comparison of isradipine and nifedipine in chronic stable angina

International Journal o/ Curdioloa, 18 (1988) 15-26

Elsevier 15

IJC 00608

Comparison of isradipine and nifedipine in chronic stable angina

Clive E. Handler *. Eric Rosenthal, Demetrius Tsagadopoulos

and Yusuf Najm

Department of Cardiolog~~, Gtg’s Hospttal. London. U.K.

(Received 1 April 1987: rewsion accepted 23 June 1987)

Handler CE, Rosenthal E, Tsagadopoulos D. Najm Y. Comparison of isradipine

and nifedipine in chronic stable angina. Int J Cardiol 1988;18:15-26.

Isradipine, a new dihydropyridine calcium antagonist, was compared to nifedipine in the treatment of 11 male patients with angina and coronary artery disease in a

randomised, double-blind cross-over study. Patients received 5 mg nifedipine three times a day rising to 20 mg three times a day in three dosage increments over six weeks or 2.5 mg isradipine three times a day rising to 7.5 mg three times a day in

three dosage increments over six weeks, and then received the alternate preparation.

There were no significant differences between the drugs in terms of the frequency

and severity of angina attacks or the consumption of glyceryl trinitrate. The increases

in systolic blood pressure and the double product during exercise were significantly less with isradipine than with nifedipine. There was a similar trend in heart rates.

There was no difference between the treatments in respect of exercise induced ST-segment depression or diastolic blood pressure.

We conclude that isradipine and nifedipine have similar anti-angina1 effects and

that isradipine may be a useful new anti-angina1 agent.

Key words: Isradipine; Nifedipine; Calcium blocker: Angina pectoris; Exercise testing; Statistics

Introduction

Calcium antagonists have a broad spectrum of therapeutic effects and similar but not identical modes of action in the treatment of chronic stable angina pectoris [l].

Correspondence to: Dr. Clive E. Handler, M.D.. Department of Cardiology. Middlesex Hospital. London WlN 8AA. U.K.

* Present address: Department of Cardiology. Middlesex Hospital, London WlN 8AA. U.K.

0167-5273/88/$03.50 0 1988 Elsevier Science Publishers B.V. (Biomedical Division)

16

lsradipine

Fig. 1.

Although widely used, the most appropriate choice of calcium antagonist for the majority of patients with angina is at present unclear.

Nifedipine is a dihydropyridine calcium antagonist which reduces symptoms of

angina, improves haemodynamics and exercise tolerance and reduces electrocardio-

graphic signs of myocardial ischaemia [2-61. Isradipine (Sandoz) is a new dihydro-

pyridine calcium antagonist (Fig. 1). We have previously studied the effects of isradipine at rest and during exercise in 12 patients with angina and coronary artery

disease. In this single-blind study, increasing doses of isradipine (2.5, 5.0, and 10.0 mg) were given on 4 consecutive days and the patients were assessed clinically, with

biochemical and haematological tests and with symptom-limited treadmill exercise

testing. No serious side effects were reported by the patients and biochemical and

haematological tests were normal. Isradipine did not produce any deleterious effects

on blood pressure either at rest or during exercise [7]. The aim of this study was to compare isradipine and nifedipine in patients with

chronic stable angina pectoris and documented coronary artery disease.

Methods

Patients

Twelve male patients aged between 48 and 66 years entered the study. One

patient with abnormal laboratory data on entry was excluded before taking the trial medication. It was not considered necessary to replace this patient since the design

of the study permitted satisfactory statistical inference from a study group of 11

patients. All patients had angina (Canadian Heart Association class 2 or 3) present for at least 9 months. All patients were taking nitrates, 9 were taking calcium antagonists and 7 patients were taking a beta-blocker before the study. Exercise-induced reversible myocardial ischaemia had been demonstrated in several previous treadmill exercise tests in every case and so all the patients were familiar with the exercise test procedures. Two patients had suffered a previous myocardial infarction. All patients had coronary artery disease confirmed by coronary arteriography.

17

No patient had unstable symptoms, a myocardial infarction within six months of start of the trial, cardiac valve disease. heart failure, hypertension, cardiac arrhythmias, any conduction abnormalities, other major systemic disease, or other disease precluding exercise testing.

All patients gave informed consent and the trial protocol was approved by the Hospital Ethical Committee.

Study Design

A randomised double-blind crossover design was employed. So far as possible there was a wash-out period of two weeks immediately prior to the study during

which patients were to take no medication other than glyceryl trinitrate. Patients received 2.5 mg isradipine three times a day for 2 weeks, then 5 mg three times a day for 2 weeks, and 7.5 mg three times a day for the final 2 weeks, or 5 mg nifedipine

three times a day for 2 weeks, then 10 mg three times a day for 2 weeks, then 20 mg three times a day for the final 2 weeks. Five patients received nifedipine first, then

isradipine; six patients received the opposite sequence. The doses of isradipine were based on previous work [7], those for nifedipine cover the dose range commonly

used in this type of patient. During the study period patients took glyceryl trinitrate

only to abort attacks of angina, not prophylactically. No other cardiac medication was to be taken. Double dummy techniques were used with placebo capsules to

ensure “blindness” to treatment. The patients included in this study had moderate to severe angina. Since

nifedipine has been shown in several placebo controlled studies to improve clinical,

haemodynamic and exercise test responses [2-61, no placebo control was used in

this study. Assessments were carried out immediately before the study and after each

two-week treatment period. On each occasion a physical examination of each

patient was carried out. A count was made of the number and severity of angina attacks and the number of glyceryl trinitrate tablets taken during the preceding two

weeks, This information was obtained from diary cards. All medication taken and any adverse reactions were also recorded. Before entry to the study, and at the end

of each six-week treatment phase, blood samples were taken for biochemical and

haematological screening. Symptom-limited treadmill exercise tests were carried out at each assessment.

The Naughton protocol was used, in which the myocardial oxygen consumption rate increases by approximately one metabolic equivalent (being approximately a myocardial oxygen consumption rate of 3.5 ml/kg per minute for a 70-kg man

supine at rest) with each stage [8]. Two exercise tests were performed at the same time of day. at least two hours after the last meal, and at least one hour after the last glyceryl trinitrate capsule. No study medication was taken within the two hours

prior to the exercise tests. To eliminate the known physiological improvement on a second test [9], data were taken from the second test only, the first serving as a “warm up”. All exercise tests were supervised by the same physician throughout the

studv.

18

A twelve-lead electrocardiogram, heart rate and cuff blood pressure were recorded at rest immediately before the exercise test, at the time of onset of angina, at maximum exercise, immediately post exercise and five minutes post exercise. An

oscilloscope displaying a three-channel rhythm strip was monitored continuously.

Indications for terminating exercise were severe angina, severe dyspnoea or fatigue,

serious arrhythmias (ventricular ectopic beats more frequent than 20 per minute. multifocal ventricular ectopic beats, ventricular couplets or ventricular tachycardia),

or a fall in blood pressure of more than 25 mm Hg. The times to onset of angina and to termination of exercise, and the reason for terminating the exercise test, were

recorded. ST-segment depression was measured in the lead showing the greatest

shift. The electrocardiogram was also recorded at one-minute intervals during the recovery period after exercise.

Statistical Analysis

All statistical tests were carried out on the changes from the pre-study values. Significance levels quoted are in all cases to P < 0.05.

The data are derived from repeated measurement of two groups of patients. The

common practice of employing repeated tests without correction at each assessment point is incorrect and has been avoided where possible. Where the data were

normally distributed according to the Wilk-Shapiro test [lo] an analysis of variance

for a repeated measures design has been employed [ll]. Subjects were grouped according to the order in which the drugs were given. The actual treatment received and the two weeks of treatment were included as trial factors. For some exercise test

data, the assessment point of the exercise test was incorporated as an additional trial factor. Where significant effects were detected, the contributing factors were sought using a priori r-tests with error terms corrected for the dependence structure within

the data. For data which were not normally distributed, namely the frequency and severity

of angina attacks, the consumption of glyceryl trinitrate and the ST-segment depression, median rather than mean values have been quoted in the relevant tables. No similar analysis of variance approach for non-parametric data is available. In these cases, therefore, comparisons were made at the end of each six week treatment

period using the Wilcoxon test [12] without further correction.

Results

The 11 patients who commenced taking the study medication completed the study. All patients progressed to the highest dose of each medication. One patient received the highest nifedipine dose for one week only. suffering severe headaches, and took the medium dose (10 mg three times a day) for the final week of this phase. This patient subsequently commenced isradipine treatment at the ap-

propriate time and completed the trial without further difficulty. He took the medium dose of nifedipine (10 mg three times a day) for the final week.

19

TABLE 1

Frequency and severity of attacks of angina, and consumption of glyceryl trinitrate.

Nifedipine Nifedipine Nifedipine Isradipine Isradipine Isradipine

Week 0 Week 2 Week 4 Week 6 Week 2 Week 4 Week 6

Total of angina attacks

Median 12.0 5.0 4.0

Mean 16.9 15.4 16.0

SEM 3.4 5.8 7.0

n 11 11 11

Seventy of angina attacks

Median 2.0 1.0 1.0

Mean 1.8 1.7 1.4

SEM 0.2 0.3 0.2

n 11 11 I1

Total of g!vcetyl trinitrate tablets taken Median 3.0 1.0 1.0

Mean 28.6 8.5 10.1

SEM 15.9 4.7 6.3

n 9 10 9

3.0 7.0 2.0 5.0

15.3 17.9 14.1 14.9

7.2 7.3 8.4 7.0

11 11 11 11

1.0

1.3

0.3

10

0.0 1.0 0.0 0.5

8.8 10.3 5.2 6.9

4.8 5.8 3.3 4.3

10 10 10 10

1.0

1.3

0.1

11

1.0

1.2

0.3

10

1.0

1.5

0.3

10

One patient who refused glyceryl trinitrate is not included in the summary statistics. Scoring: 0 = absent,

1 = mild, 2 = moderate, 3 = severe. 4 = intolerable.

Attacks of Angina and Consumption of Glgceryl Trinitrate

The frequency and severity of angina attacks, and the consumption of glyceryl

trinitrate are shown in Table 1. There was a reduction in the median severity and

number of angina attacks and the number of glyceryl trinitrate tablets taken compared to the pre-study measurement. There was no significant difference

between the two drugs in this respect.

Exercise Test Data

The increase in systolic blood pressure during exercise was significantly less during isradipine treatment than during nifedipine treatment (Table 2). There was a

significant increase in diastolic blood pressure over the first four weeks of the study. irrespective of whether nifedipine or isradipine was being taken, with no significant

difference between the two treatments. Nor was there any overall difference between the treatments in relation to heart rate, although on two occasions the exercise-induced increase in heart rate was significantly less with isradipine. The elevation in the double product during exercise, and by implication the myocardial

oxygen consumption, was significantly less with isradipine than nifedipine overall. The time to onset of angina and the total exercise duration are shown in Table 3.

Both increased with the study medication in relation to pre-study values, with no

significant differences between the treatments. However. the time to termination of

20

exercise was longer in the early weeks of the patients’ second treatment, irrespective

of what that treatment was. No significant differences were detected in respect of

ST-segment depression at any time.

TABLE 2

Exercise test.



Systolic blood pressure - summary data (mm Hgigi Pre-exercise

Mean 128.6 124.5 121.8 122.7

SEM 6.1 5.3 4.1 5.8

n 11 11 11 11

Onset of angina

Mean 156.4 158.6 162.3 155.5

SEM 5.4 6.8 6.2 6.9

n 11 11 11 11

Maximum exercise

Mean 162.7 165.0 171.4 163.6

SEM 6.3 7.2 7.8 5.1

n 11 11 11 11

Immediately post-exercise

Mean 160.0 160.9 164.5 157.3

SEM 8.1 7.6 7.4 8.0

n 11 11 11 11

Five minutes post-exercise

Mean 134.1 132.7 123.2 125.9

SEM 6.5 6.8 8.0 5.4

n 11 11 11 11

Diastolic blood pressure - summar?, data (mm Hg) Pre-exercise

Mean 81.4 82.7 80.5 76.4

SEM 3.2 3.3 2.4 2.5

n 11 11 11 11

Onset of angina

Mean 81.8 82.3 80.0 78.2

SEM 3.4 4.2 3.0 3.4

n 11 11 11 11

Maximum exercise

Mean 82.3 81.8 80.0 77.3

SEM 2.9 3.6 1.9 4.2

n 11 11 11 11


Mean 79.5 79.5 77.3 77.7

SEM 3.0 3.0 2.7 4.2

n 11 11 11 11


Mean 80.5 80.5 76.8 73.6

SEM 4.0 3.1 3.2 1.5

n 11 11 11 11

120.0 120.9 119.1

5.0 4.0 3.9

11 11 11

160.5 158.2 146.8

7.0 6.1 7.0

11 11 11

161.4 156.4 160.0

6.9 5.4 4.8 11 11 11

157.3 151.8 150.9

7.0 5.1 5.9

11 11 11

125.0 120.1 125.5

5.2 4.3 3.5

11 11 10

17.7

1.9

11

79.5

3.5

11

75.0

2.2

11

82.7 80.9 79.1

3.0 3.7 2.6

11 11 11

82.3 84.5 79.1

4.8 3.3 2.3

11 11 11

80.0 82.3 76.4

5.0 2.8 2.6

11 11 11

74.9 74.1 71.0

2.6 3.1 2.2

11 11 11

21

TABLE 2 (continued)



Heart rate - summay data (beats/min)

Pre-exercise

Mean 86.8 86.6 85.0

SEM 4.1 5.6 4.3

n 11 11 11

Onset of angina

Median

Mean 127.3 127.3 128.1

SEM 6.1 4.7 5.9

n 11 11 11

Maximum exercise

Mean 136.5 137.0 139.4

SEM 6.0 5.5 6.5

n 11.0 11 11


Mean 127.7 133.2 133.3

SEM 6.2 6.4 6.3

n 11 11 11


Mean 89.0 89.8 89.6

SEM 4.9 5.2 4.8

n 11 11 11

Double product - summary data ( X IO’) Pre-exercise

Mean 112.1 108.8 103.5

SEM 8.0 9.4 6.1

” 11.0 11.0 11.0

Onset of angina

Mean 199.9 202.6 208.7

SEM 12.5 11.9 13.1

n 11.0 11.0 11.0

Maximum exercise

Mean 223.0 226.8 238.1

SEM 13.9 13.5 13.4

n 11.0 11.0 11.0


Mean 206.8 215.4 219.1

SEM 16.3 15.6 12.5

” 11.0 11.0 11.0


Mean 122.1 120.1 112.4

SEM 12.4 10.2 12.8

n 11.0 11.0 11.0

85.8 83.3 87.2 84.9

3.8 4.1 4.1 4.7

11 11 11 II

132.0

131.2

4.5

11

124.8 127.5 127.0

5.0 4.1 5.2

11 11 11

142.3 134.9 135.1 136.5

5.3 5.0 5.2 5.5

11 11 11 11

133.6 129.6 129.8 129.4

6.7 5.3 5.2 6.3

11 11 11 11

87.7 91.0 87.2 89.7

3.5 5.3 3.3 4.7

11 11 11 10

105.6 100.6 106.1 101.6

7.1 7.2 7.0 7.2

11.0 11.0 11.0 11.0

204.8 201.7 203.3 189.4

12.6 13.7 12.6 15.3

11.0 11.0 11.0 11.0

233.4 217.4 210.7 219.8

12.4 11.6 9.9 12.2

11.0 11.0 11.0 11.0

212.3 203.7 196.3 197.4

17.9 12.3 8.6 14.2

11.0 11.0 11.0 11.0

111.2 114.3 105.2 113.4

7.8 8.8 6.3 8.0

11.0 11.0 11.0 10.0

In all cases the reason for terminating the exercise test was angina or angina and fatigue combined. Several patients were also short of breath. Six patients recorded arrhythmias during exercise testing at some stage of the study, none had serious

22

TABLE 3

Exercise test.

Nifedipine Nifedipine Nifedipine Isradipine Isradipine Isradipine Week 0 Week 2 Week 4 Week 6 Week 2 Week 4 Week 6

Time to onset of angina Median 300.0 630.0 612.5 Mean 426.4 602.7 641.0 SEM 77.6 89.6 122.5 ,1 11 11 10

Time to terminatton of exercise (seconds) Median 540.0 900.0 1020.0 Mean 625.3 837.5 921.3 SEM 72.9 101.5 100.8 ,* 11 11 11

645.0 642.0 758.0 830.0 665.6 633.1 708.5 688.0 97.6 19.3 88.4 89.7 11 11 11 11

960.0 780.0 840.0 960.0 943.6 837.1 889.1 912.3 101.1 72.9 81.1 84.5 11 11 11 11

ventricular arrhythmias during or after exercise. There was no apparent difference between the type and number of arrhythmias recorded with either medication.

Adverse Effects (Table 4)

One patient who refused glyceryl trinitrate therapy felt generally ill throughout. Four patients felt generally well, one of whom had a short (two-day) period of depression whilst taking isradipine. The most common complaint was of headaches.

One patient had headaches during both treatment phases, three others had headaches

only during nifedipine treatment. One patient felt depressed during nifedipine treatment. Two patients reported gastrointestinal problems, one with nifedipine and

one with isradipine. One patient reported shortage of breath, and another a feeling

of nervousness with isradipine. The majority of haematological and biochemical values were normal, with the

exception of triglyceride levels, which were generally high for most patients, and cholesterol levels which were high in approximately one half of the patients at some

stage of the study.

Discussion

The frequency of attacks of angina and the consumption of glyceryl trinitrate are essential aspects of the evaluation of anti-angina1 drugs [13]. In this study we observed no significant difference between isradipine and nifedipine in respect of

these parameters. Two main patterns of response were evident from the exercise tests. Firstly, the

time to onset of angina and the time to termination of exercise increased significantly in the early stages of the first treatment period, irrespective of treatment. This is consistent with the appearance of a training effect, observed in other studies [14,15]. The diastolic blood pressure behaved similarly, levelling off during the

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25

second treatment phase. Secondly, significant differences were detected between nifedipine and isradipine, whatever the order of treatment. Systolic blood pressure increased during exercise, the increase being significantly less with isradipine than

with nifedipine. There was a slight indication that heart rates behaved similarly. Consequently the increase in the double product during exercise was also significantly less with isradipine than with nifedipine. Since the double product is an

approximate measure of myocardial oxygen consumption [16], the presumption is

that there is a smaller increase in myocardial oxygen consumption during exercise with isradipine than with nifedipine at the doses employed here. This may have

clinical relevance in these patients.

Nifedipine acutely reduces left ventricular afterload by peripheral vasodilation, and increases cardiac output with a corresponding decrease in myocardial oxygen

consumption [17]. It may exert a negative inotropic effect [18], particularly in patients with impaired left ventricular function [19]. This may produce a reflex increase in heart rate. These are not consistent findings and we did not find that

either drug produced deleterious effects on blood pressure at rest or during exercise. The haemodynamic effects of nifedipine reported here are consistent with previous

studies [3,4,6]. Nifedipine has been reported to reduce myocardial oxygen consump-

tion [4] and to increase coronary artery blood flow [20]. The present data do not

permit firm conclusions to be drawn, but the similarity of the clinical response to isradipine and nifedipine suggests a similar mode of action.

In this small patient study group, we could not detect any significant difference in either clinical or exercise test variables between isradipine and nifedipine. Isradipine appears to merit further investigation.

Acknowledgements

We are grateful to Dr. Edgar Sowton for his constructive criticism of the manuscript, to Dr. M.I. Foreman of Data Analysis and Research (D.A.R.) Ltd., for

the statistical analysis, and to Sandoz Ltd. for supplying the trial medication. C.E.H. is grateful to the Medical Research Council for support during this study.

References

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2 Lynch P, Dargie H. Krikler S. Krikler D. Objective assessment of anti-angina1 treatment: a

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3 Mueller HS, Chahine RA. Interim report of multicentre. double-blind, placebo-controlled studies of

nifedipine in chronic stable angina. Am J Med 1981;71:645-657.

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26

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