1. ¹University of Tennessee College of Medicine, Veterans Affairs Medical Center, Memphis, Tennessee; USA
2. ²St. Louis University Medical Center, St. Louis, Missouri; USA
3. ³East Edinger Medical Clinic, Santa Ana, California; USA
4. ⁴Orlando Clinical Research Center, Orlando, Florida; USA
5. ⁵Medical Parameters, Martinez, Georgia; USA
6. ⁶Arizona Heart Institute and Foundation, Phoenix, Arizona. USA

Correspondence: William C. Cushman, MD, Veterans Affairs Medical Center (111Q), 1030 Jefferson Avenue, Memphis, TN 38104-2193 E-mail: cushman@memphis.va.gov

⁷See the Acknowledgements for a full list of participants.

^*This work was supported by a grant from Merck Research Laboratories, Blue Bell, Pennsylvania.

Received 5 September 1996; Revised  00; Accepted 28 July 1997.

Abstract

The safety and efficacy of two fixed dose combinations of enalapril and diltiazem extended release formation (ER) (E/D) were compared with their monotherapies and placebo in patients with stage 1 to 3 hypertension. The trial design was a multicenter, randomized, double blind, placebo controlled, parallel group, 12 week treatment phase, followed by a 36 week, open label phase. A total of 891 patients with sitting diastolic blood pressure (SiDBP) between 95 and 115 mm Hg were randomly assigned to enalapril 5 mg, diltiazem ER 120 mg, diltiazem ER 180 mg, enalapril 5 mg/diltiazem ER 120 mg (E5/D120), enalapril 5 mg/diltiazem ER 180 mg (E5/D180), or placebo. In the open label phase, 562 patients received the fixed combination, titrated as needed to control SiDBP < 90 mm Hg. Efficacy was determined with trough (24 2 h postdose) sitting blood pressure measurements at week 12 and at the end of the open label part of the study. Safety was evaluated based on patient symptoms, clinical laboratories, and electrocardiograms (ECG).

E5/D120 and E5/D180 significantly reduced trough SiDBP (-7.6 and -8.3 mm Hg, respectively; P < .05) versus their monotherapies. E5/D120 and E5/D180 significantly reduced trough sitting systolic blood pressure (-7.9 and -9.0, respectively; P < .05) versus both diltiazem ER monotherapies. All active treatments significantly decreased SiDBP and SiSBP versus placebo. E/D effectively lowered SiDBP and SiSBP during the open label extension. No significant difference was seen among treatment groups for the overall incidence of adverse events. The most common drug related adverse events were headache, edema/swelling, dizziness, asthenia/fatigue, cough, rash, and impotence. The event frequency for the combinations were similar to those seen with the monotherapies.

Fixed combinations of E/D were generally well tolerated, with an increased blood pressure lowering effect as compared with the individual components in patients with stage I to III hypertension.