Cardiovascular Drugs and Therapy 4: 451-456, 1990 �9 Kluwer Academic Publishers, Boston. Printed in U.S.A.

Nisoldipine Tablets once Daily versus Nifedipine Capsules three times daily in Patients with Stable Effort Angina Pectoris Pretreated with Atenolol

Terje R. Pedersen, ~ Michae l K a n t o r 2 ~Cardioloyy Department, Aker Sykehus, Oslo, Norway; 2Bayer (Sverige) AB, Stockholm, Sweden

Summary. T r e a t m e n t wi th n isold ip ine (2 • 10 m g table ts once dai ly) and n i fedip ine (2 • 10 mg capsu les th ree t imes daily) in pa t i en t s wi th severe, bu t s table effort a n g i n a pre- t rea ted wi th a tenolo l (100 m g once daily in 19 pa t i en t s and 50 m g once dai ly in one pa t ien t ) were compared for the i r effects on bicycle exerc i se to l e rance and the i r adverse effects in a r andomized 2 • 4 week, double-bl ind, d o u b l e - d u m m y cross- over s tudy . All pa t i en t s had mul t ivesse l disease, 16 pa t ien ts had occ lus ion o f at leas t one vessel, and e ight pa t ien ts had a h i s to ry o f myoca rd i a l in fa rc t ion . Two pa t ien t s left the s tudy d u r i n g the ini t ia l n i so ld ip ine period, one because of aggrava- t ion o f the a n g i n a and the o t he r because o f suspec ted allergic reac t ion . Addi t ion o f n i fedip ine to a tenolol t r e a t m e n t s ign i f ican t ly improved the var iab les m e a s u r e d for severi ty of ang ina , such as t ime of exerc ise unt i l 1 m m and 2 m m ST- s e g m e n t depress ion , total exerc ise t ime and total workload. In con t r a s t , no such i m p r o v e m e n t was noted af te r the addi- t ion of n iso ld ip ine to a tenolol . However , n isoldipine resul ted in a s ign i f ican t p ro longa t ion o f the t ime to the in i t i a t ion of ches t d i scomfor t , t he m a x i m u m hea r t ra te , and the double product .

In a t eno lo l - t r ea ted pa t i en t s wi th severe effort a n g i n a pec- tor is , n i fed ip ine 20 m g tid improved exercise capaci ty , while n iso ld ip ine 20 m g once dai ly did not have a s imi la r effect .

Key Words. a n g i n a pector is , nifedipine, nisoldipine, atenolol .

Nisoldipine is a calcium antagonist of the dihydro- pyridine family. In animal studies it has been shown to have a higher vascular specificity than nifedipine, the vasodilating effect being highest in the coronary and femoral arteries [1-3]. It has been shown to have a more prolonged effect than nifedipine [3]. The anti- ischemic effect in patients with angina pectoris has been reported to persist over at least 7 hours after administration of 20 mg of nisoldipine [4]. In the pres- ent study the antianginal effect of 20 mg nisoldipine once daily was compared with the effect of nifedipine 20 mg tid in patients with severe angina who were pretreated with atenolol. The effect was compared us- ing a graded bicycle exercise test.

M e t h o d s

Patients of both sexes, below 70 years of age, who were submitted to the hospital for coronary angiog- raphy because of severe effort angina pectoris were asked to participate in the study. Patients were eligi- ble for entry if they had had angiographically confirmed severe coronary ar tery disease and a symp- tom-limited bicycle exercise test with at least 1 mm ST-segment depression in lead CF5. Patients were excluded fl'om entry if they had angina at rest, unsta- ble angina, diastolic blood pressure of 100 mmHg or above, congestive heart failure, cardiac valvular dis- ease, significant noncardiac disease, or if they re- quired therapy with longlasting nitrates, digitalis, o1" other drugs that might influence the study results. Patients with previous adverse experience with di- hydropyridine drugs were also excluded.

After having given informed consent, 20 patients entered the study. Since the waiting time for coronary artery bypass surgery in patients with stable angina was 4-6 months or more in Oslo at the time of the study, no patient had to delay their operation because of study participation. Of the 20 patients, 17 had been treated with beta-adrenergic blocking agents, six of them in combination with long-acting nitrates, six with nifedipine, and five with both. The remaining three patients had received monotherapy with either nifedipine, isosorbide dinitrate, or sublingual nitro- glycerin, respectively. Two patients had previously had aortocoronary bypass grafting. Other patient characteristics are listed in Table 1. The study was approved by the local ethical committee and by the National Bureau for Drug Control.

Address for correspondence and reprint requests: Terje R. Pedersen, M.D., Cardiology Department, Aker Sykehus, N 0514 Oslo 5, Norway.

451

452 Pedersen and Kantor

Table I. Characteristics of the 20 patie~ds randomized.

Number M e a n Range

Age (years) 55 39-69 Sex

male 16 female 4

Height (cm) 173 154-190 Weight (kg) 71 59-86 Smokers 11 Duration of angina (years) 6.3 1-21 NYHA

class I I 2 class Ill 18

Previous iIffarction 8 Ejection fraction (c/c) 68 44-84 Coronary angiography Occlusions

i artery 13 2 arteries 2 3 arteries 1

> 70~ stenosis 1 artery 1 2 arteries 8 > 3 arteries 11

Collaterals Not visible 3 Few/little 2 Moderate 9 Extensive 6

S t u d y D e s i g n

After 2-4 weeks (mean, 2.95) of monotherapy with atenolol 100 mg once daily (50 mg in one patient), each patient performed an exercise tolerance test to confwm the presence of exercise-induced angina with ST-segment depression of at least 1 ram. Thereafter the patients were randomly allocated to adding either nifedipine or nisoldipine. After 4 weeks of therapy, a second exercise test was performed followed by cross- over of the two treatments for another 4 weeks. At the end of this period, a third exercise test was per- formed. Sublingual nitroglycerin was taken whenever necessary.

Double blindness of the study was ensured through a double-dummy technique. Nisoldipine/nisoldipine- placebo tablets was taken every morning along with nifedipine/nifedipine-placebo capsules three times daily. Atenolol and trial drugs were supplied in indi- vidually labeled drug dispensers, each for one week. Atenolol was given as two 50 mg tablets to be taken every morning. The dosage of nisoldipine was 10 mg daily the first week, thereafter 20 mg daily. Nifedipine was given as 10 mg capsules. The starting dose was one capsule three times daily, increased every week

by 10 rag, to a maximum of 20 mg tid during the fourth week.

An upright bicycle exercise test was performed 6-9 hours (mean 7.1 hours) after the morning intake of study medication and 1.5-2.5 hours (mean 2.1 hours) after the midday intake. This testing time was chosen since it represents a time of the day with heavy exer- cise demands for most patients, as well as an adequate time from the morning dose of nisoldipine to test this drug's long-acting capability. The patients were al- lowed to have a light meal a minimum of 2 hours be- fore the exercise test. Smoking or consumption of cof- fee or tea was not allowed. All tests were performed with the same Elema-Sch6nander electrically braked bicycle, and measures were taken to keep the room temperature constant at each test for each individual patient. The starting level was 300 kpm/min (49.05 W); this was increased every 4 minutes in steps of 300 kpm/min, until the patient experienced symptoms that prevented him or her from further exercise.

The variables analyzed included: resting and max- imum heart rate and blood pressure, time until initia- tion of chest discomfort, total exercise time, total workload, time until 1 mm and 2 mm ST-segment de- pression and maximum ST-segment depression, dou- ble product (heart rate x systolic blood pressure) and heart rate, systolic blood pressure, and ST recovery of 2 and 4 minutes after termination of the test.

S t a t i s t i c a l Methods

Statistical analyses were performed with Student's t test for paired samples for normal variables such as heart rate, systolic and diastolic blood pressure, and double product. Time variables and total workload were compared using the Wilcoxon matched-pairs signed rank test. The Wilcoxon-Mann-Whitney test of the total exercise time, the total workload and the time until chest discomfort (the main variables of the study) did not show any difference attributable to the time of inclusion or the order of treatment. Two- tailed tests were used and the differences were con- sidered statistically significant when p < 0.05.

Results

Of 20 patients randomized into the study, two patients were withdrawn during the initial period while taking nisoldipine. One patient experienced aggravation of angina necessitating hospitalization; this patient underwent aortocoronary bypass grafting earlier than originally planned. The other patient reported by phone the occurrence of rash or erythema the second

Nisoldipbte vs N(fedipb~e b~ At~gb~a Pectoris 453

9 -

B -

7 -

6 -

5

z

~ 4

3

2

1

j p (0.01

[---p (0.01

I

ATENOLOL NISOLDIPINE NIFEDIPINE

ONLY AND AND

AIENOLDL ATENOLOL

Fig. 1. Time tu#il ot~sel of chest p((b~ durb~g e.rercise.

day after randomization and subsequently dropped out of the study.

Exercise tolerance The time until the onset of chest pain was sigmificantly increased during both the nisoldipine and nifedipine periods, compared with the baseline values while re- ceiving atenolol only (Figure 1) (Table 2). The increase was significantly longer when nifedipine was added, compared with the addition of nisoldipine.

The time until 1 mm (Figure 2) and 2 mm ST- segment depression, the total exercise time, and the total workload (Figure 3) were increased with the ad- dition of nisoldipine as well as nifedipine; however. only the increase during nifedipine treatment reached statistical significance. When comparing the addition of nisoldipine with that of nifedepine, the time until 1 mm and 2 mm ST-segment depression, as well as total exercise time, were significantly more prolonged with nifedipine.

ST-segment depression at peak exercise, measm'ed in lead CR5, decreased in five and increased in three patients during nisoldipine treatment, while it de-

p 40.01

{---p <0.05----i

L.~

Z ~ 4

]

ATENOLOL NISOLDIPINE NIFEDIPINE

ONLY AND AND

ATENOLOL ATENOLOL

Fig. 2. Time zudil ottset qf e.rercise-b~d~r 1 mm ST-segme,t depression.

creased in six and increased in one patient during nifedipine treatment. The addition of either nisol- dipine or nifedipine abolished ST-segment depression in two and one patients, respectively.

Leg fatigue instead of chest pain was the reason for termination of the exercise test in four patients receiv- ing nifedipine and in three of these patients while re- eeiving nisoldipine.

Heart rate and blood pressure Heart rate prior to the exercise test, after 5 minutes resting on the bicyc]e was not influenced by adding any of the two calcium antagonists. The maxinmm heart rate during exercise and after 2 and 4 minutes rest was, however, significantly increased, both dur- ing nisoldipine and nifedipine therapy, and no signifi- cant differences appeared between these treatments.

454 Pederse~ a~d Ka~tor

Table 2. Comparison• ql'atem~Iol .hme, ~tim~hlipitu' plus (~h'm~h,I, .~d ~nfedcpi~w pl.s atem~lol bl l,S' p~diettts tw~jf.rmit~g a graded bicycle exercise test

Level of Nisoldipine Nifedipine Nis. + sivnificance

Atenolol plus plus aten. vs. nif. + aten. Nif. + aten. alone atenolol atenolol aten. alone vs. aten. alone vs. his. + aten.

Heart rate (beats/min) At rest 5g • 7 5~ 2 6 60 + 6 ns ns ns Max exercise 101 • 12 108 • 13 106 + 111 p < 0.05 l) < 0.05 ns 4 min after exercise 65 _+ 8 72 + 16 72 • 12 p < 0.05 p < 0.01 ns Systolic BP (mmHg) At rest 129 • 13 129 • 19 121 • 16 ns p < 0.01 p < 0.05 Max exercise 150 • 26 155 • 25 15.~1 • 29 ns ns ns 4 min after exercise 135 r 15 13:3 • 21 131 + 16 ns ns ns Diastolic BP at rest (mmHg) 79 : 11 ~2 • 11) 77 : ~ ns ns p < 0.05 Rate-pressure product at

max exercise (0.01 • U) 152 = ;:;g 16g ~ 39 17o : 34 p < 0.05 p < (I.05 p < 0.05 Time until begim~ing

of chest pain (• 5.1 + 1.6 5.6 • 1.7 6.2 : 2.1 p .< 0.01 I) < 0.01 ns Total exercise time (• 7.0 • 1.5 7.6 • 2.(I S.1 ~ 2.0 ns 1) < (1.01 p < 0.05 Time until 1 mm

ST depression (min) 4.7 _-= 2..11 5.0 • 2.4 5.7 _+ 2.3 ns p < 0.111 l) < 0.05 Time until 2 mm

ST depression (mini 5.8 = 1.5 6.1 + 2.4 7.(I _-- 2.0 ns 1) < 0.01 1 ) < 0.01 ST depression

at peak exercise (ram) 2.3 • 1.0 2.2 • 1.0 2.1 = 1.0 ns ns ,Is Total workload (kpm) 3025 = .q82 3563 • 1422 3900 = 1471) ns p < (}.l)l ns

Values are mean : 1 standard deviation. BP - blood pressure: max - maximal: • - minutes: his - nisoldipine: nif. nifedipine; aten. =

atenolol, ns = not signfificant.

Blood p r e s s u r e p r i o r to t h e t e s t was s igni f icant ly

r e d u c e d by n i f ed ip ine only, e v e n in c o m p a r i s o n wi th

n i so ld ip ine . N e i t h e r t h e m a x i m u m sys to l ic blood p re s -

s u r e n o r t h e sys to l i c p r e s s u r e a f t e r 2 and 4 m i n u t e s

r e s t fo l lowing e x e r c i s e w e r e , h o w e v e r , s igni f icant ly

in f luenced by e i t h e r d rug . The r a t e - p r e s s u r e p r o d u c t at m a x i m u m e x e r c i s e

w a s s ign i f i can t ly i n c r e a s e d by n i so ld ip ine and nifed-

ipine; t h e i n c r e a s e b e i n g l a r g e r w i th n i fed ip ine .

A d v e r s e R e a c t i o n s

D u r i n g t h e n i so ld ip ine pe r iod s e v e n p a t i e n t s r e p o r t e d

a d v e r s e r e a c t i o n s ; t h e s e w e r e of mild or m o d e r a t e in-

t e n s i t y , w i t h t h e e x c e p t i o n of t h e r a s h or e r y t h e m a

r e p o r t e d by one p a t i e n t , wh ich led to d rop out. How-

e v e r , t h e p a t i e n t r e f u s e d to be e x a m i n e d at t he t ime of

t h e r eac t i on . T w e l v e p a t i e n t s r e p o r t e d a to ta l of 15 a d v e r s e reac-

t ions d u r i n g t h e n i f ed ip ine pe r iod , l ead ing to a dose

r e d u c t i o n to 10 m g rid in one p a t i e n t and p r e m a t u r e

c o m p l e t i o n of t h e s t u d y pe r i od in t h e t h i rd and fou r th

w e e k , r e s p e c t i v e l y , in t w o p a t i e n t s . The o t h e r reac-

t ions w e r e m o s t l y t r a n s i e n t and of mild or m o d e r a t e

i n t e n s i t y . The n u m b e r of p a t i e n t s r e p o r t i n g s ide e f fec t s was

not s ignif icant ly d i f f e r en t d u r i n g the two t r e a t m e n t

per iods .

D i s c u s s i o n

This s t u d y s h o w e d a b e t t e r i m p r o v e m e n t in ex e r c i s e

t o l e r ance w h e n n i fed ip ine capsu les 20 mg tid w e r e

a d d e d to a tenolol c o m p a r e d wi th the add i t ion of nisol-

d ipine t a b l e t s 20 m g qd in p a t i e n t s wi th s e v e r e coro-

na ry a r t e r y d i sease .

C o r o n a r y a r t e r y d i la ta t ion is by m a n y r e g a r d e d as

t he m o s t i m p o r t a n t antiang-inal m e c h a n i s m of act ion of

d i h y d r o p y r i d i n e calcium a n t a g o n i s t s . H o w e v e r , t h e s e

d r u g s m a y e x e r t t h e i r an t i i s ehemic e f fec t t h r o u g h sev-

eral d i f f e r en t c h a n g e s of t he ca rd iovascu l a r s y s t e m .

D i f f e r ences b e t w e e n d r u g s wi th r e s p e c t to vascu la r

specif ic i ty may t h e r e f o r e be of i m p o r t a n c e . Nisol-

d ip ine has been s h o w n to be a more p o t e n t c o r o n a r y

vasod i l a to r t han n i fed ip ine [1,5-8] . H o w e v e r , th is

d r u g p r o p e r t y may be of less i m p o r t a n c e in p a t i e n t s

wi th v e r y a d v a n c e d co ro n a ry a r t e r y d i sease in w h o m

co rona ry a r t e r i e s have b e c o m e too a t h e r o s c l e r o t i c to

r e s p o n d to any vasod i l a t ing d r u g s [9]. In such p a t i e n t s

calcium a n t a g o n i s t s are e f fec t ive , main ly t h r o u g h a

r educ t i on in p e r i p h e r a l r e s i s t a n c e and t h r o u g h t h e i r

n eg a t i v e inot ropie effect , bo th m e c h a n i s m s con t r i bu t -

Nisoldipi~te t,.s Nifedipine i~ Am_lina Pectoris 455

kpm

6000

5000

4000

3000

2000

1000

F p <0.01-

AIENOLOL NISOLDIPINE NIFEDIPINE

ONLY AND AND

ATENOLOL AIENOLOL

Fig. 3. Total workload at tl~e exercise test.

ing to a reduction in oxygen demand. In our study, nifedipine 20 mg tid was clearly more effective in re- ducing systolic blood pressm'e at rest than was nisol- dipine 10 rag. Although nisoldipine has been reported to be an effective peripheral vasodilator, the dosage regimens of the two drugs that were used in our study may not have been comparable in this respect. The negative inotropic effect of nifedipine is well known. Nisoldipine, however, has been reported to be practi- cally devoid of any effect on myocardial contractility, at least in animals [1,10]. Our results, which are in some conflict with those of other investigators [11,12] may therefore be explained by a different selection of patients, as our patients were representative of those with the uppermost advanced coronary disease.

It should be noted that in a similar study in elderly patients with a mean age of 62 years, the addition of 10 mg nisoldipine to beta-blocker therapy produced only a slight and nonsignificant improvement in exercise parameters [13].

Another explanation of the differential effect of nisoldipine and nifedipine in this study may be that nisoldipine has a more variable pharmacokinetic profile than nifedipine. The bioavailability of nisol- dipine is 4-10%, whereas it is 40-60% for nifedipine [Raemsch, data on file, Bayer]. Nisoldipine is subject to an extensive first-pass metabolism, which is highly variable and is dependent on genetic polymorphism. Although Lain et al. found a persistent improvement of exercise tolerance over at least 8 hours in 12 pa- tients using 20 mg nisoldipine, a small decline in the extent of improvement was observed at 8 hours com- pared with 3 hours after drug ingestion, and the effect of 10 mg nisoldipine was largely dissipated at 8 hours [11]. This might indicate that the dosage of nisoldipine should have been higher than in our study or that divided dosages are necessary to obtain maximum benefit.

Schultz et al. reported that nifedipine reduces isch- emic ST-segrnent depression if high-grade coronary stenosis is present and that this effect is lacking when occlusions are collateralized [14]. This differential ef- fect was related to a steal phenomenon by the authors. Since nisoldipine has a stronger specificity for coro- nary arteries than nifedipine, a differential steal phe- nomenon may thus have contributed to the difference in effect that we observed between the two drugs. In our study 15 of the 20 patients had coronary occlusion combined with extensive collateralization. Rank cor- relation according to Kendall showed a weak inverse correlation (0.05 < p < 0.08) between the extent of collateralization and the total workload during the nifedipine period. This correlation was even weaker (p < 0.10) with nisoldipine. This analysis, and the fact that nifedipine was quite effective in the overall as- sessment, makes the hypothesis of a steal phenome- non doubtful.

We conclude that nifedipine, 20 mg tid, improves exercise tolerance in patients with angina and severe coronary artery disease when added to atenolol treat- ment and that the improvement is better than that observed during treatment with nisoldipine 20 mg qd. The difference in effect may be due to a difference in vascular specificity, which becomes important when patients with less responsive coronary arteries are treated.

Acknowledgments

We are grateful for the expert assistance of nurses Ellen Balto and Torunn Holm in carrying out the exercise tests.

This study was made possible through a grant from Bayer AG.

456 Pedersen a~d Kat~tor

References 1. Kazda S, Garthoff B, Meyer H, et al. Pharmacol%,3, of a new

calcium antagonistic compound, isobutyl methyl 1,4-dihy- dro-2,6-dimethyl-4-(2-nitrophenyl)-a,5-1)yridine-dicarboxy- late (nisoldipine, BAY K 5552). Arz.e im Forseh (Drug Res) 1980:80:2144-2162.

2. Alexander GJ, Dias Souza J, Segal SA, et a). Experimental coronary artery spasm: Prevention by nisoldipine and nifedil)ine but not by verapamil. Clin Res 1983;31:166a.

3. Kazda S, Garthoff B, R~,msch K-D, et al. Nisoldit)ine. In: Scriabine A, ed, New drugs a~t~unl: Cardi.rascldnr dr~.ls. New York: Raven Press, 1983:243-257.

4. Brfigqnann U, Blasini R, Rudolph W. Analysis of extent and duration of the antiischemic effects of nisoldipine: Results of a double-blind, randomized, crossover, placebo-tin, trolled. acute and long-term study. Et~rHcart J 1.q84;S(Supl)l 1):274.

5. Warltier DC, Meils CM, Gross G J, et al. Blood flow in nor- real and acutely isehemic myocardium after verapamil, dil- tiazem and nisoldipine (Bay K 5552), a new dihydropyridine calcium antagonist, g Phar,v~eo[ Ea'p T/wr IgSl;Olg:2.q6 - 302.

6. Vogt A, Neuholds KL. Krenzer H. Hemodynamic effects of the new vasodilator drug Bay K 5552 in man. Arz~wim For.seh 1980;>10:2162-2164.

7. Maxwell GH, Crompt(m S, Renics V. Efect of nisoldipine Ul)On the general and coronary hemodynamics of the anes- thetized dog. J Cardi.l,.sc l'tlarmae.I 1.qg2:4::-193-:'kq7.

8. Warltier D, Zyvoloski M, Gross G. et at. Comparative ac- tions of dihydropyridine slow channel calcium blocking agents in conscious dogs: Systemic and coronary hemody- namics with and without combined beta adrenergic block- ade. J Pharmaeol E.,'p Ther 1984;2::~0:367-375.

9. Lichtelen PR, Engel H-J. Raffenbeul W. Calcium entry blockers, especially nifedipine, in angina of effm't: Possible mechanisms and clinical implications. In: Opie LH, ed. gal- cleon a~dagonists and cardi.rasc~dar dise.se. New York: Raven Press, 1984:221-236.

10. Schipke JD. Burkhoff D, Alexander J, et al. Effect of nisol- dipine on the contractile state (ff the isolated canine left ventricle. Cardiorose Dr~r Tbcr 1987;1:287,

11. Lain J, Chairman BR, Crean P, et al. A dose-ranging, placebo-controlled, double-blind trial of nisoldipine in effort angina: Dm'ation and extent of antianginal effect. J Am ('~ll Cnrdiol 1985;6:447-452.

12. Reicher-Reiss H, Vered Z, Goldtmurt H, et al. Efficacy of nisoldipine compared to niDdil)ine in chr(mic stable angina. Cardiol,as Drugs Tber 1987:1:279.

13. Prager G. Weiss K-H. Schmitz H. Efficacy . f nisoidipine on myocardial ischemia during 24-hmu" ECG-monitoring. Car- dicwase Drugs Ther 1987:1:277.

14. Schulz. Antianginal effectiveness of the calcium antagonist nifedipine depending on the type of tin-(mary disease. Z K.r- diol 1983;72:657-61~4.