CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 6, JUNE 1994

A COMPARISON OF FELODIPINE AND NIFEDIPINE AS MONOTHERAPY IN PATIENTS WITH MILD-TO-MODERATE HYPERTENSION

ALEXANDER W. GOUDIE, 10MI P. GUPTA, 2 PETER L. GRAY, z JOHN R. M. ROSS, 4 JOHN R. COVES, s BARRY J. MCKENNA, e IAN A. BLOMFIELD, 7

KEITH W. BRAMLEY, e ROBERT W. SHARP, 9 DERWYN F. JONES, I~ ROBERT J. HADLEY, II AND DEBORAH A. WA~IvrS 12

1Health Centre, Motherwell, Scotland; 2Grays, Essex, England; 3Health Centre, Portadown, Northern Ireland; 4Almondbury, West Yorkshire, England; 5Spendlove Centre Surgery,

Charlbury, Oxfordshire, England; eScawthorpe, South Yorkshire, England; 7Leeds, England; SForest Gate Surgery, Totton, Southampton, England; 9Medical Centre,

Wellingborough, Northamptonshire, England; leThe Mount Surgery, Pontypool, Gwent, Wales; llRiversdale House, Bridgend, Mid-Glamorgan, Wales; and 12Astra

Pharmaceuticals Ltd., Kings Langley, Hertfordshire, England

ABSTRACT

Felodipine is a vascular-selective calcium antagonist developed for the t reatment of hypertension. The purpose of this study was to investi- gate whether felodipine extended release (ER) has benefit as mono- therapy when compared with the established, widely used dihydropyr- idine, nifedipine retard (R). One hundred thirty-four patients with uncomplicated mild-to-moderate primary hypertension (seated dia- stolic blood pressure [DBP], 95 to 115 mm Hg) entered this multi- center, comparative, randomized, double-blind, parallel-group study of the efficacy and tolerability of felodipine ER versus nifedipine R. Following a 4.week run-in period, patients were randomized to receive either felodipine ER 5 mg once in the morning or nifedipine R 10 mg twice daily. I f seated DBP was >90 mm Hg after 2 weeks of treatment, the doses were doubled and treatment continued for another 2 weeks. After 4 weeks of treatment, seated mean DBP values had decreased from 105 -+ 6 mm Hg to 89 -+ 7 mm Hg in the felodipine ER group and from 105 - 6 mm Hg to 92 - 8 mm Hg in the nifedipine R group. The mean reduction was 3 mm Hg greater with felodipine ER than with nifedipine R (95% confidence interval -- -5 .7 to -0.03; P = 0.03). Sixty- five percent of the patients in the felodipine ER group achieved a seated DBP ~<90 mm Hg versus 59% in the nifedipine R group. Thir- teen patients discontinued the study because of adverse events (five patients in the felodipine group and eight patients in the nifedipine group, one of whom died). The pattern of adverse events was similar in the two groups and they were generally mild. In this study, felodipine ER 5 to 10 mg once in the morning was shown to be more effective than nifedipine R 10 to 20 mg twice daily in reducing seated blood pressure and caused fewer patients to discontinue treatment.

Address correspondence to: Ms. D. Watts, Clinical Research Department, Astra Pharmaceuticals Ltd., Home Park, Kings Langley, Hertfordshire, WD4 8DH, England. Received for publication on March 10, 1994. Printed in the U.S.A. Reproduction in whole or part is not permitted.

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FELODIPINE VERSUS NIFEDIP1NE IN HYPERTENSION

INTRODUCTION

Primary hypertension often requires long-term treatment. A simple well- tolerated dosage regimen is needed to improve patient compliance. In ad- dition, gains in lowering blood pressure (BP) should not be achieved at the expense of more adverse reactions for the patient.

Felodipine* is a vascular-selective calcium antagonist, which has been shown in clinical trials to have no adverse cardiac effects within its ther- apeutic range. 1-3 The two dihydropyridine calcium antagonists felodipine and nifedipine are well-established antihypertensive compounds. The ex- tended release (ER) formulation of felodipine is suitable for once-daily use whereas the retard (R) formulation of nifedipine~ is given twice daily. When the antihypertensive efficacy and tolerability of felodipine ER 10 to 20 mg once daily were compared with those of nifedipine R 20 to 40 mg twice daily as additional therapy in patients with inadequately controlled BP receiving metoprolol alone, felodipine ER was shown to be more effec- tive in reducing BP. 4

The aim of the present study was to compare the efficacy and tolera- bility of felodipine ER once in the morning with nifedipine R twice daily given as monotherapy to patients with mild-to-moderate essential hypertension.

PATIENTS AND METHODS

One hundred thirty-four patients (80 men, 54 women; mean age, 56 +- 11 years; range, 25 to 78 years) with uncomplicated mild-to-moderate pri- mary hypertension entered this randomized, double-blind, parallel-group study, in which one hospital and 11 General Practice centers participated (Table I). On the day of randomization, patients received either felodipine ER 5 mg once daily in the morning or nifedipine R 10 mg twice daily. If, after 2 weeks of treatment, the seated diastolic blood pressure (DBP) was >90 mm Hg, these doses were doubled to felodipine ER 10 mg once in the morning and nifedipine R 20 mg twice daily. Patients were prospectively defined as having controlled BP if their seated DBP was ~<90 mm Hg while receiving treatment. At randomization, 60% of the patients had a medical history of hypertension of less than 3 months and 40% had a history of primary hypertension for more than 3 months; 86% of the patients had received no antihypertensive treatment in the previous 2 months.

The inclusion criteria for the patients were as follows: age between 20 and 80 years and seated DBP 95 to 115 mm Hg on three occasions during a run-in period of 4 weeks, while receiving no antihypertensive medication (any antihypertensive medication was to be discontinued 2 weeks before

* Trademark: Plendil | (Astra Pharmaceuticals Ltd., Kings Langley, Hertfordshire, England). t Trademark: Adalat Retard | (Bayer plc, Newbury, Berkshire, England).

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Table I. Patient characteristics at randomization (mean -+ SD).

Felodipine ER Nifedipine R

No. of patients 68 66 Sex

Male 43 37 Female 25 29

Age ~) 53 __ 12 58 ___ 9 Duration of hypertension (y) 2.0 --_ 4.7 1.7 _+ 3.4

Range 0-27 0-17 WHO stage of hypertension (n)

I 67 63 II 0 3 III 1 0

No. of patients previously treated for hypertension 7 12

Body weight (kg) 81 ___ 14 79 --_ 16

ER = extended release; R = retard; WHO = World Health Organization.

the start of the run-in period). Exclusion criteria were as follows: seated systolic blood pressure (SBP) > 240 mm Hg; seated DBP > 115 mm Hg; an acute myocardial infarction or cerebrovascular accident within 3 months before randomization; heart failure; atrioventricular block of second or third degree; severe angina pectoris or another severe concomitant disease; or significant impairment of cardiac, hepatic, or renal function. Women of childbearing potential were also excluded.

Clinic visits at 2-week intervals took place in the afternoon during the 4-week run-in period and during the 4 weeks after randomization. Mea- surements of BP (Korotkoff phases I and V) and heart rate (HR) were taken 7 to 12 hours after dosing. The measurements were made in dupli- cate in both the seated (after 5 minutes) and standing (after 1 minute) positions using a Hawksley random-zero sphygmomanometer (Hawksley and Sons, Lancing, Sussex, England). HR was counted from the radial pulse over 15 seconds and multiplied by 4, immediately after the BP re- cording. Adverse events were recorded at randomization and after 2 and 4 weeks of treatment in response to both an open question regarding the patients' health in the previous 2 weeks and according to a specific ques- tionnaire listing symptoms.

Analysis was performed according to the intention-to-treat principle and based on changes in variables from randomization to after 4 weeks of treatment. BP and HR changes were analyzed using a two-way analysis of variance with treatment and center as factors. The analysis of patients with controlled BP was performed using a Mantel-Haenszel test stratify- ing for centers. Data are presented as mean + standard deviation (SD) with 95% confidence intervals (CI) for adjusted mean differences between treatment groups. Times postdose are given as median values. Differences were considered significant at P < 0.05.

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FELODIPINE VERSUS NIFEDIPINE IN HYPERTENSION

The study was approved by local ethics committees and performed in accordance with the Declaration of Helsinki. All patients gave their writ- ten informed consent before the start of the study.

RESULTS

BP and HR measurements were taken 8.8 and 9 hours after dosing of felodipine ER and nifedipine R. This reflects the normal clinical situation. The changes in seated and standing BP and HR from randomization to after 4 weeks of t reatment with either felodipine ER 5 to 10 mg once in the morning or nifedipine R 10 to 20 mg twice daily are given in Table II. Seated BP was statistically significantly reduced in the two groups during the 4-week t rea tment period. Felodipine ER produced a significantly greater decrease in seated BP (mean difference = 3.0 mm Hg; 95% CI = - 5 . 7 to -0 .03) than did nifedipine R (Table II, figure).

In the felodipine ER group, 59% of the patients continued treatment at the lower 5-mg dose; the higher dose was required by 41%. In the nifed- ipine R group, 51% of patients continued receiving 10 mg twice daily and 49% received the higher 20-mg twice-daily dose. After 4 weeks, 65% of patients in the felodipine ER group had controlled BP, that is, DBP ~<90 mm Hg, compared with 59% in the nifedipine group (nonsignificant difference).

There were no differences between the two treatment groups when changes in seated and standing HR from randomization were compared.

The types of adverse events reported, as described in the methods section, were similar in the two treatment groups. Although most symp-

Table II. Blood pressure (mm Hg) and heart rate (beats/min), adjusted means, mean differ- ence in change, and 95% confidence intervals (CI) for comparisons between treat- ments at randomization (0w) and after 4 weeks of treatment (4w) with felodipine ER (5 to 10 mg once in the morning) or nifedipine R (10 to 20 mg twice daily) approximately 9 hours after dosing.

Felodipine ER Nifedipine R Mean Difference (n = 63) (n = 59) in Change

Between Ow 4w Ow 4w Treatments 95% CI P

Seated SBP 170 +- 19 150_ 15 171 +- 18 154 _+ 18 -4 .0 - 8 . 0 t o -0.01 <0.05 DBP 105 - 6 89 +-- 7 105 -+ 6 92 - 8 - 3 . 0 - 5 . 7 to -0 .03 0.03 HR 77 +_ 8 78 __ 8 76 +- 7 78 _+ 8 - 1 . 0 - 3 . 4 to 1.4 >0.20

Standing SBP 169_+18 149+-14 170+-18 152+-15 - 3 .5 - 8 . 0 t o 1 . 0 0.13 DBP 105 +- 6 90 +-- 8 105 +- 5 92 +_ 9 - 2 . 2 - 5 . 0 to 0.6 0.12 HR 79+-10 80---9 77---8 79+-9 -1 .2 - 3 . 8 to 1.4 >0.20

ER = extended release; R = retard; SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate.

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A. W. GOUDIE ET AL.

0

-10

-15 .9

O -20

-25 n = 63 n = 59 n = 63 n = 59

�9 felodipine ER ~ ] nifedipine R Figure. Reduction in seated systolic and diastolic blood pressures (BP) after 4 weeks of

treatment with felodipine extended release (ER) once daily and nifedipine retard (R) twice daily.

toms were mild and transient, five patients in the felodipine ER group and seven patients in the nifedipine R group discontinued medication because of adverse events. The patients who discontinued felodipine ER treatment did so because of headache (3 patients) and ankle edema (2 patients). The main reasons for discontinuing nifedipine R were headache (4 patients), burning pain in the legs (1 patient), flushing (1 patient), and confusion and trembling (1 patient). One patient died of acute left ventricular failure after 9 days of nifedipine R treatment; whether this death was drug related could not be determined. One patient stopped taking nifedipine R 4 days prior to the final clinic visit. His data were available for efficacy and tolerability assessments.

DISCUSSION AND CONCLUSION

In the present study, patients with mild-to-moderate primary hyperten- sion receiving felodipine ER 5 to 10 mg once daily (monotherapy) showed a better antihypertensive response in seated BP compared with those pa- tients who received nifedipine R 10 to 20 mg twice daily. In another study, Hosie et al 5 compared monotherapy treatment with felodipine ER 5 mg once daily with nifedipine R 20 mg twice daily (ie, the felodipine:nifedipine dose ratio was 1:8, whereas in our study it was 1:4). 5 In the study of Hosie et al both drugs were equally effective, although felodipine ER was better

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FELODIPINE VERSUS NIPEDIP1NE IN HYPERTENSION

tolerated. In our study, felodipine ER was more effective and caused fewer patients to withdraw than nifedipine R, even though a higher felodipine dose was used.

The BP measurements were recorded approximately 9 hours after dosing in this study, when the normal diurnal BP rhythm is still at a plateau and before the decrease at night (the low BP values occur around 3 AM). Felodipine ER 5 to 10 mg has been shown to control BP over the entire 24-hour period, as assessed by 24-hour ambulatory blood pressure monitoring as well as measurements in the clinic at 24-hours postdose. 6-9 By comparison, the retard formulation of nifedipine has shown a good antihypertensive effect at 12-hours postdoseP

In another study of patients with moderate-to-severe essential hyper- tension, where DBP was 110 to 115 mm Hg despite beta-blockade, the addition of felodipine ER 10 to 20 mg once daily was compared with ni- fedipine R 20 to 40 mg twice dailyJ Efficacy was more pronounced than in our study. However, it is well known that the higher the BP, the greater the drop in BP with antihypertensive medication, particularly with cal- cium antagonists. 1~ Thus the difference in effect between the antihyper- tensive treatments is likely to be smaller in patients with mild hyperten- sion compared with those with more severe disease. Despite the fact that our study investigated monotherapy in typical mildly hypertensive pa- tients, felodipine ER was still more efficacious than nifedipine R.

Adverse events during treatment with dihydropyridine calcium an- tagonists are predictable and are generally attributed to their calcium- channel blocking action on different tissues and vascular beds. 11 Thus vasodilating effects such as headache, flushing, and ankle swelling are the most frequently reported adverse events for compounds such as felodipine and nifedipine. These adverse events are often also more pronounced at the beginning of treatment and many resolve within a few days. Serious ad- verse events are extremely rare with this group of compounds, which is important because the treatment of hypertension is often lifelong. In this study the tolerability of felodipine was generally good and the proportion (7%) of patients discontinuing treatment because of adverse events was close to rates obtained from the pooled data from placebo-controlled trials in which felodipine ER 5 to 10 mg caused 5% of patients to discontinue treatment because of adverse events. ~2 By comparison, the treatment dis- continuation rate with nifedipine R in this study was 12%.

Compliance should be enhanced with felodipine ER, a once-daily treat- ment, compared with nifedipine R, which has to be taken twice daily.

In conclusion, felodipine ER 5 to 10 mg taken once daily as monother- apy is more effective in reducing seated DBP than nifedipine R 10 to 20 mg taken twice daily. In addition, more patients in the nifedipine R group discontinued treatment because of adverse events than in the felodipine ER group.

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2. Culling W, Ruttley MSM, Sheridan DJ. Acute haemodynamic effects of felodipine during beta blockade in patients with coronary artery disease. Br Heart J. 1984;52:431-434.

3. Amlie JP, Endresen K, Sire S. The effect of felodipine on the sinus and atrioventricular nodes in patients with ischemic heart disease. J Cardiovasc Pharmacol. 1990;15(Suppl 4):$25. Abstract.

4. Littler WA. Control of blood pressure in hypertensive patients with felodipine extended release or nifedipine retard. Br J Clin Pharmacol. 1990;30:871-878.

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8. Faison BP, Goldberg AI, Dobbins TW, et al. Dose response relationship and 24-hour efficacy were observed with once daily extended release felodipine using 24-hour ambu- latory blood pressure monitoring. Am J Hypertens. 1991;4:105A. Abstract 318.

9. Abelardo NS, Ramos EF, Mendoza VL, et al. A comparison of felodipine and nifedipine as monotherapies for the treatment of mild to moderate hypertension. J Hum Hypertens. 1989;3:57-59.

10. Blychert E, Edgar B, Elmfeldt D, Hedner T. Plasma concentration-effect relationships for felodipine: A meta analysis. Clin Pharmacol Ther. 1992;52:80-89.

11. Busemann WD, Hopf R. Kalziumantagonisten in der Therapie der koronaren Herzerkrankung. Inn Med. 1985;12:255-258.

12. Elvelin L, Kennerfalk A, Elmfeldt D. Tolerability and safety of felodipine. Cardiovasc Drug Rev. 1993;11:126-147. Review.

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