THE DILTIAZEM DIFFERENT DOSES STUDY - A DOSE-RESPONSE STUDY OF ONCE-DAILY DILTIAZEM THERAPY FOR HYPERTENSION

The objective was to evaluate the dose-related efficacy/tolerance prof ile of 240, 300, 360, and 420 mg diltiazem slow-release, once-daily (O D) doses, with emphasis on the 300 mg dose. The study was randomized a nd double-blinded with a 36-week parallel, two-branched, cross-over de sign after a single-blind, run-in period of 4 weeks on placebo and 6 w eeks on 300 mg diltiazem OD. Each branch included six 6-week active tr eatment periods with 180, 240, and 300 mg tablets, one or two tablets OD. Participants were men and postmenopausal women, aged 40-70 years, with uncomplicated primary hypertension (WHO stages I and II) and a su pine diastolic blood pressure of 95-115 mm Hg in the absence of antihy pertensive medication. A total of 138 patients from various clinics pa rticipated in the study. All were included in the intention to treat a nalysis, and 117 patients were included in the per protocol analysis. Criteria for evaluation were blood pressure, heart rate, and response rate, as well as plasma diltiazem and metabolite M1 concentration befo re morning dose. Well-being of the patients and adverse events were re corded. Electrocardiogram and standard laboratory tests were obtained. Analysis of variance was used for statistical calculations. Supine bl ood pressures and response rates in the per protocol analysis were 161 .2/97.0 for placebo (29.1%), 155.2/ 92.8 for 240 mg (54.7%), 153.8/91. 6 for 300 mg (55.6%), 155.5/92.0 for 360 mg (59.0%), and 152.0/90.5 fo r 420 mg (63.2%) of diltiazem OD. The intention to treat analysis was very similar to the per protocol analysis. There was a small but stati stically significant decrease in heart rate for all doses of diltiazem OD compared to placebo. A linear relationship existed between the dos e and the plasma concentration of both diltiazem and metabolite M1, as well as a dose-response relationship. Diltiazem OD in the dose range 240-420 mg was generally well tolerated and not differently perceived from the placebo treatment except for ankle edema (2-6%). The study sh ows that OD diltiazem is significantly superior to placebo for mild to moderate hypertension and that the effect is large enough to be clini cally valuable. It also shows that there is a linear dose-response rel ationship for diltiazem between 240 and 420 mg.