Comparison of nicardipine and propranolol for chronic stable angina pectoris

Comparisonof Nicardipineand Propranolol for ChronicStable AnginaPectoris DARRYL MCGILL, FRACP, WILLIAM MCKENZIE, FRACP, and MICHAEL McCREDlE,

In a double-blind, randomized, crossover clinical trial, a new calcium antagonist, nlcardlplne (90 mg/day in 3 divided doses), was compared with propranolol (120 r&/day in 3 divkled doses) in 25 patim with chronic stable angina. The mean weekly frequency of anglna eplsodes decreased from 7.8 f 1.2 (f standard error of the mean) with placebo to 3.8 f 1.2 with nicardlpine treatment and 3.5 f 1 with propranolol treatment (p
MD

utes, p
N

icardipine hydrochloride (Fig. l), a dihydropyridine derivative, is a new calcium channel inhibitor that is structurally similar to nifedipine. In this study the efficacy and safety of fixed doses of propranolol and nicardipine were compared using a double-blind, randomized, cross over clinical trial.

with the exception of the trial medications and sublingual nitroglycerin, if required. The initial 2 weeks comprised a single-blind placebo period [patient blind), using a “double-dummy” technique for administration of medications. The patients were then randomized to propranolol, 40 mg 3 times daily, or nicardipine, 30 mg 3 times daily, for 4 weeks. A l-week single-blind placebo washout phase preceded the next &week crossover active treatment period. Exercise testing was performed twice in the initial placebo phase and at the end of each subsequent period. Using a daily diary card, patients documented the frequency of angina, consumption of nitroglycerin tablets and side effects. At each visit a tablet count was performed, a history was taken, the patient was examined, and blood was taken for biochemical, thyroid and hematologic measurements. Exercise-testing: Exercise tests were performed using a treadmill with a computer-governed program for the Bruce protocol1 They were performed in the postabsorptive state, at approximately the same time of day and at the same time after self-medication. Variables recorded were heart rate and rhythm, blood pressure every 3 minutes, duration of exercise, time to onset of angina, time to 1 mm of ST-segment depression and maximal ST-segment depression. Calculation could be made of peak rate-pressure product, heart rate gain (maximal heart rate minus heart rate at rest], heart rate unit gain (heart rate gain divided by duration of exercise), workload to onset of angina and maximal workload achieved. The workload was calculated in watts for each 3-minute stage from the gradient of the tread-

Methods Patients: Twenty-five patients (Table I] with chronic stable angina (23 men, 2 women), mean age 61 years (range 45 to i’3), were randomized to treatment after they gave informed consent. Mean duration of angina was 56 months (range 5 to 240). Admission criteria were a stable and regular pattern of angina, triggered by physical effort and quickly relieved by rest or nitroglycerin; and reproducible electrocardiographic (ECG) ST-segment depression and angina in 2 consecutive exercise tests performed in the placebo baseline period. The minimum ECG change required was ST depression 1 mm or more from baseline at 80 ms after the J point for 3 consecutive beats. Exclusion criteria (Table II) were well defined and strictly applied. Trial design (Fig. 2): All cardiovascular preparations were withdrawn for the duration of the study From the Department of Cardiovascular Medicine, Prince Henry Hospital, Sydney, Australia. Manuscript received February 19, 1985; revised manuscript received June 19, 1985, accepted June 24.1985. Address for reprints: Michael McCredie, MD, Department of Cardiovascular Medicine, Prince Henry Hospital, Little Bay 2036, NSW, Australia. 39

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TABLE I individual Exercise Times (Minutes) with Placebo, Propranoioi and NicardIpine Age W Case

& Sex

Placebo

1 2 3 4 5 6 7 6 9 10 11 12 13 14 15 16 17 16 19 20 21 22 23 24 25 Mean fSEM

64M 47M 45M 61M 69F 61M 56M 64M 51M 45M 43M 63M 71M 69M 60M 52M 63M 64M 69M 74M 69F 73M 47M 69M 67M 61

4.1 12.5 7.9 5.7 6.6 2.2 14.3 6.4 7.4 10.5 6.4 9.4 4.9 3.6 7.0 3.1 10.2 7.0 6.6 6.0 13.3 5.1 6.5 5.0 6.7 7.1 f0.7

During

Propranolol

Nicardiplne

(120mg)

(90 mg)

2.6 12.0’ 6.0 6.1 6.5 3.7 13.2 7.2 . . 11.4 10.5 9.0 6.0 2.5 9.6 7.2 10.6 Withdrew 6.0 7.5‘ 12.0’ 6.2 6.3 5.9 9.6 6.1 f0.6

l Patients with no angina during maximal SEM = standard error of the mean.

Treatment

TABLE

Exclusion

Criteria

Electrocardiographic criteria Left bundle branch block, 2nd or B°ree heart block Rest bradycardia (heart rate <50 beatslmin) Preexcitation syndrome Left ventricular hypertrophy with “strain” pattern Underlying diseases History of complication with B-blocker treatment Congestive heart failure or cardiomyopathy Significant valvular or congenital heart disease Prinzmetal’s angina. unstable angina, myocardial infarction withln 4 months, or stroke within 2 months Acute pericarditis or myocarditls Hypotension (systolic < 105 mm Hg) Uncontrolled hypertension (diastolic >I00 mm Hg) Diabetes mellitus, significant electrolyte, renal, thyroid, hepatic or hematologic disorder Suspicion of left main coronary artery disease Concomitantly adminstered drugs Dther investigational drug Additional antianginal medications or Uigoxin Miscellaneous Inability to undergo treadmill exercise testing Other causas of false-positive exercise test response Women of child-bearing age without contraception or who are lactating

3.6 12.7’ 9.5 7.0 11.3 2.5 11.1 9.9’ Withdrew 9.4’ 10.4 6.3 4.0 9.1 6.5 10.3 .. 6.2 7.3’ 13.0 6.5 6.2 5.9 11.5 6.5 f0.6

exercise.

mill, the speed,the patient’s weight and a coefficient for gravity. Data analysis: The results were examined to determine if the order of the drug administration influenced the results, or if there was a learning effect from repeated exercisetesting.2There was no evidence of a

H,C,/

II

:: \/CH,

period or learning effect. Hence, the results for each drug were grouped togetherfor analysis,regardlessof the order of treatment. For all grouped parameters analyzed, a repeated-measuresanalysis of variance and a nonparametric method of multiple comparisons were applied to determine if there were differences between groups.In the placebo phases,groupedvariables did not differ significantly. They did significantly differ from treatment phases.The 2 drugswere compared by the normal theory analysis of variance procedurefor a a-period changeoverdesign?and by a distribution free method of analysis.2The results of this analysiswere the sameasthoseobtainedusingthe t test for paired samples. All results are expressedas mean f the standard error of the mean. A p value SO.05 is considered significant.

Results A

COOCH,CH,N

- CH, - C,H,

l HCI

NO,

f-K CH,OOC

FIGURE

1. Chemical

structure

of nicardipine

(A) and nifedipine

(B).

Adverse reactions: Twenty-two patients(20men, 2 women) completed the trial. Two patients withdrew from the study while receiving nicardipine: one complained of epigastricdiscomfort and oneof nauseaand vomiting. One patient withdrew while receiving propranolol, complaining of flushes, dizziness and nausea.Five patients receiving nicardipine and 10 receiving propranolol reported side effects (Table III). No changesin the QRS, QT or PR interval on the electrocardiogramwere observedwith nicardipine, and there were no complaints of pedal edema or symptoms of severe vasodilation. No abnormality of electrolyte or cardiac enzyme levels, renal, thyroid or liver function, or hematologic indexes were attributable to either drug. Clinical response to therapy: The meannumber of angina episodesper week was significantly reduced during treatment with both drugs comparedwith placebo(Fig. 3).A reduction in nitroglycerin consumption did not reach statistical significance [Fig. 3). Seven

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7

9

Intervention

A

B

Propranolol

Nicardipine baseline FIGURE weeks,

2. Ciinicai trial design. 0 weeks at randomization.

lime

period

in

s a 3

or placebo

: Propranolol

.

visit

stress

test

patients receiving nicardipine and 4 receiving propranolol were angina free during the treatment periods. Exercise test evaluation: Exercise time was increased from the mean time of 7.1 f 0.7 minutes during placebo treatment to 8.5 f 0.6 minutes during nicardipine treatment and 8.1 f 0.6 minutes during propran0101 treatment. A significant reduction occurred in heart rate at rest (55 f 3.1 beats/min, p 0.05) compared with placebo. Exercise time (Fig. 4) was longer during treatment with both drugs than during placebo (1.3 f 0.3 minutes, p
.

.

.

.

TABLE

or

ill

.

Reported

Side

.

.

.

.

.

.

Propranolol (10 Patients) Mild insomnia Mild persistent headache Depression, tiredness Lethargy (2 patients) Dyspnea (4 patients) Pruritus, indigestion

Maculopapular eruption Mild transient headache Mild constipation lrritibility Mild dyspnea

l

l

1 IT 8-

.

Effects

Nlcardipine (5 Patients)

10

Nicardipine

s

l

p-co.05 p
9

7% 62 al 5“E z 4-

. II ..

TT

32loPl

Pr

N

Angina per week

T

ns I-IS

ii

Pl

Pr

N

GTN per week

FIGURE 3. Left, mean frequency of angina (episodes/week) during placebo (Pi), nicardipine (N) and propranoiol (Pr) treatments. Right, mean consumption of nitroglycerin (GTN) sublingually. Comparison of nicardipine and propranoiol group means to placebo. ns = not significant.

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veloped (Fig. 5) compared with propranolol(l7 f 8 W, p <0.05) and placebo (28 f 9 W, p
Discussion Nicardipine hydrochloride (Fig. l), a dihydropyridine derivative, has a chemical structure similar to that

of nifedipine. Nicardipine acts as a vasodilatofi by directly affecting vascular smooth muscIe5*6 and has been used effectively to treat hypertension.‘*8 Nicardipine appears to be as effective as nifedipine,g but has fewer side effects for doses of nicardipine up to 120 mg/day.lO Nicardipine, in the intact heart, does not result in suppression of sinus node automaticity or atrioventricular nodal conduction. It is associated with increased atrioventricular nodal conduction and sinus node recovery time, which is attributed to increased sympathomimetic reflex resulting from the vasodilator action.lO Only limited data demonstrate the efficacy of nicardipine in treatment of chronic stable angina.*1J2 In this study, exercise duration did not differ significantly between treatment periods A and B. In the initial baseline placebo phase there was a reproducible pattern of measured exercise variables. Thus, it is unlikely that the results were biased owing to improved mechanical efficiency or peripheral adaptation to exercise. The fixed dose of propranolol produced an adequate rest bradycardia and reduction in maximal heart rate and peak rate-pressure product compared with placebo treatment. In contrast, nicardipine had no significant effect on heart rate at rest, maximal heart rate, or peak rate-pressure product compared with the placebo. Nicardipine had a measurable antianginal effect, with a significant decrease in the frequency of angina, a decrease in the time to onset of angina with exercise, and an increase in the workload before pain developed. Maximal workload attained and the

11 200 10 9

T

_

160

8 7 T

120

jj 2 ‘g

6

Ill II is 2

5

80

4 3 2 1

0

N n22

Pr n22

PI n22

Exercise Time

N

n17

Pr n19

PI n22

Angina onset Time

FIGURE 4. Leff, mean exercise duration in minutes for nicardipine (N), propranoioi (Pr) and placebo (Pi) treatments. Right, mean time to angina onset in minutes. n = number of patients.

N

n22

Pr n22

PI n22

Maximum Workload

N

n17

Pr n19

PI

n22

Workload to Angina

FIGURE 5. Left, mean maximal workload performed on treadmill testing for nicardipine (N), propranoioi (Pr) and placebo (Pi) treatments. Right, mean workload to the onset of angina. n = number of patients.

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6.5.

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6,

3.0

5.

2.0

4. v) al 3 .r E 3-

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2-

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l-

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0. N n22

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PI n22

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traction of the myocardium,13 heart rate,14 cardiac output and systemic arterial pressure. In this study nicardipine did not affect the mean heart rate or mean peak rate-pressure product, an indirect approximation of myocardial oxygen consumption.13 Patients receiving nicardipine had an increased workload and decreased degree of ischemia for the same peak rate-pressure product. Apparently, nicardipine improves the myocardial oxygen supply to demand ratio. Nicardipine was well tolerated and had fewer side effects than propranolol. Pedal edema did not develop. Symptoms arising from the vasodilator properties of nicardipine were negligible. The low incidence and mild side effects appear favorable for nicardipine compared with other calcium channel inhibitors.lO In conclusion, in the doses used in this study, nicardipine was more effective than propranolol for shortterm treatment of stable angina and had fewer side effects.

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References

N n17

Pr n19

PI n22

Timeto 1mmSTI

FIGURE 6. Left, mean maxlmum ST-segment depression with nlcardiplne (N), propranolol (Pr) and placebo (PI) treatments. R/ght, mean time to onset of 1 mm of ST depression. n = number of patlents.

threshold level of workload causing angina were significantly greater with nicardipine compared with propranolol. Thus, patients receiving nicardipine more frequently exercised to a higher stage on the Bruce protocol. The heart rate gain from rest to maximal exercise during the propranolol and nicardipine periods did not differ from that during the placebo period. However, nicardipine and propranolol enabled significantly more work to be performed for the same heart rate gain, with the subsequent development of less myocardial ischemia as measured by ECG ST changes. The degree of ST-segment depression was significantly decreased at peak exercise. Furthermore, the time to the development of 1 mm of STsegment depression was significantly and equally prolonged for both drugs. Propranolol reduces myocardial oxygen consumption by decreasing the velocity of con-

1. Bruce RA, Hornsten TR. Exercise stress testing in evohmtion of patients with ischemic heart disease. Prog Cardiovasc Dis 1969;11:371-390. 2. Koch CG. The use of non-parametric methods in the statistical analysis of the two-period change over design. Biometrics 1972;28:577-584. 3. Grizzle JE. The two period change-over design and its use in clinical trials. Biometrics 1965;21:487-480. 4. McCredie RM, McKenzie WB, McGill DM. The acute hoemodynamic effects of oral nicordipine. Br J Clin Pharmacol 1985;20:1635-1685. 5. Taylor SH, Silke 8, Ahuja RC, Okoli R. Influence of nicardipine on the blood pressure at rest and on the pressor responses to cold, isometric exertion, ond dynamic exercise in hypertensive patients. J Cordiovasc Pharmacol 1982;4:803-807. 6. Iliopoulou A, Warrington SJ. Turner P. Preliminary study of the haemodynamic effects of nicordipine, o new calcium channel antagonist, in man (abstr). Br J Clin Pharmocol 1982;14:586. 7. Takabatake T, Ohta H, Yamamoto Y, Maekawa M. Arai S, Hattori N. Nomura G. The ontihypertensive effect of nicordipine hydrochloride in essential hypertension. Int J Clin Phormocol Ther Toxicol 1982;20:346-352. 6. Jones RI, Hornung RS. Sonecha TS, Raftery EB. The effect of a new calcium channel blocker nicordipine on 24 hour ambulatory blood pressure and the pressor response to isometric and dynamic exercise. Hypertension 1983;1:85-89. 9. Iliopoulou A, Turner P, Warrington SJ. Acute haemodynamic effects of a new calcium antagonist. nicardipine. in mon. A comparison with nifidipine. Br J Clin Phormacol 1983;15:59-65. 10. Matsui M, Nishiwaki H. Yoshino J. Endo M, Yoshikawa M, Sugi K, Ito H. Nimomiya K, Ebine K, Yabuki S, Seki K. Effects ofnicordipine hydrochloride on the conduction system of the heart in mon. Jpn Heart J 1982;23:243-245. 11. Bala Subramanian V, Bowles MJ, Khurmi NS. Raftery EB. Comparative evaluation of four slow channel blockers with proppanolol in stable angina pectoris (abstr). Circulation 1982:66:suppI II:II-18. 12. Bowles MJ, Bala Subramanian V, Khurmi NS, Davies AB, Raftery EB. Efficacy of o new calcium blocking agent nicordipine in chronic stable angina (abstr). Br J Clin Pharmacol 1982;13:590. 13. Braunwald E. Control of myocordiol oxygen consumption. Physiologic and clinical considerations. Am J Cordial 1971:27:416-432. 14. Boerth RC, Cove11 JW, Pool PE, Ross J Jr. Increased myocardiol oxygen consumption and contractile state associated with increased heart rate in dogs. Circ Res 1969;24:725-734.