CURRENT THERAPEUTIC RESEARCH” VOL. 57, NO. 4, APRIL 1996

AMLODIPINE VERSUS NIFEDIPINE IN THE TREATMENT OF MILD-TO-MODERATE HYPERTENSION IN BLACK AFRICANS

AMBROSE 0. ISAH,’ AUGUSTINE 0. OBASOHAN,’ EDWARD A. OYEWO,’ AND JOHN OHAJU-OBODO’

‘Department of Medicine, University of Benin Teaching Hospital, Benin City, and 2PfEer Products PLC, Ikeja, Lagos, Nigeria

ABSTRACT

This single-blind, parallel-group, randomized trial compared the effi- cacy and tolerability of amlodipine with sustained-release nifedipine in 45 black African patients between the ages of 29 and 65 years. Amlodipine and nifedipine were administered after a 2-week washout period at a dose of 5 mg once daily and 20 mg twice daily, respectively. Dose was increased to 10 mg once daily for amlodipine and 40 mg twice daily for nifedipine in patients with diastolic blood pressure >90 mm Hg after 2 weeks. Treatment lasted for 12 weeks. Blood pressure was significantly reduced in both groups by week 12, with normalization rates of 75.0% for amlodipine and 72.2% for nifedipine. There was also a significant increase in heart rate in both groups by week 1 (heart rate in the erect position, +6.2 beats/min and +14.3 beats/min for amlodipine and nifedipine, respectively). No changes were observed in body weight or laboratory variables. Three patients in the nifedipine group withdrew from the study because of adverse effects (headache, two patients; severe palpitationsltachycardia, one patient). Other ad- verse effects, including pedal edema, frequent micturition, and dizzi- ness, were mild and transient in most cases. Amlodipine and nifed- ipine have similar antihypertensive effects; amlodipine appeared to be better tolerated.

INTRODUCTION

The calcium antagonists have rapidly become established as effective an- tihypertensive agents in the last decade, surpassing other more conven- tional drugs.’ The acceptance of these agents by physicians could be at- tributed to the unique features of the dihydropyridine derivatives which also have several indications (eg, hypertension, ischemic heart disease, and hypertrophic cardiomyopathy).2 The antihypertensive activity of am- lodipine and nifedipine, both dihydropyridines, is a result of vasodilation of the peripheral vasculature. The first-generation prototype, nifedipine, showed some limitation in clinical use and produced some adverse effects3;

Address correspondence to: Dr. A. 0. Isah, Department of Medicine, University of Benin Teaching Hospi- tal, P.M.B. 1111, Benin City, Nigeria. Received forpublication on November 21, 1995. Printed in the U.S.A. Reproduction in whole or part is not permitted.

300 OOll-393W96/$3.50

A. 0. ISAH ET AL.

these problems have been addressed in newer generation derivatives, in- cluding amlodipine.

Amlodipine has unique pharmacokinetic and pharmacodynamic prop- erties and may offer some advantages over nifedipine. It has a long half- life of 35 to 60 hours2>* and a gradual absorption, with time to peak plasma levels of 6 to 12 hours; these factors allow the once-daily dosing. Further- more, amlodipine is more vasoselective, and its slow association and dis- sociation at the receptor site contribute to a favorable safety profile and a lower incidence of vasodilatory side effects than nifedipine.’ Remarkable efficacy has been observed with amlodipine6 and nifedipine’vs in African blacks.

Hypertension in black patients, with its characteristic low renin ac- tivity and volume dependence, differs from hypertension found in white patients, which is characterized by high renin and augmented vascular activity. This study compared the efficacy and tolerability of amlodipine (5 to 10 mg, once daily) with sustained-release nifedipine (20 to 40 mg, twice daily) in black African patients with hypertension.

PATIENTSANDMETHODS

This study was a single-blind, parallel-group design that included 45 black African patients (18 men and 27 women) aged 29 to 65 years. Patients were recruited into the study from the hypertension clinic of the University of Benin Teaching Hospital, Benin City, Nigeria. All patients had mild-to- moderate elevated blood pressures (diastolic blood pressure [DBPI, 95 to 115 mm Hg) and were at stages I and II according to the World Health Organization criteria.s Patient characteristics are shown in Table I.

Exclusion criteria included a history or features of cerebrovascular, cardiac, or renal dysfunction; concomitant therapy for other diseases; and hypersensitivity to dihydropyridines. Pregnant and lactating women also

Table 1. Patient characteristics.

Amlodipine Wifedlpine

Female Age (Y)’

d~%ght (kg)* Heart rate (beatsimin)’ Blood pressure (mm Hg)*

Systolic Diastolic

22 23

6 1:

44.5 2 2.4

693E43 1

4&62.0

76:l 2 2:l 66.6 * 2.7 76.9 + 2.3

173.1 k 3.3 177.3 + 2.7 112.2 + 1.3 111.0 2 2.0

l Mean 2 SEM.

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AMLODIPINE VS NIFEDIPINE IN BLACK AFRICANS

were excluded. Verbal informed consent was obtained from all patients, and the protocol was approved by the hospital ethics committee.

Patients were assessed on entry and at completion of the study by use of a clinical examination and laboratory tests, which included hemato- logic tests (hemoglobin, hematocrit, and complete blood count), bio- chemical tests (electrolytes, urea, blood glucose, and liver function tests) and electrocardiography.

Patients were randomized to receive either an initial dose of 5 mg once daily of amlodipine (n = 22) with an adjustment to 10 mg once daily after 2 weeks if supine DBP was >90 mm Hg or, an initial dose of 20 mg twice daily of sustained-release nifedipine (n = 23) with an adjustment to 40 mg twice daily after 2 weeks if DBP was >90 mm Hg. The study was 14 weeks and consisted of three phases: (1) an initial 2-week washout period; (2) a 4-week dose-titration period; and (3) an &week maintenance period for responders. Patients were blind to the study drugs. For ethical reasons in the clinic setting, placebo was not used.

Patients were assessed weekly for 4 weeks and at 6, 8, and 12 weeks of therapy. At each clinic visit, blood pressure, heart rate, and body weight were recorded. Blood pressure was measured with an Accoson Mercury sphygmomanometer (A. C. Cossor and Son [Surgical] Ltd Accoson Work, London, United Kingdom) (Korotkoff phases 1 and 5) at trough level (24 + 2 hours and 12 ? 2 hours after the last dose for amlodipine and nifedipine, respectively). Readings were obtained after a lo-minute rest in the supine position and after 2 minutes in the sitting and standing positions. The radial pulse was measured in all positions.

To determine compliance, a pill count was made out of the view of pa- tients, and patients were interviewed about intake of medication. Sponta- neous reports of adverse effects were recorded at each visit and assessed for severity and association with treatment.

Response to therapy was defined as a decrease in the supine DBP of 10 mm Hg or a drop to <90 mm Hg with reduction of >5 mm Hg. Blood pressure was considered normalized if the DBP was <90 mm Hg. The effects of treatment on the various variables were assessed by comparing the values at each visit with the pretreatment baseline values.

Student’s t test (paired and unpaired) was used for within-group and between-group comparisons at similar time points. A P value co.05 was regarded as significant. Data are given as mean + SEM.

RESULTS

Of the 45 patients recruited (amlodipine, n = 22; nifedipine, n = 23), 2 patients were withdrawn from each group for protocol violation (poor at- tendance at the clinic or poor compliance with medication intake), 3 were

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A. 0. ISAH ET AL.

withdrawn from the nifedipine group due to adverse effects (headache, 2 patients; severe palpitations/tachycardia, 1 patient), and 1 was withdrawn from the nifedipine group due to poor response by week 4 (but was included in efficacy analysis). Thus antihypertensive efficacy data were assess- able in 20 and 18 patients in the amlodipine and nifedipine groups, respectively.

Baseline systolic blood pressure (SBP) and DBP were comparable in all positions for both groups (Table II). ARer treatment the blood pressures fell significantly (P < 0.001) by week 1 in both groups (Figure 1). A further mild decrease followed after the third week of doubling of the dose in 11 patients receiving amlodipine and 4 patients receiving nifedipine. There- after, SBP and DBP remained stable until week 12 (Figure 2). No statis- tically significant differences were observed between groups.

The response rates (proportion of patients with a fall in DBP of ~10 mm Hg) were 100% and 94.4% for amlodipine and nifedipine, respectively; the respective normalization rates were 75.0% and 72.2%. There was a significant increase in the heart rate by week 1 in both groups (Figure 3). This effect was more pronounced in the erect position ( + 6.2 beats/min, P < 0.002 vs baseline for amlodipine; + 14.3 beats/min, P < 0.001 vs baseline for nifedipine). No further significant increase was observed thereafter despite the upward dosage adjustment at the end of the second week.

There were no significant changes in body weight in either group. Baseline values were 69.0 rt 3.1 kg and 68.6 + 2.7 kg, and week 12 values were 68.5 f 2.9 kg and 68.5 + 3.0 kg for amlodipine and nifedipine, respectively.

Adverse effects are shown in Table III. Three patients receiving ni- fedipine withdrew from the study; two as a result of severe headache and one due to marked palpitations/tachycardia accompanying therapy in the first 2 days. Other adverse effects, notably pedal edema, frequent mictu- rition, and dizziness, were mild and transient. However, the one patient

Table II. Supine blood pressure (mean k SEM) following amlodipine and nifedipine therapy.

Ouration(~jTherapy Amlodipine Nlledipine

Baseline 173.1 -t 3.3 177.3 f 2.7

112.2 2 1.3 111.0 2 2.0

1 155.1 k 3.6 146.2 2 4.6

95.1 + 1.7 . 2 . 4 143.5 f 2.9 141.8 + 3.6

06.0 2 1.8 86.8 2 2.2

12 143.7 f 2.2 145.5 + 3.3

86.2 + 1.4 07.1 + 1.6

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AMLODIPINE VS NIFEDIPINE IN BLACK AFBICANS

Amlodipine

Standing

Nifedipine

Sinlng

Supine

:@&_;, .

f loo k

!a+ I

0 2 4 8 a 10 12

Duration of Therapy (wk)

Figure 1. Mean systolic (0) and diastolic (0) blood pressures following treatment with am- lodipine or nifedipine.

who withdrew for poor response to nifedipine therapy developed significant pedal edema, which improved on discontinuation and replacement of treat- ment with a fixed dose combination of prazosin and polythiazide. Of special interest was the observed frequent micturition, which was marked at night (10 times in 1 patient); urine volume despite meticulous collection, was less than 2.0 L. All laboratory variables at baseline and at the end of the study were essentially normal and not significantly different between or within groups.

DISCUSSION AND CONCLUSIONS

This study compared the efficacy and tolerability of two dihydropyridine calcium antagonists-a sustained-release preparation of the first- generation, nifedipine, and a more vascular-selective and specific second- generation, amlodipine. The efficacy profiles were similar with a high rate

304

A.O.ISAHETAL

1 4 8 12

Duration of Therapy (wk) Figure 2. Mean supine blood pressure of amlodipine (W) and nifedipine (0) through week 12

of treatment.

of normalization (~70%) with both drugs. These findings confirm findings of earlier studies of either drug alone in a similar population.6*7*g It further confirms the usefulness of the calcium antagonists in antihypertensive monotherapy among the black population. Other therapies, such as the beta-blockers,” the quinazoline alpha-blockers,” and the angiotensin- converting enzyme inhibitors, l2 have shown less efficacy in a similar population.

The increase in heart rate, which was likely due to the vasodilatory action of the dihydropyridines, was minimal for amlodipine and more pro- nounced for nifedipine, especially in the erect position. Though these find- ings are similar to findings in an earlier study,’ the calcium antagonists are known not to affect heart rate significantly among white patients.13 The mild response for amlodipine compared with nifedipine could be at- tributed to its unique pharmacokinetic (slow absorption) and pharmaco- dynamic (longer onset of action, slow association/dissociation at the recep- tor sites) properties.4,5

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AMLODIPINE VS NIFEDIPINE IN BLACK AFRICANS

35 2 m

20

15

10

5

0

20

15

10

5

0

I

I-

I_

I-

I-

t

T

t

T

t

rI t t

ti

1 4

t

I

I I

t

Supine

t

II

Erect

t

Duration of Therapy (weeks) 12

Figure 3. Change in mean heart rate from baseline following treatment with amlodipine (W) or nifedipine (0). *P < 0.002 versus baseline; tP < 0.001 versus baseline.

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A. 0. ISAH ET AL.

Table III. Adverse drug reactions.*

Pedal edema Frequent micturition

Headache PalpitationsAachycardia

Dizziness Poor erection Total patients reporting

l Some patients experienced more than one adverse effect. t Led to patient withdrawal.

Both drugs presented a similar profile in adverse effects with slightly higher numbers in the nifedipine group, although the differences were not statistically significant. The observed effects were related mainly to the vasodilatory pharmacologic action of the test drugs,l* and most were mild and transient. However, of special interest was the observed increased frequency of micturition, which was also seen in an earlier study.5 The number of times patients with this untoward effect had to void relative to the urinary volume could not be explained by mere diuresis or natriure- sis.5 Although this effect may be beneficial as with conventional diuret- ics,15 further studies are needed to characterize this phenomenon.

Drug compliance, an important consideration in therapy,16 was good for both treatment groups, although better for the once-daily regimen of amlodipine. However, the close supervision in the clinical trial setting may have confounded the probable behavior in ordinary circumstances.

In conclusion, these results show that the antihypertensive efficacy profile for both nifedipine and amlodipine, in the doses studied, is similar; however, more adverse effects were observed with nifedipine. These re- sults, together with the convenience of once-daily dosing with amlodipine, suggest that amlodipine may enhance patient compliance and thus provide better control of hypertension. Further studies with larger numbers of patients will be required to confirm the findings of this study and to clarify any subtle differences in the efficacy and safety of these drugs.

Acknowledgments

The authors gratefully acknowledge the drugs supplied by Pfizer Products PLC, Ikeja, Lagos, Nigeria.

This study is dedicated to the memory of Dr. E. A. Oyewo.

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AMLODIPINE VS NIFEDIPINK IN BLACK AFBICANS

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3. Krebs R. Adverse reactions with calcium antagonists. Hypertension. 1983;5(Suppl 2):125- 129.

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