- Email: [email protected]
Comparison of isradipine and nifedipine in chronic stable angina
International Journal o/ Curdioloa, Elsevier
18 (1988) 15-26
15
IJC 00608
Comparison of isradipine and nifedipine in chronic stable angina Clive
E. Handler
*. Eric Rosenthal, and Yusuf
Demetrius
Tsagadopoulos
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 and nifedipine in chronic stable angina. Int J Cardiol
Y. Comparison 1988;18:15-26.
of isradipine
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; testing; Statistics
Nifedipine;
Calcium
blocker:
Angina
pectoris;
Exercise
Introduction Calcium antagonists have a broad spectrum not identical modes of action in the treatment
of therapeutic effects and similar but 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 electrocardiographic signs of myocardial ischaemia [2-61. Isradipine (Sandoz) is a new dihydropyridine 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 appropriate 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 Frequency
1 and severity
Week 0 Total ofangina attacks Median 12.0 Mean 16.9 SEM 3.4 n 11 Seventy Median Mean SEM n
of attacks
of angina,
and consumption
of glyceryl
trinitrate.
Nifedipine Week 2
Nifedipine Week 4
Nifedipine Week 6
Isradipine Week 2
Isradipine Week 4
5.0 15.4 5.8 11
4.0 16.0 7.0 11
3.0 15.3 7.2 11
7.0 17.9 7.3 11
14.1 8.4 11
Isradipine Week 6
2.0
5.0 14.9 7.0 11
ofangina attacks 2.0 1.8 0.2 11
1.0 1.7 0.3 11
1.0
1.0
1.0 1.4 0.2 I1
1.3 0.3 10
1.0 1.3 0.1 11
1.0 1.2 0.3 10
1.5 0.3 10
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
0.0 8.8 4.8 10
1.0 10.3 5.8 10
0.0 5.2 3.3 10
0.5 6.9 4.3 10
One patient who refused glyceryl trinitrate is not included 1 = mild, 2 = moderate, 3 = severe. 4 = intolerable.
Attacks of Angina and Consumption
in the summary
statistics.
Scoring:
0 = absent,
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.
Week 0
Nifedipine Week 2
Systolic blood pressure - summary Pre-exercise Mean 128.6 124.5 SEM 6.1 5.3 n 11 11 Onset of angina Mean 156.4 158.6 SEM 5.4 6.8 n 11 11 Maximum exercise Mean 162.7 165.0 SEM 6.3 7.2 n 11 11 Immediately post-exercise Mean 160.0 160.9 SEM 8.1 7.6 n 11 11 Five minutes post-exercise Mean 134.1 132.7 SEM 6.5 6.8 n 11 11
Nifedipine Week 4
Nifedipine Week 6
Isradipine Week 2
Isradipine Week 4
Isradipine Week 6
data (mm Hgigi 121.8 4.1 11
122.7 5.8 11
120.0 5.0 11
120.9 4.0 11
119.1 3.9 11
162.3 6.2 11
155.5 6.9 11
160.5 7.0 11
158.2 6.1 11
146.8 7.0 11
171.4 7.8 11
163.6 5.1 11
161.4 6.9 11
156.4 5.4 11
160.0 4.8 11
164.5 7.4 11
157.3 8.0 11
157.3 7.0 11
151.8 5.1 11
150.9 5.9 11
123.2 8.0 11
125.9 5.4 11
125.0 5.2 11
120.1 4.3 11
125.5 3.5 10
17.7 1.9 11
79.5 3.5 11
75.0 2.2 11
82.7 3.0 11
80.9 3.7 11
79.1 2.6 11
82.3 4.8 11
84.5 3.3 11
79.1 2.3 11
80.0 5.0 11
82.3 2.8 11
76.4 2.6 11
74.9 2.6 11
74.1 3.1 11
71.0 2.2 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 Immediately post-exercise Mean 79.5 79.5 77.3 77.7 SEM 3.0 3.0 2.7 4.2 n 11 11 11 11 Five minutes post-exercise Mean 80.5 80.5 76.8 73.6 SEM 4.0 3.1 3.2 1.5 n 11 11 11 11
21 TABLE
2 (continued)
Week 0 Heart rate - summay Pre-exercise Mean 86.8 SEM 4.1
Nifedipine Week 2
Nifedipine Week 4
Nifedipine Week 6
Isradipine Week 2
Isradipine Week 4
Isradipine Week 6
data (beats/min) 86.6 5.6
n 11 11 Onset of angina Median Mean 127.3 127.3 SEM 6.1 4.7 n 11 11 Maximum exercise Mean 136.5 137.0 SEM 6.0 5.5 n 11.0 11 Immediately post-exercise Mean 127.7 133.2 SEM 6.2 6.4 n 11 11 Five minutes post-exercise Mean 89.0 89.8 SEM 4.9 5.2 n 11 11
11
85.8 3.8 11
83.3 4.1 11
11
84.9 4.7 II
128.1 5.9 11
132.0 131.2 4.5 11
124.8 5.0 11
127.5 4.1 11
127.0 5.2 11
139.4 6.5 11
142.3 5.3 11
134.9 5.0 11
135.1 5.2 11
136.5 5.5 11
133.3 6.3 11
133.6 6.7 11
129.6 5.3 11
129.8 5.2 11
129.4 6.3 11
89.6 4.8 11
87.7 3.5 11
91.0 5.3 11
87.2 3.3 11
89.7 4.7 10
105.6 7.1 11.0
100.6 7.2 11.0
106.1 7.0 11.0
101.6 7.2 11.0
204.8 12.6 11.0
201.7 13.7 11.0
203.3 12.6 11.0
189.4 15.3 11.0
233.4 12.4 11.0
217.4 11.6 11.0
210.7 9.9 11.0
219.8 12.2 11.0
212.3 17.9 11.0
203.7 12.3 11.0
196.3 8.6 11.0
197.4 14.2 11.0
111.2 7.8 11.0
114.3 8.8 11.0
105.2 6.3 11.0
113.4 8.0 10.0
85.0 4.3
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 Immediately post-exercise Mean 206.8 215.4 219.1 SEM 16.3 15.6 12.5 ” 11.0 11.0 11.0 Five minutes post-exercise Mean 122.1 120.1 112.4 SEM 12.4 10.2 12.8 n 11.0 11.0 11.0
87.2 4.1
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.
Week 0
Nifedipine Week 6
Isradipine Week 2
Isradipine Week 4
Week 6
612.5 641.0 122.5 10
645.0 665.6 97.6 11
642.0 633.1 19.3 11
758.0 708.5 88.4 11
830.0 688.0 89.7 11
of exercise (seconds) 900.0 1020.0 837.5 921.3 101.5 100.8 11 11
960.0 943.6 101.1 11
780.0 837.1 72.9 11
840.0 889.1 81.1 11
960.0 912.3 84.5 11
Nifedipine Week 2
Time to onset of angina Median 300.0 630.0 Mean 426.4 602.7 SEM 77.6 89.6 ,1 11 11 Time to terminatton Median 540.0 Mean 625.3 SEM 72.9 ,* 11
Nifedipine Week 4
Isradipine
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
Patients’
Patient number
Nifedipine week 2
normal headache early morning
not too bad
very well indeed
some angina at rest, generally off-colour
marvellous, well
not too bad
very well indeed
not good
4
6
Nifedipinejirst, then isradipine 1 rotten, off colour, generally ill very bad
complaints.
Week 0
4
TABLE
in
angina at rest, up and down
very well
not too bad at all
not bad, headache morning
very limited, feels as if hung-over
Nifedipine week 4
quite bad angina
very well, last week bad: headaches and giddiness on high dose 2 hr after medication severe face flushing, painful glands right side neck feeling well
generally awful especially first few days
Nifedipine week 6
more short of breath
feels fit
very good
very well
no change. swollen hands. burning, numb little finger
PN 200-110 week 2
good
some fair days, others very short of breath
very well
pretty
very well
bad
PN 200-l 10 week 4
very well indeed in spite of bouts of angina
no flushing. feels very well
fainted once, stomach cramps, heartburn, off food well
PN 200-I 10 week 6
quite good
slight headache immed. after medication
sweating last week, has had cold since yesterday worst 2 weeks in a long time
OK, well
10
12
bad headache
very well except for last 2 days
hot feet and ankles, unwell, depressed, but often so headache better
tablets
9
after tablets,
cold weather angina at each walk. mainly evenings
headache, arm-ache unrelated to exercise, tingling in feet last few days very well
occasional headaches
giddiness,
well. avoids very heavy exertion
stomach
bloated
i hr after
in feet
tingling
last 2 weeks
not bad
3
not as good as
not bright
recent cold, not too bad
well
not too bad
Isradipine first, then nifedipine OK 2 not too bad, fairly well
11
well, feels nervy and
pretty
fair
felt tired. lot of work
1st week felt awful, headache, last few days very well
better
very well indeed
jumpy
ill,
pretty
OK
fair
improved except last few days, felt peculiar for few days
hot feet
generally
great
very well
pretty
OK
fair
headaches, leg puffed
wind, left up
generally OK, 2 bad days of depression quite well
well, feels shaky
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 consumption [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 1 Braunwald E. Mechanism of action of calcium channel blocking agents. N Engl J Med 1982;307:1618-1627. 2 Lynch P, Dargie H. Krikler S. Krikler D. Objective assessment of anti-angina1 treatment: a double-blind comparison of propranolol, nifedipine and their combination. Br Med J 1980;281:184-187. 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. 4 Sherman LG, Liang C-S. Nifedipine in chronic stable angina: a double-blind placebo controlled crossover trial. Am J Cardiol 1983;51:706-711. 5 Chaitman BR. Wagniart P, Pastemac A, Brevers G, Scholl J-M. Improved exercise tolerance after propranolol, diltiazem or nifedipine in angina pectoris: comparison at 1, 3 and 8 hours and correlation with plasma drug concentrations. Am J Cardiol 1984;53:1-9.
26 6 Higginbotham MB, Morris KG, Coleman RE, Cobb FR. Comparison of nifedipine alone and with propranolol alone for stable angina pectoris including hemodynamics at rest and during exercise. Am J Cardiol 1986;57:1022-1028. 7 Handler CE, Sowton E. Safety, tolerability and efficacy of PN 200-110, a new calcium antagonist, in patients with angina and coronary heart disease. Em J Clin Pharmacol 1984:27:415-417. 8 Naughton J, Sevelius G, Balke B. Physiological responses of normal and pathological subjects to a modified work capacity test. J Sports Med 1963;3:201-207. 9 Burkhart F, Barold S, Sowton E. Hemodynamic effects of repeated exercise. Am J Cardiol 1967;75:509-515. 10 Dunn OJ, Clark VA. Applied statistics: analysis of variance and regression. New York: John Wiley. 1974. 11 Winer BJ. Statistical principles in experimental design. New York: McGraw-Hill, 1974. 12 Conover WJ. Practical nonparametric statistics. New York: John Wiley, 1971. 13 Parisi AF, Strauss WE, McIntyre KM, Sasahara AA. Considerations in evaluating new anti-angina1 drugs. Circulation 1982;65(suppl 1):138-142. 14 Smokler PE, MacAlpine RN, Alvaro A, Kattus AA. Reproducibility of a multi-stage near maximal treadmill test for exercise tolerance in angina pectoris. Circulation 1973;48:346-351. 15 Hossack KF, Bruce RA. Improved exercise performance in persons receiving diltiazem. Am J Cardiol 1981;47:95-101. 16 Detry J-MR, Piette F, Brasseur LA. Hemodynamic determinants of exercise ST-segment depression in coronary patients. Circulation 1970;42:593-599. 17 Henry PD. Comparative pharmacology of calcium antagonists: nifedipine. verapamil and diltiazem. Am J Cardiol 1980;46:1047-1058. 18 Banzet 0, Colin JN, Thibonnier M. Singlas E, Alexandre JM, Corvol P. Acute antihypertensive effect and pharmacokinetics of a tablet preparation of nifedipine. Eur J Clin Pharmacol 1983:24:145-150. 19 Ludbrook PA, Tiefenbnmn AJ, Reed FR, Sobel BE. Acute hemodynamic responses to sublingual nifedipine: dependence on left ventricular function. Circulation 1982;65:489-498. 20 Zacca NM, Verani MS. Chahine RA, Miller RR. Effect of nifedipine on exercise induced left ventricular dysfunction and myocardial hypoperfusion in stable angina. Am J Cardiol 1982:50:689-695.
18 (1988) 15-26
15
IJC 00608
Comparison of isradipine and nifedipine in chronic stable angina Clive
E. Handler
*. Eric Rosenthal, and Yusuf
Demetrius
Tsagadopoulos
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 and nifedipine in chronic stable angina. Int J Cardiol
Y. Comparison 1988;18:15-26.
of isradipine
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; testing; Statistics
Nifedipine;
Calcium
blocker:
Angina
pectoris;
Exercise
Introduction Calcium antagonists have a broad spectrum not identical modes of action in the treatment
of therapeutic effects and similar but 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 electrocardiographic signs of myocardial ischaemia [2-61. Isradipine (Sandoz) is a new dihydropyridine 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 appropriate 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 Frequency
1 and severity
Week 0 Total ofangina attacks Median 12.0 Mean 16.9 SEM 3.4 n 11 Seventy Median Mean SEM n
of attacks
of angina,
and consumption
of glyceryl
trinitrate.
Nifedipine Week 2
Nifedipine Week 4
Nifedipine Week 6
Isradipine Week 2
Isradipine Week 4
5.0 15.4 5.8 11
4.0 16.0 7.0 11
3.0 15.3 7.2 11
7.0 17.9 7.3 11
14.1 8.4 11
Isradipine Week 6
2.0
5.0 14.9 7.0 11
ofangina attacks 2.0 1.8 0.2 11
1.0 1.7 0.3 11
1.0
1.0
1.0 1.4 0.2 I1
1.3 0.3 10
1.0 1.3 0.1 11
1.0 1.2 0.3 10
1.5 0.3 10
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
0.0 8.8 4.8 10
1.0 10.3 5.8 10
0.0 5.2 3.3 10
0.5 6.9 4.3 10
One patient who refused glyceryl trinitrate is not included 1 = mild, 2 = moderate, 3 = severe. 4 = intolerable.
Attacks of Angina and Consumption
in the summary
statistics.
Scoring:
0 = absent,
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.
Week 0
Nifedipine Week 2
Systolic blood pressure - summary Pre-exercise Mean 128.6 124.5 SEM 6.1 5.3 n 11 11 Onset of angina Mean 156.4 158.6 SEM 5.4 6.8 n 11 11 Maximum exercise Mean 162.7 165.0 SEM 6.3 7.2 n 11 11 Immediately post-exercise Mean 160.0 160.9 SEM 8.1 7.6 n 11 11 Five minutes post-exercise Mean 134.1 132.7 SEM 6.5 6.8 n 11 11
Nifedipine Week 4
Nifedipine Week 6
Isradipine Week 2
Isradipine Week 4
Isradipine Week 6
data (mm Hgigi 121.8 4.1 11
122.7 5.8 11
120.0 5.0 11
120.9 4.0 11
119.1 3.9 11
162.3 6.2 11
155.5 6.9 11
160.5 7.0 11
158.2 6.1 11
146.8 7.0 11
171.4 7.8 11
163.6 5.1 11
161.4 6.9 11
156.4 5.4 11
160.0 4.8 11
164.5 7.4 11
157.3 8.0 11
157.3 7.0 11
151.8 5.1 11
150.9 5.9 11
123.2 8.0 11
125.9 5.4 11
125.0 5.2 11
120.1 4.3 11
125.5 3.5 10
17.7 1.9 11
79.5 3.5 11
75.0 2.2 11
82.7 3.0 11
80.9 3.7 11
79.1 2.6 11
82.3 4.8 11
84.5 3.3 11
79.1 2.3 11
80.0 5.0 11
82.3 2.8 11
76.4 2.6 11
74.9 2.6 11
74.1 3.1 11
71.0 2.2 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 Immediately post-exercise Mean 79.5 79.5 77.3 77.7 SEM 3.0 3.0 2.7 4.2 n 11 11 11 11 Five minutes post-exercise Mean 80.5 80.5 76.8 73.6 SEM 4.0 3.1 3.2 1.5 n 11 11 11 11
21 TABLE
2 (continued)
Week 0 Heart rate - summay Pre-exercise Mean 86.8 SEM 4.1
Nifedipine Week 2
Nifedipine Week 4
Nifedipine Week 6
Isradipine Week 2
Isradipine Week 4
Isradipine Week 6
data (beats/min) 86.6 5.6
n 11 11 Onset of angina Median Mean 127.3 127.3 SEM 6.1 4.7 n 11 11 Maximum exercise Mean 136.5 137.0 SEM 6.0 5.5 n 11.0 11 Immediately post-exercise Mean 127.7 133.2 SEM 6.2 6.4 n 11 11 Five minutes post-exercise Mean 89.0 89.8 SEM 4.9 5.2 n 11 11
11
85.8 3.8 11
83.3 4.1 11
11
84.9 4.7 II
128.1 5.9 11
132.0 131.2 4.5 11
124.8 5.0 11
127.5 4.1 11
127.0 5.2 11
139.4 6.5 11
142.3 5.3 11
134.9 5.0 11
135.1 5.2 11
136.5 5.5 11
133.3 6.3 11
133.6 6.7 11
129.6 5.3 11
129.8 5.2 11
129.4 6.3 11
89.6 4.8 11
87.7 3.5 11
91.0 5.3 11
87.2 3.3 11
89.7 4.7 10
105.6 7.1 11.0
100.6 7.2 11.0
106.1 7.0 11.0
101.6 7.2 11.0
204.8 12.6 11.0
201.7 13.7 11.0
203.3 12.6 11.0
189.4 15.3 11.0
233.4 12.4 11.0
217.4 11.6 11.0
210.7 9.9 11.0
219.8 12.2 11.0
212.3 17.9 11.0
203.7 12.3 11.0
196.3 8.6 11.0
197.4 14.2 11.0
111.2 7.8 11.0
114.3 8.8 11.0
105.2 6.3 11.0
113.4 8.0 10.0
85.0 4.3
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 Immediately post-exercise Mean 206.8 215.4 219.1 SEM 16.3 15.6 12.5 ” 11.0 11.0 11.0 Five minutes post-exercise Mean 122.1 120.1 112.4 SEM 12.4 10.2 12.8 n 11.0 11.0 11.0
87.2 4.1
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.
Week 0
Nifedipine Week 6
Isradipine Week 2
Isradipine Week 4
Week 6
612.5 641.0 122.5 10
645.0 665.6 97.6 11
642.0 633.1 19.3 11
758.0 708.5 88.4 11
830.0 688.0 89.7 11
of exercise (seconds) 900.0 1020.0 837.5 921.3 101.5 100.8 11 11
960.0 943.6 101.1 11
780.0 837.1 72.9 11
840.0 889.1 81.1 11
960.0 912.3 84.5 11
Nifedipine Week 2
Time to onset of angina Median 300.0 630.0 Mean 426.4 602.7 SEM 77.6 89.6 ,1 11 11 Time to terminatton Median 540.0 Mean 625.3 SEM 72.9 ,* 11
Nifedipine Week 4
Isradipine
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
Patients’
Patient number
Nifedipine week 2
normal headache early morning
not too bad
very well indeed
some angina at rest, generally off-colour
marvellous, well
not too bad
very well indeed
not good
4
6
Nifedipinejirst, then isradipine 1 rotten, off colour, generally ill very bad
complaints.
Week 0
4
TABLE
in
angina at rest, up and down
very well
not too bad at all
not bad, headache morning
very limited, feels as if hung-over
Nifedipine week 4
quite bad angina
very well, last week bad: headaches and giddiness on high dose 2 hr after medication severe face flushing, painful glands right side neck feeling well
generally awful especially first few days
Nifedipine week 6
more short of breath
feels fit
very good
very well
no change. swollen hands. burning, numb little finger
PN 200-110 week 2
good
some fair days, others very short of breath
very well
pretty
very well
bad
PN 200-l 10 week 4
very well indeed in spite of bouts of angina
no flushing. feels very well
fainted once, stomach cramps, heartburn, off food well
PN 200-I 10 week 6
quite good
slight headache immed. after medication
sweating last week, has had cold since yesterday worst 2 weeks in a long time
OK, well
10
12
bad headache
very well except for last 2 days
hot feet and ankles, unwell, depressed, but often so headache better
tablets
9
after tablets,
cold weather angina at each walk. mainly evenings
headache, arm-ache unrelated to exercise, tingling in feet last few days very well
occasional headaches
giddiness,
well. avoids very heavy exertion
stomach
bloated
i hr after
in feet
tingling
last 2 weeks
not bad
3
not as good as
not bright
recent cold, not too bad
well
not too bad
Isradipine first, then nifedipine OK 2 not too bad, fairly well
11
well, feels nervy and
pretty
fair
felt tired. lot of work
1st week felt awful, headache, last few days very well
better
very well indeed
jumpy
ill,
pretty
OK
fair
improved except last few days, felt peculiar for few days
hot feet
generally
great
very well
pretty
OK
fair
headaches, leg puffed
wind, left up
generally OK, 2 bad days of depression quite well
well, feels shaky
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 consumption [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 1 Braunwald E. Mechanism of action of calcium channel blocking agents. N Engl J Med 1982;307:1618-1627. 2 Lynch P, Dargie H. Krikler S. Krikler D. Objective assessment of anti-angina1 treatment: a double-blind comparison of propranolol, nifedipine and their combination. Br Med J 1980;281:184-187. 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. 4 Sherman LG, Liang C-S. Nifedipine in chronic stable angina: a double-blind placebo controlled crossover trial. Am J Cardiol 1983;51:706-711. 5 Chaitman BR. Wagniart P, Pastemac A, Brevers G, Scholl J-M. Improved exercise tolerance after propranolol, diltiazem or nifedipine in angina pectoris: comparison at 1, 3 and 8 hours and correlation with plasma drug concentrations. Am J Cardiol 1984;53:1-9.
26 6 Higginbotham MB, Morris KG, Coleman RE, Cobb FR. Comparison of nifedipine alone and with propranolol alone for stable angina pectoris including hemodynamics at rest and during exercise. Am J Cardiol 1986;57:1022-1028. 7 Handler CE, Sowton E. Safety, tolerability and efficacy of PN 200-110, a new calcium antagonist, in patients with angina and coronary heart disease. Em J Clin Pharmacol 1984:27:415-417. 8 Naughton J, Sevelius G, Balke B. Physiological responses of normal and pathological subjects to a modified work capacity test. J Sports Med 1963;3:201-207. 9 Burkhart F, Barold S, Sowton E. Hemodynamic effects of repeated exercise. Am J Cardiol 1967;75:509-515. 10 Dunn OJ, Clark VA. Applied statistics: analysis of variance and regression. New York: John Wiley. 1974. 11 Winer BJ. Statistical principles in experimental design. New York: McGraw-Hill, 1974. 12 Conover WJ. Practical nonparametric statistics. New York: John Wiley, 1971. 13 Parisi AF, Strauss WE, McIntyre KM, Sasahara AA. Considerations in evaluating new anti-angina1 drugs. Circulation 1982;65(suppl 1):138-142. 14 Smokler PE, MacAlpine RN, Alvaro A, Kattus AA. Reproducibility of a multi-stage near maximal treadmill test for exercise tolerance in angina pectoris. Circulation 1973;48:346-351. 15 Hossack KF, Bruce RA. Improved exercise performance in persons receiving diltiazem. Am J Cardiol 1981;47:95-101. 16 Detry J-MR, Piette F, Brasseur LA. Hemodynamic determinants of exercise ST-segment depression in coronary patients. Circulation 1970;42:593-599. 17 Henry PD. Comparative pharmacology of calcium antagonists: nifedipine. verapamil and diltiazem. Am J Cardiol 1980;46:1047-1058. 18 Banzet 0, Colin JN, Thibonnier M. Singlas E, Alexandre JM, Corvol P. Acute antihypertensive effect and pharmacokinetics of a tablet preparation of nifedipine. Eur J Clin Pharmacol 1983:24:145-150. 19 Ludbrook PA, Tiefenbnmn AJ, Reed FR, Sobel BE. Acute hemodynamic responses to sublingual nifedipine: dependence on left ventricular function. Circulation 1982;65:489-498. 20 Zacca NM, Verani MS. Chahine RA, Miller RR. Effect of nifedipine on exercise induced left ventricular dysfunction and myocardial hypoperfusion in stable angina. Am J Cardiol 1982:50:689-695.