Acta Med Scand 201: 579-584, 1977
Atenolol in the Treatment of Angina Pectoris J . Erikssen, K. Osvik and J. Dedichen From Medical Department B and the Department of Medical Outpatients, Rikshospitalet, Oslo, Norway
ABSTRACT. Nineteen men, aged 41-64 years, with stable angina pectoris have completed a random double-blind study of atenolol, 50 mg b.i.d., atenolol, 100 mg b.i.d., and placebo. Fifteen patients had subjective improvement on atenolol, two were unchanged and two felt worse (because of asthenia/leg fatigue). No significant placebo effect was found. On both atenolol dosages there were highly significant reductions in heart rate at rest and during exercise and in BP. Only the maximal heart rate decreased significantly more on 100 mg atenolol than on 50 mg ( p < 0.01). Fourteen patients had the same or a better physical performance on the 50 mg b.i.d. regimen than on the 100 mg b i d . regimen, although this difference was not significant. Sixteen patients had higher bicycle exercise performance on atenolol than on placebo. Disregarding the three non-responders, a mean increase of 44% in bicycle performance was found. No serious side-effects were seen. Most individuals reported an increased feeling of well-being on atenolol.
In recent years p-adrenergic blocking agents (pblockers) have been used extensively in the treatment of angina pectoris (2, 7). Atenolol (Tenormin) has been used for some time as an antihypertensive agent b u t t o judge from the literature, experience with this drug in the treatment of ischaemic heart disease is almost negligible. In an earlier paper (3) w e have presented evidence suggesting a probable beneficial effect of atenolol in the treatment of angina pectoris using dosages far below those recommended hitherto. The present study was started in order t o assess the effects of atenolol on the subjective and objective effort tolerance a n d quality of life in individuals with stable angina pectoris. Address for reprints: K. Osvik, Dept. of Medical Outpatients, Rikshospitalet, Oslo, Norway.
M A T E R I A L A N D METHODS Twenty patients with a mean age of 54.3 years (range 41-
64,S.D. 6.3) were selected for this double-blind, randomly assigned study. They were selected provided they fulfilled the following criteria: Presence of typical angina pectoris for at least 1 year, being stable for at least 3 months prior to the trial. During the baseline examination, angina and/ or a positive exercise ECG had to be elicited during a bicycle exercise test to permit assessment and quantification of any change in effort tolerance during the exercise test to come. Patients with cardiac failure necessitating digitalis and/ or diuretics were excluded, as were those treated with antiarrhythmics, those with 2nd or 3rd degree AV block, bundle branch block, diabetes mellitus treated with insulin or severe peripheral artery insufficiency. Obstructive airway disease (in two cases), resting pulse rate below 50 (one), previous myocardial infarction (four) and cardiac enlargement (one) were not considered absolute contraindications, but particular care was taken in such cases. The subjects were outpatients treated by J. D. and K. 0. for at least one year in all instances, in most cases far longer. They were known to be reliable in taking prescribed medicines and they were all thought to be mentally stable. They were fully informed about the procedures, except that they were told they would receive the drug in 4 different doses, each dose given for 3 weeks. During the first 3 weeks all patients received a placebo. The trial proper consisted of three 3-week periods during which each patient received each of the following treatments according to a random Latin square design: placebo; atenolol, 50 mg b i d . ; atenolol, 100 mg b.i.d. Identical-looking tablets of placebo and atenolol were supplied by ICI, Pharmaceuticals Division, Macclesfield, England, who also performed the randomization. Initially and at the end of each 3-week period the following examination was made: clinical examination with recording of symptoms, resting systolic blood pressure (SPB), resting pulse rate and possible signs of heart failure. In addition, patients were asked about possible sideeffects and their opinion on the effects of the “drug”. The results were graded crudely as: worse -, unchanged 0, definite improvement + , considerable improvementlfree from angina + +. All had free access to medical supervision and control during the trial. Peak expiratory flow was measured with a Wright’s
580
J . Erikssen et al.
Table I. Subjective vs. objective improvement during the various trial periods (i.e. subjective drug pre$ erence v s . highest performance on bicycle) Subjective preference ~
Objective preference Placebo Atenolol 50 mgx2 100 mgx2 Total
Placebo
Atenolol Indifferent (=no change) 50 mgx2
I"
1 2
2 2
I" 1 8
100 mgx2
Total
2
3
1
9 I 19
4"
7
Patients with concordance between subjective and objective effect.
peak flow meter. An exercise test was performed on an electrically braked Elema bicycle, starting with a load of 300 kpm ( 4 0 W) and with a stepwise increase by 300 kpm (-50 W) every 4 min. Details about leads used, methods of recording during and after exercise and general supervision are presented elsewhere (3). The exercise was continued until terminated by angina, fatigue or dyspnoea, or the occurrence of an ST depression of 3 mm. The reason@) for discontinuing the test was recorded individually, and common safeguards were used during the test. In theory the trial was double-blind, but of course at examination any P-blocking effect was easily disclosed. The individuals were instructed to take the drug at exactly the same time in the morning, and particular care was taken to ensure that the exercise tests were performed at exactly the same time of the day. Using the baseline test time as the reference, all other tests in all individuals were performed within f 10 min of that test time. All clinical examinations and judgement of the subjective effect were assessed independently of the exercise test, and in all instances the clinical assessment preceded the exercise test. Patients were not allowed to eat or smoke during the last 2 hours before the test, which took place within 3 4 hours of the ingestion of the drug in all instances. RESULTS One patient was excluded during the run-in period because he developed atrial fibrillation. All the others fulfilled the complete trial without complications. One man had rib fracture during his placebo period 11, and could therefore not perform the exercise test at the end of this period. Table I shows the subjective vs. objective preference of the various drug regimens. Two patients complained of deterioration while on atenolol, and two noted no difference between the four periods. A complete subjectivelobjective concordance was found in 12 cases, i.e. 7 showed more or less discordance between subjective effects and objective
measurements as assessed by the bicycle exercise test. Fig. 1 shows that in 8 of the 19 patients the 50 mgx 2 dosage gave the highest exercise performance. In 6 patients the two atenolol dosages were equal in this respect and only 5 (of whom 2 weighed approximately 100 kg) had a higher performance on 100 mgx 2. Thus 50 mg atenolol was equal to or better than 100 mg in 14 of the 19 cases. Table I1 indicates the number of patients who had, or did not have, angina, severe leg fatigue, and/or a positive exercise ECG during and/or after exercise. Almost identical results were found during the baseline examination and the two placebo examinations. During both atenolol periods, significantly fewer had angina during the tests. Simultaneously, however, significantly more patients discontinued the exercise tests due to leg fatigue as the main reason. The number of ECGs with S T depressions remained roughly unchanged during all periods. Table 111 shows the exercise parameters obtained during the five exercise tests. As mentioned above, one of the patients had a rib fracture during placebo period 11. If we extrapolate from baseline and pre-
Atenolol 50mg.2
,
Atenolol" 100 mg a 2
Fig. 1 . Venn diagram presenting the relation between highest exercise performance and dosage of atenolol. ', ' '=highest performance on the dosages indicated.
Atenolol in angina pectoris
Table 11. Presence (+)/absence (-) of angina pectoris ( A ) , leg fatigue (F) and significant ST depressions (ST)during the various periods of treatment A + * A-
Baseline examination Placebo Period I PeriodII" Atenolol 50 mgx2 100mgx2
F+** F-
16
3
1
18
16 17
3 1
2 2
10 8
11
8
9
8
11
11
ST+***ST10
9
17
11
16
10
8 8
10 8
9 11
One individual had a rib fracture during placebo period 11, and could not perform the exercise test.
Difference in occurrence rate during placebo vs. atenolol *p=0.0014, **pSO.OOI,***p30.10.
vious placebo average data for this individual, approximately two beats in maximal pulse rate during exercise and approximately 300 kpm should be added to the mean value for cumulative work during placebo period I1 (i.e. the placebo period during the trial proper). Provided that this extrapolation is valid, there are no significant differences in any of the exercise parameters during the three non-drug tests. There are highly significant reductions in resting pulse rate, maximal heart rate and maximal BP during the two atenolol periods as compared with placebo, and also a significant increase in cumulative work performed. There is a significantly lower maximal pulse rate on atenolol 100 mgx2 vs. atenolo1 50 mgx2, while the differences concerning resting pulse rate, maximal BP and cumulative work are not significant. The grading of the subjective effects on angina symptoms is indicated in Table IV. Two patients deteriorated subjectively on atenolol. Fifteen reported no effect of placebo even though they all thought they were taking an active drug during all trial periods. Peak expiratory flow averaged 605 1lmin on placebo and 596 I/min during atenolol therapy. The difference is not significant. Fig. 2 shows the exercise performance in the individual patient in the two atenolol periods vs. the mean baseline/placebo performance. It is seen that 8 of the 10 individuals with the highest performance did less well on the higher dose of atenolol. In the 9 individuals with the lowest performance, 6 had a
581
similar or better performance on the higher than on the lower dose. BP showed a consistent fall during atenolol therapy both in normotensives and in hypertensives. A) Resting SBP was almost identical at the three non-atenolol examinations, mean 141.6 mmHg (S.D. 19.7). B) On atenolol, 50 mgx2, SBP was 128.9 mmHg(S.D. 20.4). C) On atenolol, 100 mgx2, SBP was 124.2 mmHg (S.D. 17.0). Differences (paired t-test): A-B ~ ( 0 . 0 1 , A-C p o . 10.
A few patients complained spontaneously of leg fatigue, particularly on the higher dose of atenolol, and some had a feeling of malaise when initiating P-blocker therapy. No case of asthma or cardiac failure occurred. Most individuals reported cold hands on inquiry. No nightmares were recorded. Three patients reported colicky abdominal pain while on atenolol 100 mg b.i.d. but not on 50 mg b.i.d. The general trend, however, was that most individuals reported an increasing feeling of wellbeing while on atenolol. In particular no rebound effect was seen, i.e. none reported a sudden and
01
&
Pklcc!bo A t A d avemge SOmg.2 lWmg.2
Fig. 2. Individual variation in physical performance (cumulative work during bicycle exercise test) on placebo and two atenolol dosages in 19 men with angina pectoris.
582
J . Erikssen et al.
Table 111. Data from bicycle exercise test duringjive tests in 19 men with angina pectoris i=mean value of each parameter, S.D.=standard deviation of X=probability of significant differences in mean among groups
Baseline data Placebo Period I Period I1 Atenolol 50 mgx2 100 mgx2
Resting pulse rate (beatslmin)
Maximal heart rate during exercise (beatshin)
X
S.D.
X
S.D.
73.9
10.2
138.1
20.5
138.4 132.4
16.8
;:: ;: 1
p
NS
Atenolol in the Treatment of Angina Pectoris J . Erikssen, K. Osvik and J. Dedichen From Medical Department B and the Department of Medical Outpatients, Rikshospitalet, Oslo, Norway
ABSTRACT. Nineteen men, aged 41-64 years, with stable angina pectoris have completed a random double-blind study of atenolol, 50 mg b.i.d., atenolol, 100 mg b.i.d., and placebo. Fifteen patients had subjective improvement on atenolol, two were unchanged and two felt worse (because of asthenia/leg fatigue). No significant placebo effect was found. On both atenolol dosages there were highly significant reductions in heart rate at rest and during exercise and in BP. Only the maximal heart rate decreased significantly more on 100 mg atenolol than on 50 mg ( p < 0.01). Fourteen patients had the same or a better physical performance on the 50 mg b.i.d. regimen than on the 100 mg b i d . regimen, although this difference was not significant. Sixteen patients had higher bicycle exercise performance on atenolol than on placebo. Disregarding the three non-responders, a mean increase of 44% in bicycle performance was found. No serious side-effects were seen. Most individuals reported an increased feeling of well-being on atenolol.
In recent years p-adrenergic blocking agents (pblockers) have been used extensively in the treatment of angina pectoris (2, 7). Atenolol (Tenormin) has been used for some time as an antihypertensive agent b u t t o judge from the literature, experience with this drug in the treatment of ischaemic heart disease is almost negligible. In an earlier paper (3) w e have presented evidence suggesting a probable beneficial effect of atenolol in the treatment of angina pectoris using dosages far below those recommended hitherto. The present study was started in order t o assess the effects of atenolol on the subjective and objective effort tolerance a n d quality of life in individuals with stable angina pectoris. Address for reprints: K. Osvik, Dept. of Medical Outpatients, Rikshospitalet, Oslo, Norway.
M A T E R I A L A N D METHODS Twenty patients with a mean age of 54.3 years (range 41-
64,S.D. 6.3) were selected for this double-blind, randomly assigned study. They were selected provided they fulfilled the following criteria: Presence of typical angina pectoris for at least 1 year, being stable for at least 3 months prior to the trial. During the baseline examination, angina and/ or a positive exercise ECG had to be elicited during a bicycle exercise test to permit assessment and quantification of any change in effort tolerance during the exercise test to come. Patients with cardiac failure necessitating digitalis and/ or diuretics were excluded, as were those treated with antiarrhythmics, those with 2nd or 3rd degree AV block, bundle branch block, diabetes mellitus treated with insulin or severe peripheral artery insufficiency. Obstructive airway disease (in two cases), resting pulse rate below 50 (one), previous myocardial infarction (four) and cardiac enlargement (one) were not considered absolute contraindications, but particular care was taken in such cases. The subjects were outpatients treated by J. D. and K. 0. for at least one year in all instances, in most cases far longer. They were known to be reliable in taking prescribed medicines and they were all thought to be mentally stable. They were fully informed about the procedures, except that they were told they would receive the drug in 4 different doses, each dose given for 3 weeks. During the first 3 weeks all patients received a placebo. The trial proper consisted of three 3-week periods during which each patient received each of the following treatments according to a random Latin square design: placebo; atenolol, 50 mg b i d . ; atenolol, 100 mg b.i.d. Identical-looking tablets of placebo and atenolol were supplied by ICI, Pharmaceuticals Division, Macclesfield, England, who also performed the randomization. Initially and at the end of each 3-week period the following examination was made: clinical examination with recording of symptoms, resting systolic blood pressure (SPB), resting pulse rate and possible signs of heart failure. In addition, patients were asked about possible sideeffects and their opinion on the effects of the “drug”. The results were graded crudely as: worse -, unchanged 0, definite improvement + , considerable improvementlfree from angina + +. All had free access to medical supervision and control during the trial. Peak expiratory flow was measured with a Wright’s
580
J . Erikssen et al.
Table I. Subjective vs. objective improvement during the various trial periods (i.e. subjective drug pre$ erence v s . highest performance on bicycle) Subjective preference ~
Objective preference Placebo Atenolol 50 mgx2 100 mgx2 Total
Placebo
Atenolol Indifferent (=no change) 50 mgx2
I"
1 2
2 2
I" 1 8
100 mgx2
Total
2
3
1
9 I 19
4"
7
Patients with concordance between subjective and objective effect.
peak flow meter. An exercise test was performed on an electrically braked Elema bicycle, starting with a load of 300 kpm ( 4 0 W) and with a stepwise increase by 300 kpm (-50 W) every 4 min. Details about leads used, methods of recording during and after exercise and general supervision are presented elsewhere (3). The exercise was continued until terminated by angina, fatigue or dyspnoea, or the occurrence of an ST depression of 3 mm. The reason@) for discontinuing the test was recorded individually, and common safeguards were used during the test. In theory the trial was double-blind, but of course at examination any P-blocking effect was easily disclosed. The individuals were instructed to take the drug at exactly the same time in the morning, and particular care was taken to ensure that the exercise tests were performed at exactly the same time of the day. Using the baseline test time as the reference, all other tests in all individuals were performed within f 10 min of that test time. All clinical examinations and judgement of the subjective effect were assessed independently of the exercise test, and in all instances the clinical assessment preceded the exercise test. Patients were not allowed to eat or smoke during the last 2 hours before the test, which took place within 3 4 hours of the ingestion of the drug in all instances. RESULTS One patient was excluded during the run-in period because he developed atrial fibrillation. All the others fulfilled the complete trial without complications. One man had rib fracture during his placebo period 11, and could therefore not perform the exercise test at the end of this period. Table I shows the subjective vs. objective preference of the various drug regimens. Two patients complained of deterioration while on atenolol, and two noted no difference between the four periods. A complete subjectivelobjective concordance was found in 12 cases, i.e. 7 showed more or less discordance between subjective effects and objective
measurements as assessed by the bicycle exercise test. Fig. 1 shows that in 8 of the 19 patients the 50 mgx 2 dosage gave the highest exercise performance. In 6 patients the two atenolol dosages were equal in this respect and only 5 (of whom 2 weighed approximately 100 kg) had a higher performance on 100 mgx 2. Thus 50 mg atenolol was equal to or better than 100 mg in 14 of the 19 cases. Table I1 indicates the number of patients who had, or did not have, angina, severe leg fatigue, and/or a positive exercise ECG during and/or after exercise. Almost identical results were found during the baseline examination and the two placebo examinations. During both atenolol periods, significantly fewer had angina during the tests. Simultaneously, however, significantly more patients discontinued the exercise tests due to leg fatigue as the main reason. The number of ECGs with S T depressions remained roughly unchanged during all periods. Table 111 shows the exercise parameters obtained during the five exercise tests. As mentioned above, one of the patients had a rib fracture during placebo period 11. If we extrapolate from baseline and pre-
Atenolol 50mg.2
,
Atenolol" 100 mg a 2
Fig. 1 . Venn diagram presenting the relation between highest exercise performance and dosage of atenolol. ', ' '=highest performance on the dosages indicated.
Atenolol in angina pectoris
Table 11. Presence (+)/absence (-) of angina pectoris ( A ) , leg fatigue (F) and significant ST depressions (ST)during the various periods of treatment A + * A-
Baseline examination Placebo Period I PeriodII" Atenolol 50 mgx2 100mgx2
F+** F-
16
3
1
18
16 17
3 1
2 2
10 8
11
8
9
8
11
11
ST+***ST10
9
17
11
16
10
8 8
10 8
9 11
One individual had a rib fracture during placebo period 11, and could not perform the exercise test.
Difference in occurrence rate during placebo vs. atenolol *p=0.0014, **pSO.OOI,***p30.10.
vious placebo average data for this individual, approximately two beats in maximal pulse rate during exercise and approximately 300 kpm should be added to the mean value for cumulative work during placebo period I1 (i.e. the placebo period during the trial proper). Provided that this extrapolation is valid, there are no significant differences in any of the exercise parameters during the three non-drug tests. There are highly significant reductions in resting pulse rate, maximal heart rate and maximal BP during the two atenolol periods as compared with placebo, and also a significant increase in cumulative work performed. There is a significantly lower maximal pulse rate on atenolol 100 mgx2 vs. atenolo1 50 mgx2, while the differences concerning resting pulse rate, maximal BP and cumulative work are not significant. The grading of the subjective effects on angina symptoms is indicated in Table IV. Two patients deteriorated subjectively on atenolol. Fifteen reported no effect of placebo even though they all thought they were taking an active drug during all trial periods. Peak expiratory flow averaged 605 1lmin on placebo and 596 I/min during atenolol therapy. The difference is not significant. Fig. 2 shows the exercise performance in the individual patient in the two atenolol periods vs. the mean baseline/placebo performance. It is seen that 8 of the 10 individuals with the highest performance did less well on the higher dose of atenolol. In the 9 individuals with the lowest performance, 6 had a
581
similar or better performance on the higher than on the lower dose. BP showed a consistent fall during atenolol therapy both in normotensives and in hypertensives. A) Resting SBP was almost identical at the three non-atenolol examinations, mean 141.6 mmHg (S.D. 19.7). B) On atenolol, 50 mgx2, SBP was 128.9 mmHg(S.D. 20.4). C) On atenolol, 100 mgx2, SBP was 124.2 mmHg (S.D. 17.0). Differences (paired t-test): A-B ~ ( 0 . 0 1 , A-C p o . 10.
A few patients complained spontaneously of leg fatigue, particularly on the higher dose of atenolol, and some had a feeling of malaise when initiating P-blocker therapy. No case of asthma or cardiac failure occurred. Most individuals reported cold hands on inquiry. No nightmares were recorded. Three patients reported colicky abdominal pain while on atenolol 100 mg b.i.d. but not on 50 mg b.i.d. The general trend, however, was that most individuals reported an increasing feeling of wellbeing while on atenolol. In particular no rebound effect was seen, i.e. none reported a sudden and
01
&
Pklcc!bo A t A d avemge SOmg.2 lWmg.2
Fig. 2. Individual variation in physical performance (cumulative work during bicycle exercise test) on placebo and two atenolol dosages in 19 men with angina pectoris.
582
J . Erikssen et al.
Table 111. Data from bicycle exercise test duringjive tests in 19 men with angina pectoris i=mean value of each parameter, S.D.=standard deviation of X=probability of significant differences in mean among groups
Baseline data Placebo Period I Period I1 Atenolol 50 mgx2 100 mgx2
Resting pulse rate (beatslmin)
Maximal heart rate during exercise (beatshin)
X
S.D.
X
S.D.
73.9
10.2
138.1
20.5
138.4 132.4
16.8
;:: ;: 1
p
NS
