title: Determining the trough-to-peak ratio in parallel-group trials. Systolic Hypertension in Europe (SYST-EUR) Trial Investigators.
abstract: We explored how in parallel-group trials interindividual variability, correction for placebo effects, and smoothing of blood pressure profiles can be handled in measuring the trough-to-peak ratio in 244 individuals with isolated systolic hypertension (> or = 60 years) enrolled in the placebo-controlled Systolic Hypertension in europe Trial. Net treatment effects were computed by subtracting the mean changes from baseline during placebo (n = 133) from those during active treatment (n = 111). At entry, systolic/diastolic pressures averaged 176/86 mm Hg in the clinic and 149/80 mm Hg on 24-hour ambulatory monitoring. With corrections applied for baseline and placebo, nitrendipine (10 to 40 mg/d), with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d), reduced (P < .001) these blood pressure values by 16.6/7.3 and 9.8/4.7 mm Hg, respectively. The net trough-to-peak ratios were first determined from blood pressure profiles (12 hours) with 1-hour precision, synchronized by the morning and evening doses of the double-blind medication. According to the usual approach, disregarding interindividual variability, the systolic/diastolic net trough-to-peak ratios were 0.46/0.40 in the morning and 0.77/0.99 in the evening. In individual subjects, the baseline-adjusted trough-to-peak ratios were nonnormally distributed. We therefore used a nonparametric technique to calculate the net trough-to-peak ratios from the results in individual subjects. In the morning, these ratios averaged 0.25 systolic (95% confidence interval, 0.09 to 0.41) and 0.15 diastolic (95% confidence interval, 0.00 to 0.31) and in the evening, 0.19 and 0.36 (95% confidence intervals, 0.00 to 0.38 and 0.14 to 0.56), respectively. When the blood pressure profiles were smoothed by substituting the 1-hour averages by moving or fixed 2-hour averages or by Fourier modeling, the trough-to-peak ratios remained unchanged after the morning dose (0.20/0.13, 0.20/0.14, and 0.16/0.21, respectively) but tended to increase in the evening (0.32/0.38, 0.28/0.40, and 0.48/0.49). In conclusion, the parallel-group analysis proposed makes it possible for one to correct the trough-to-peak ratio for baseline as well as placebo, to account for interindividual variability, and to calculate a confidence interval for the net trough-to-peak ratio. Accounting for interindividual variability reduces the trough-to-peak ratio. Smoothing affects the individualized net trough-to-peak ratios in an unpredictable way and should therefore be avoided.
authors.affiliation: Klinisch Laboratorium Hypertensie, Inwendige Geneeskunde-Cardiologie, UZ Gas-thuisberg, Leuven, Belgium.
authors.forename: J A
authors.initials: JA
authors.lastname: Staessen
authors.forename: L
authors.initials: L
authors.lastname: Thijs
authors.forename: G
authors.initials: G
authors.lastname: Bijttebier
authors.forename: D
authors.initials: D
authors.lastname: Clement
authors.forename: E T
authors.initials: ET
authors.lastname: O'Brien
authors.forename: P
authors.initials: P
authors.lastname: Palatini
authors.forename: J L
authors.initials: JL
authors.lastname: Rodicio
authors.forename: J
authors.initials: J
authors.lastname: Rosenfeld
authors.forename: R
authors.initials: R
authors.lastname: Fagard
mesh_terms: D000368:Aged; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D008875:Middle Aged
chemical_list: D000959:Antihypertensive Agents