that it is effective. To avoid this complication dose responses cannot be transferred. In the we studied the patients in the present trial on - Received 30 November I970. 3 different dose levels 200 mg a day, 400 mg 1 Present address: Guy's Hospital, London S.E.r. a day, and 800 mg a day. 12 Br Heart J: first published as 10.1136/hrt.33.4.601 on 1 July 1971. Downloaded from 602 Sowton and Smithen

Patients and methods TABLE i Details ofpatients studied All patients were attending the outpatient depart- ment of the National Heart Hospital, London. Case Sex Age Period of Previous infarction Other drugs Angina pectoris was diagnosed on the basis of a No. (yr) angina (yr) typical clinical story in association with ischaemic I M 55 2 Inferior changes in the electrocardiogram; typical ST seg- 2 M 63 6 - Anticoagulants ment depression occurred during exercise in all 3 M 57 4 Inferior Digoxin cases. Patients with a normal resting cardiogram, 4 M 74 8 Inferior Digoxin, diuretic heart failure, valve lesions, chronic respiratory 5 M 43 3 disease, or arthritis limiting exercise on a bicycle 6 M 37 IO ergometer, were excluded. The patients were 7 M 51 2 8 M 49 7 Anterior Clofibrate, diuretic, studied during a stable phase of the disease with guanethidine no significant alteration in severity of anginal 9 M 46 3 Inferior Anticoagulants pain over the past 3 months, and all patients were IO M 6o 14 Inferior Anticoagulants experiencing at least one attack of angina a day II M 64 9/12 - at the start ofthe trial. Three patients were receiv- 12 M 54 3 Anticoagulants ing digoxin and five were on anticoagulants; these I3 M 68 9 drugs were continued during the trial. I4 F 6i 2 There were 17 men and 2 women with ages I5 M 6I I Inferior i6 M 42 - Clofibrate, ranging from 37 tO 74 (mean age 55). Details of anticoagulants the patients studied are shown in Table i. All 17 M 48 4 subjects were aware that the trial included new i8 M 54 I2 Inferior and drugs in varying doses, and informed consent true posterior was obtained in all cases. I9 F 56 3 Digoxin, diuretic The effect of the drug was assessed in terms of the increase of the total work performed on a bicycle ergometer before pain, by the degree of They were asked not to take nitroglycerin tablets ST segment depression during effort, and by the prophylactically and were supplied with a known consumption of trinitrin tablets during the place- number of trinitrin tablets so that the number bo and active periods. Exercise tests were per- could be assessed at their next visit. They were formed in the erect position on a bicycle ergo- also given a box containing a fortnight's supply of meter (Elema Schonander), with the exercise load the trial tablets to be taken twice daily. The trial

being increased every 3 minutes until the patient was double-blind and the box contained either http://heart.bmj.com/ was stopped by pain. Electrocardiograms were active alprenolol or identical appearing placebo continuously recorded and used for subsequent tablets allocated randomly. After taking the tab- calculations of heart rate at different exercise lets for 2 weeks the patients returned when clinical levels. The total work performed was calculated examination, exercise tests, laboratory test, and as the sum of the products of time and work load. This method of assessment has the advantage that the work performed increases slowly at the beginning but more rapidly as the test continues FIG. i The electrocardiogram is recorded

so that it is applicable to patients with all degrees The on September 28, 2021 by guest. Protected copyright. of limitation (Fig. i). The protocol for the exercise during a standard exercise test. end point test was identical for an individual patient at all is taken at the onset ofpain and not at the visits, but the work loads chosen were not neces- development of ST segment depression, and sarily the same for different patients since their the total work performed is calculated from total exercise tolerance differed. Resuscitation the exercise levels and the time for which each equipment including a defibrillator was immedi- is sustained. ately available throughout all exercise testing, but there were no complications associated with the exercise test during this study. Work food Exercise test in an_in pectoris {kpm/min) ...... Many of the patients participating in this trial <. had previously taken part in a similar trial with rest practolol (Sowton et al., 197I), and this acted as _ a very effective run-in period. Patients who joined the present trial without previously participating in a similar trial started with a one-month run-in 200 ft-I.IJW period including exercise tests at the start, again at 2 weeks, and at 4 weeks. *. On entering the trial patients were given a full examination including i2-lead electrocardiogram 400 and chest x-ray, and their total exercise tolerance before pain was assessed with an exercise test...... Blood was taken for measurements of haemoglo- bin, white cell count, urea, serum enzymes (GOT 600 7 and GPT), cholesterol, and serum drug levels...... Br Heart J: first published as 10.1136/hrt.33.4.601 on 1 July 1971. Downloaded from Double-blind three-dose trial of oral alprenolol in angina pectoris 603

electrocardiogram were repeated and the number TABLE 2 Results with alprenolol compared with placebo of trinitrin tablets assessed. The patient then received the second fortnight's supply of the trial Dose of No. of Heart rate Heart rate Total work Trinitrin tablets. alprenolol patients at rest at onset of performed consumption The clinical duration of action in producing pain before pain bradycardia (7 hours) together with information from previous published reports suggests that oral IOO mg twice I7 Reduced by Reduced by Increased by Reduced by alprenolol should be given four times a day. Our daily IO% 7% 2I% 5% experience with other antianginal drugs indicated NS NS P < 0-02 NS that many patients forgot or found it too difficult 200 mg twice I4 Reduced by Reduced by Increased by Reduced by to take drugs consistently in this way and so the daily 17% I6% I7% 12% alprenolol in this trial was taken in two equal P

FIG. 2 The electrocardiogram in two patients showing less ST segment depression after alprenolol than after placebo during exercise at identical work loads.

placebo alprenolol (400mg bd) patient Nol -¾ exercise Fevelal minute at 60 PMt

patient Nl2 4. ---_ . ..: exercise level-1 minute at 400 KPM Br Heart J: first published as 10.1136/hrt.33.4.601 on 1 July 1971. Downloaded from Double-blind three-dose trial of oral alprenolol in angina pectoris 6o0

TABLE 5 Serum alprenolol levels after ance, whereas the low dose group (200 mg a oral treatment day) had statistical improvement in effort tolerance but no statistical change in heart Case Dose Active/placebo ng alprenolol/g rate. Our results are in keeping with those of No. (mg/day) serum Bjorntorp (I968) who carried out double- blind trials with oral alprenolol in a dosage 3 400 Active o-8 3 8oo Active 20 of 100 mg 4 times a day, and showed that the 5 200 Active 32 frequency of anginal attacks was statistically 5 400 Placebo 2 significantly reduced. 5 800 Active 43 The same dose was used in a multicentre 6 400 Active 98 6 800 Active I2 trial in Australia reported by Hickie (I970) in 7 800 Active 24 which the frequency of anginal attacks was 8 200 Placebo I-3 reduced 40 per cent by placebo treatment and 8 200 Active 66-i 69 per cent by alprenolol. H. Ikram (1970, 8 400 Placebo o-8 8 400 Active 2I-3 personal communication) also chose a dose 8 800 Active 223 of I00 mg 4 times daily and reported a 9 200 Active 4 significant reduction in frequency of attacks 9 400 Placebo I during the treatment periods, but our data 9 400 Active 29 9 800 Placebo 5 do not confirm his suggestion that a greater 9 800 Active i6i therapeutic effect would be expected from 10 800 Placebo I higher doses. Aubert et al. (I970) were able I4 200 Placebo 5 to show in Norway that 400 mg a day of I4 200 Active 2 I4 400 Active 6 alprenolol produced important clinical im- I4 800 Active 6 provement in two-thirds of 2I patients, but i8 400 Active 7 Wasserman et al. (1970) failed to show an ic8 800 Active 35 antianginal effect from I00 mg alprenolol I9 200 Active 23 I9 400 Placebo 2 given 4 times a day, to 9 patients. I9 400 Active 298 In another trial using a small dose, 75 mg I9 800 Active 144 3 times a day, Arstila et al. (I969) concluded that the dose was probably inadequate since they noticed a larger fall in nitroglycerin con- http://heart.bmj.com/ can be obtained as false positives by the sumption than in the frequency of attacks, but method used. Applying this criterion, the Sealey et al. (I97i) have studied the optimum results on the other patients taking placebo dose in individual patients during exercise suggest that there was no carry-over effect (see and shown that it can vary between 50 and Cases 9 and I9 in Table 5), so that the exer- 200 mg. cise tolerance we have measured at the end of There is no clear definition by which a a fortnight of placebo treatment is unlikely to patient can be said to have improved while be influenced by the preceding period on taking an antianginal drug. While one patient on September 28, 2021 by guest. Protected copyright. active tablets. The mean levels for all available may have fewer attacks of angina in the week, results are 23-5 ng/g, with a dose of I00 mg another patient may utilize the increased twice a day (n = 6), 66 ng/g with a dose of 200 effort tolerance to perform more exercise and mg twice a day (n = 7), and 74 ng/g with a still experience the same number or even more dose of 400 mg twice a day (n = 9). attacks of angina. A further possibility is that the frequency of attacks remains constant but Discussion that their character changes so that the pain The results of our trial show that alprenolol is less severe. This information must relate is an effective agent in the prophylaxis of to the period when the patient is out of hospi- angina pectoris and that statistically signifi- tal living his ordinary life and so can only be cant increases in effort tolerance are produced obtained by questioning him at his next by oral doses of 200 mg a day and 400 mg a attendance. Though we made an attempt to day. This is in agreement with Arstila, Iisalo, assess patients' preference between placebo and Kallio (I969) who found significant in- and active periods, we were unable to draw creases in exercise tolerance with a dose of satisfactory conclusions. A similar attempt 225 mg a day. was made by Aubert et al. (I970) in their study The improvement in exercise tolerance is of alprenolol (400 mg a day), pentaerythritol unlikely to be related entirely to the changes tetranitrate (30 mg four times a day), and in heart rate since the high dose group (800 placebo in patients with angina pectoris. They mg a day) had a statistically significant reduc- were unable to determine any difference in tion in rate but no improvement in work toler- severity in attacks between pentaerythritol Br Heart J: first published as 10.1136/hrt.33.4.601 on 1 July 1971. Downloaded from 606 Sowton and Smithen

tetranitrate and placebo tablets, and concluded The improvement in effort tolerance ob- that the means available to evaluate the point tained by our patients was appreciable and were inadequate, though they reported a was associated with electrocardiographic evi- reduction in the severity of attacks with dence suggesting less cardiac ischaemia at all alprenolol. exercise levels. We do not feel this evidence is The device of issuing a known number of negated by our failure to show a reduction in nitroglycerin tablets at each visit and count- nitroglycerin consumption, and we conclude ing those remaining at the next visit in order that alprenolol is an effective drug for the to assess the number of anginal attacks is prophylactic treatment of patients with angina widely used, but it assumes that the patients pectoris. will take nitroglycerin tablets in exactly the same way during placebo and active periods We would like to acknowledge the willing co- of treatment and also that they will not use operation of our patients who attended hospital the tablets prophylactically. The instruction so frequently for exercise tests. to a patient not to use the tablets prophylactic- We are grateful to Dr. B. Comerford of AB ally contravenes standard clinical practice and Hassle of Goteborg, Sweden, for supplies of is almost certainly the exact opposite of advice alprenolol (Betaptin) and placebo tablets. given throughout his previous medical treat- ment. Though the practice may be justified ethically, there is no doubt that many patients are confused by the conflict of advice and in this study close questioning revealed that several patients had taken their tablets prophylactically on at least a few occasions. References This may account for the failure of the nitro- Ablad, B., Brogard, M., and Ek, L. (I967). Pharmaco- logical properties of H56/28 - a beta-adrenergic glycerin consumption figures to drop statistic- receptor antagonist. Acta Pharmacologica et Toxico- ally. We have experienced similar difficulties logica, 25, Suppl. 2, 9. with tablet counts in other double-blind cross- Arstila, M., Iisalo, E., and Kallio, V. (I969). Alpreno- over trials ofantianginal agents (Sowton et al., lol in angina pectoris. Annals of Clinical Research, I, 13. 197i), and we no longer feel that this method Aubert, A., Nyberg, G., Slaastad, R., and Tjeldflaat, http://heart.bmj.com/ of assessment is satisfactory. L. (I970). Prophylactic treatment of angina pec- Our results show an increased effort toler- toris. A double-blind cross-over comparison of ance with doses of Ioo mg and 200 mg twice alprenolol and pentanitrol. British Medicaljournal, I, 203. a day but not 400 mg twice a day. This differ- Bjomtorp, P. (I968). The treatment of angina pec- ence is unlikely to be due to inadequate ab- toris with beta-receptor blockade, mode of action. sorption since Johansson (i969) showed Acta Medica Scandinavica, I84, 259. alprenolol to be completely absorbed and the Forsberg, S.-A., and Johnsson, G. (I967). Hemo- mean serum two dynamic effects of propranolol and H56/28 in man levels in these groups in the - a comparative study of two beta-adrenergic on September 28, 2021 by guest. Protected copyright. present study were higher for the 800 mg a receptor antagonists. Acta Pharmacologica et day group than for the 400 mg a day group. Toxicologica, 25, Suppl. 2, 75. Alternatively it might be due to an exercise Gibson, D., Hoy, J., and Sowton, E. (I970). Com- parison of the haemodynamic effects ofoxprenolol, depression of cardiac function by the large alprenolol and sotalol. Presentation to the Medical doses of alprenolol or possibly to peripheral Research Society, London. effects limiting the total amount of exercise Hickie, J. B. (I970). Alprenolol (Aptin) in angina pec- possible. There were no clinical findings to toris. Medical journal of Australia, 2, 268. Johansson, R. (I969). Serum levels of alprenolol in support the view that cardiac output was un- humans after single oral and intravenous adminis- duly depressed with a large dose, and if this tration. Hassle Report, Biochemical Laboratory, were the explanation it would then be ex- G6teborg, Sweden. pected that the systolic blood pressure of Sealey, B. J., Liliedal, J., Nyberg, G., and Ablad, B. these patients was lower and that they (1971). Acute effects of oral alprenolol on ex- ercise tolerance in patients with angina pectoris. achieved a total work less than that achieved A dose-response study. British Heart journal, 33, on lower doses. The actual figures illustrated 48I. in Table 3 show that it is unlikely that the Sowton, E., Smithen, C., Leaver, D., and Barr, I. high level group were experiencing undue (I97I). The effect of practolol on exercise tolerance in patients with angina pectoris. American journat depression of cardiac function. The failure of of Medicine, Si (July). In the press. high doses to improve exercise tolerance may Wasserman, A. J., Proctor, J. D., Allen, F. J., and therefore be due to a minor degree of general- Kemp, V. E. (I970). Human cardiovascular effects ized muscle weakness such as is produced by of alprenolol, a beta-adrenergic blocker: hemo- dynamic, antiarrhythmic and antianginal. journaT high doses of most other beta-adrenergic of Clinical Pharmacology andJournal of New Drugs, blocking drugs. I0, 37-