Summary

Drugs 35 (Suppl. 4): 51-55 (1988)

00 12-666 7 /88/0400-0051/$2.50/0 © AD1S Press Limited All rights reserved.

Atenolol with and without Nifedipine in the Treatment of Angina Pectoris Preliminary Report

M. Sandberg and R.A. Foale Department of Cardiology, St Mary's Hospital, London

Atenolol and nifedipine have been shown to be effective single agents in angina pectoris. but reports suggest that additional benefits may be conferred by combining the 2 drugs. Therefore. to establish that the combination regimen was at least as effective as either atenolol or nifedipine alone. a multicentre study was performed to compare the treatment regimens in 94 patients with characteristic chest pain compatible with a diagnosis of stable angina pectoris which was provoked by effort and relieved by glyceryl trinitrate. After 4 weeks on atenolol 50mg twice daily. the patients were randomised to receive. in a double­blind crossover fashion. atenolol 50mg twice daily either with or without sustained release nifedipine 20mg twice daily for 4 weeks.

Compared with entry. all treatments apparently reduced the number of anginal attacks per week and the number of glyceryl trinitrate tablets taken. It was notable that blood pressure in patients during the study was normal. Treatment with atenolol or the com­bination appeared to improve exercise tests measured by time to onset of pain. time to ~ lmm ST segment depression and duration. The ST segment depression was substantially lower on the fixed combination compared with atenolol alone; ST segment depression during exercise was recorded in 82% of patients after atenolol and 75% after the combin­ation. compared with 100% on entry. There was a substantial improvement in the number of patients rendered pain free: 29% on atenolol and 42% on combination. There was little difference between treatments in terms of adverse effects. This interim report. which awaits statistical analysis. appears to suggest additional benefit from combining nifedipine with atenolol compared with atenolol alone in the treatment of stable angina pectoris.

Both atenolol and nifedipine have been shown to be effective in the treatment of angina pectoris when given as single agents (Boyle et al. 1983; Shapiro 1985; Vetrovec & Parker 1986). Reports have also suggested an additional beneficial effect when the 2 agents are used in combination (Find­lay et al. 1986; Rowland 1983). Atenolol and nifedipine combined in a single preparation may offer additional advantages in terms of patient con­venience and compliance. There are, furthermore, certain subgroups of patients in whom a fixed com-

bination may offer particular advantages, namely, patients who have both angina and hypertension, and patients suffering from cold extremities on a ~-blocking agent alone. Before advocating the use of a fixed combination, however, it should be es­tablished that such a preparation is at least as ef­fective as conventional therapy such as ~-blockers, and that it does not have additional deleterious ef­fects. We have, therefore, studied this combination and a widely used ~-blocking agent, atenolol, and have compared the frequency of angina pectoris and

Atenolol plus Nifedipine versus Atenolol

measured changes in exercise ability and unwanted effects.

1. Patients

Patients were selected for this study on the basis of complaints of chest pain compatible with a diag­nosis of angina pectoris which was provoked by effort and relieved by rest or glyceryl trinitrate, and if this pain accompanied significant ST segment depression on 12-lead ECG recorded during a standard Bruce protocol exercise test. Significance was defined by the OCCurrence of ~ 1 mm ST seg­ment depression, which was flat or downsloping, occurring 40msec after the J-point of the QRS­complex. Many patients had angiographic docu­mentation of significant narrowing of a major COr­onary artery or one of its primary branches. Patients were then included by conforming to all of the fol­lowing criteria: clinically stable uncomplicated an­gina pectoris; age 18-69 years; being previously un­treated, or receiving fj-blocker or calcium antagonist alone; clinically normal haematological and bio­chemical profiles. Patients were specifically ex­cluded from the study if they experienced angina at rest Or complained of other unstable features; were unable to undertake the treadmill exercise test; had experienced a myocardial infarction within the last 3 months; showed sufficient abnormalities on the resting ECG to cloud evaluation of exercise­induced ischaemic ECG change; had significant cardiac valvular disease; were women of child­bearing age; or had the usual contraindications to atenolol or nifedipine therapy.

Up to September 1986, 94 patients (81 male, 13 female) had been recruited. The average age was 55.2 years, average weight 77.8kg and average height 170.4cm. fj-Blockers had been used in 57, calcium antagonists in 23 and other treatments in 43; II patients were untreated.

Examination of patients' medical history showed that in most cases angina was chronic with an av­erage duration of 25.1 months since onset. The at­tack rate suggested angina of moderate severity, with episodes occurring approximately once per day on prestudy medical therapy (mean 8.4 episodes

52

per week). The estimated number of glyceryl tri­nitrate tablets taken per week averaged 5.8.

2. Methods

This was a multicentre study incorporating patients recruited from 14 centres and using a ran­domised, double-blind, CrOSsover design. An initial 4-week run-in period comprised atenolol 50mg twice daily alone. The patients were then random­ised to I of the 2 active treatment groups: atenolol 50mg twice daily Or atenolol 50mg in fixed com­bination with sustained-release nifedipine 20mg twice daily, for 4 weeks. Patients then crossed to the other therapy for a further 4-week period. The total study period was 3 months.

Patients were closely supervised throughout and made 4 clinic visits (at the beginning of run-in, at randomisation, at Crossover and on completion). Anginal attack rate and glyceryl trinitrate con­sumption were recorded from patient diaries. In addition, at each visit resting blood pressure and pulse rate were measured, and rest and exercise ECGs were performed. Exercise testing used a standard Bruce protocol and was undertaken be­tween 2 and 5 hours after the morning dose. A variety of exercise test parameters were measured; the total exercise time, and time to the first oc­currence of significant ST segment depression and to the first onset of typical anginal chest pain were recorded. Heart rate and systolic blood pressure were recorded at rest, at the first onset of pain, at the onset of significant ST depression and at the end of exercise. Maximum heart rate, double-prod­uct (maximum heart rate multiplied by maximum systolic blood pressure) and maximum ST segment depression were also recorded.

3. Results 3.1 Anginal Attacks and Glyceryl Trinitrate Consumption

There appeared to be a reduction in the mean number of anginal attacks and consumption ofgly­ceryl trinitrate tablets per week during run-in, at-

Atenolol plus Nifedipine versus Atenolol

9

"" 6

~ lii 0. 4

.li E 3

" z 2

o I

Angina attacks -­

GTN tablets

t·. ~ n=94··........... I I

nJ~~·········I·················J84 n=85

Entry Run·in Atenolol Atenolol + Nifedipine

Fig. 1. Mean (± SE) number of anginal attacks and glyceryl trinitrate tablets taken per week.

enolol and combination periods compared with entry (fig. 1).

3.2 Blood Pressure and Heart Rate

Figure 2 summarises the effects on blood pres­sure and heart rate of the different treatments. It was noteworthy that blood pressure recordings in the study group were normal at entry. The blood pressure lowering effect was greatest with the fixed combination. There was a slight increase in both sitting and standing heart rates with the combin­ation compared with atenolol alone, but heart rate was still lower than values at entry.

140

130

120

110

100

90

80 70

60

50 :f

~~~~ 1···~ ........... f.L.·········f

Entry Run·in Atenolol Atenolol + Nifedipine

Fig. 2. Mean (± SE) blood pressure (mm Hg) and heart rate (beats/min) [sitting D ••••• ; standing rn. --J.

45

Onset of pain

,,1 mmST depression

Duration of exercise

53

Fig. 3. Differences between randomised treatments and the run-in period for mean exercise test parameters; 0 = atenolol. In = atenolol + nifedipine.

3.3 Exercise Tests

Figure 3 shows the difference in terms of 3 ex­ercise parameters between the atenolol or combin­ation periods and the run-in period. For both the atenolol and fixed combination periods there ap­peared to be little difference between active treat­ments and the end of run-in for time to onset of pain, time to ~ 1 mm ST segment depression and duration of exercise. The effect of the combination was superior to that of single-agent therapy. Al­though patients received the same regimen of at­enoiol (50mg twice daily) during run-in and active treatment, there appeared to be an advantage with the blinded treatment phase, which could be due to a training effect.

The mean time to ~ 1 mm ST segment depres­sion is shown in figure 4a for all treatment periods. As well as the increase apparent in this parameter, the mean maximum ST segment depression ap­peared to be substantially lower on the fixed com­bination than on atenolol alone (fig. 4b).

At the end of atenolol treatment, 82% of patients had positive exercise tests judged by ~ Imm ST segment depression compared with all patients on entry. On the fixed combination, 75% of patients were positive for ST segment depression (table I).

Atenolol prolonged mean exercise time before

Atenolol plus Nifedipine versus Atenolol

8

7

6

:g 5 :; .~ 4 c: .~ 3

F 2

n~63 n~:78 ,,-u,

ao~'--~----~--~---------

--t-E 'E 00_

2.0

1.5

1.0

n~=4 n=90 n=84

n=84

b 0 I Aten;'lol + Nifedipine Entry Run·in Atenolol

Fig. 4. Mean (± SE) time to ;;. 1 mm ST segment depression (a) and maximum ST segment depression (b) observed during exercise testing.

the onset of pain and the fixed combination con­ferred additional benefit (fig. 5a). There was a sub­stantial improvement in the number of patients who remained pain free during exercise testing: 29% were pain free on atenolol and 42% on the fixed combination (table I). There was a definite in­crease in duration of exercise with atenolol alone

Table I. Number of patients achieving ;;. 1 mm ST segment depression and number experiencing pain during exercise testing

Treatment Total no.

Run-in 90

Atenolol 84

Atenolol + 84 nifedipine

ST depression ;;'1mm

no. %

78 87

69

63

82

75

Pain

no.

72

60

49

%

78

71

58

8

7

6

5

4

3

2

n~49

a o~'----~------~-------r--------~------

8

6

:g 5 :; ~ 4 .£ ~ 3 F 2

n~84

bO~'--~----~~----T-------~--Entry Run·in Atenolol Atenolol + Nifedipine

54

Fig. 5. Mean (± SE) time to onset of pain during exercise test­ing (a) and total duration of exercise (b).

(active treatment) and some additional benefit was provided by the addition of nifedipine (fig. 5b).

3.4 Adverse Effects

There did not appear to be any major difference in the incidence of volunteered side effects during the run-in, atenolol treatment and fixed combin­ation periods (table II).

4. Conclusions

This interim report of results, which have not been analysed for statistical significance, appears to suggest an additional beneficial effect in favour of the fixed combination of atenolol and sustained release nifedipine over atenolol alone in terms of duration of exercise, onset of pain, and time to sig­nificant ST segment depression during exercise testing in patients with angina. It was clear that

Atenolol plus Nifedipine versus Atenolol

Table II. Incidence of volunteered side effects

Complaint Number of patients

run-in atenolol combination

Depression/irritability 2 1 0 Deteriorating angina 3 2 2 Oedema 0 1 1

Postural hypotension 0 0 Headaches/dizziness 1 6 6 Paraesthesia 2 1 3 Muscular pain/cramps 2 5 1

Palpitations 1 0 0 Breathlessness 2 1 3 GI disturbances 2 2 4 Flushes/hot sweats 2 Sleep disorders 1 1

Tiredness/lethargy 4 3 3

Total 22 24 26

fewer patients in the fixed combination group ex­perienced pain and significant ST segment depres­sion. An important effect of the fixed combination was that it reduced the magnitude of maximum ST segment depression compared with atenolol alone.

There may have been fewer anginal attacks on the combination therapy, but this is only a tenta­tive suggestion, which will require statistical sup­port.

55

The results do suggest that the fixed combina­tion of sustained release nifedipine and atenolol is at least as effective as, and probably more effective than, atenolol alone in the treatment of stable an­gina pectoris. This may have important implica­tions in terms of patient convenience and compli­ance. In addition, the additive hypotensive effect of the fixed combination may make it particularly useful in anginal patients who are also hyperten­sive.

References

Boyle RM. Bray CL. Naqvi N. Croxson RS. Cruickshank JM. Atenolol in angina. Drugs 25 (Suppl. 2): 193-194. 1983

Findlay IN. Macleod K. Ford M. Gillen G. Elliot AT. et al. Treatment of angina pectoris with nifedipine and atenolol: ef­ficacy and effect on cardiac function. British Heart Journal 55: 240-245. 1986

Rowland E. Razis P. Sugrue D. Krikler OM. Acute and chronic haemodynamic and electrophysiological effects of nifedipine in patients receiving atenolol. British Heart Journal 50: 383-389. 1983

Shapiro W. Comparison of once-daily atenolol and placebo in the treatment of stable angina pectoris. Cardiovascular Reviews and Reports 6: 1292-1304. 1985

Vetrovec GW. Parker VE. Alternative medical treatment for patients with angina pectoris and adverse reactions to beta blockers. American Journal of Medicine 81 (Suppl. 4A): 20-27. 1986

Author's address: Dr R.A. Faa/e. Consultant Cardiologist. St Mary's Hospital. Praed Street. London W2 I NY (United King­dom).