Combined Enalapril and Felodipine Extended Release (ER) for Systemic Hypertension

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Abstract

This multicenter, placebo-controlled, double-blind trial of factorial design evaluated the safety and efficacy of combination treatment with the angiotensin-converting enzyme inhibitor, enalapril, and the vascular selective calcium antagonist felodipine extended release (ER) in patients with essential hypertension. After a 4-week, single-blind placebo baseline period, 707 patients with sitting diastolic blood pressures (BPs) in the range of 95 to 115 mm Hg received placebo, enalapril (5 or 20 mg), felodipine ER (2.5, 5, or 10 mg), or their combinations for an 8-week double-blind treatment period. All doses of enalapril and felodipine ER had a statistically significant (p <0.05) additive effect in reducing both systolic and diastolic BP. The trough to peak ratios for the combinations ranged from 0.63 (enalapril 5 mg-felodipine ER 2.5 mg) to 0.79 (enalapril 20 mg-felodipine ER 10 mg) and were consistent with effective BP control with 1 dose/day. Patients aged ≥65 years demonstrated a greater reduction in diastolic BP. Combinations of enalapril-felodipine ER were associated with less drug-induced peripheral edema (4.1%) compared to felodipine ER monotherapy (10.8%). There were no serious drug-related adverse effects observed during the study. In this trial, the combination of enalapril and felodipine ER effectively lowered BP and was generally well tolerated with an excellent safety profile when used in the treatment of hypertension.

The efficacy, safety, and tolerability of combination treatment with enalapril and felodipine extended release (ER) were evaluated in 707 patients with essential hypertension in a multicenter, factorial design study. The combination had significant additive blood pressure-lowering effects compared with each of the monotherapies over a wide range of doses, was generally well tolerated, and was associated with a lower incidence of drug-related peripheral edema than that from higher doses of felodipine ER monotherapy.

Section snippets

Patient Selection and Study Design

Seven hundred seven patients (457 men [65%], 548 white [78%]), mean age 53.5 years, with essential hypertension and sitting diastolic BP in the range of 95 to 115 mm Hg were enrolled in a multicenter, placebo-controlled, double-blind, parallel, randomized 3 × 4 factorial design study after giving informed consent. Patients with evidence of significant renal (calculated creatinine clearance <60 ml/min) or hepatic dysfunction, recent myocardial infarction, or congestive heart failure were

Results

The baseline characteristics of the 707 patients who took part in the study are given in Table 2. The 12 treatment groups were similar with respect to age, gender, race, duration of hypertension, and baseline BP. Of the 707 patients, data were available on 705 for efficacy analysis (2 patients without treatment records were excluded).

The estimated (additive model) trough sitting systolic and diastolic BP reductions at week 8 are presented in Fig. 1Fig. 2. All doses of enalapril and felodipine

Discussion

In this study, the combination of enalapril and felodipine ER effectively lowered BP and was generally well tolerated with an excellent safety profile when used in the treatment of hypertension. Moreover, both efficacy and tolerability were enhanced when these drugs were used in combination compared to their monotherapies. At each combination dose, both drugs contributed significantly to lowering BP. The trough to peak ratios were consistent with 1dose/day in that BP reduction 24 hours after

Acknowledgements

We gratefully acknowledge the assistance of Clara Hwang, MS, for conducting the statistical analyses of the study.

This study was supported in part by Astra Merck, Inc., Wayne, Pennsylvania.

References (16)

  • AH Gradman

    Hemodynamic effects of the vascular selective calcium antagonist felodipine in patients with impaired left ventricular function

    Am Heart J

    (1992)
  • FM Fouad et al.

    Cardiac factors in response to antihypertensive treatment

    Hypertension

    (1983)
  • HR Brunner et al.

    Treatment the individual hypertensive patient: considerations on dose sequential monotherapy and drug combinations

    J Hypertens

    (1990)
  • A Anderson et al.

    Interaction of enalapril with sodium restriction, diuretics, and slow-channel calcium-blocking drugs

    Nephron

    (1990)
  • HJ Dengler et al.

    Report of a workshop on fixed-ratio drug combinations

    Eur J Clin Pharmacol

    (1975)
  • CT Dollery

    Pharmacological basis for combination therapy of hypertension

    Annu Rev Pharmacol Toxicol

    (1977)
  • WH Frishman et al.

    A multifactorial trial design to assess combination therapy in hypertension

    Arch Intern Med

    (1994)
  • J Ménard et al.

    Calcium antagonists-ACE inhibitors combination therapy: objectives and methodology of clinical development

    J Cardiovasc Pharmacol

    (1993)
There are more references available in the full text version of this article.

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A list of participating investigators appears in the Appendix.

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