CHRONOTHERAPY WITH A FIXED VALSARTAN/HYDROCHLOROTHIAZIDE COMBINATION: IMPROVED NIGHTTIME BLOOD PRESSURE CONTROL WITH BEDTIME DOSING: PP.5.168

Abstract

Objectives: We have previously documented a significant change in the dose-response curve, increased proportion of controlled patients, and improved efficacy on nighttime blood pressure (BP) when valsartan was ingested at bedtime, as compared to upon awakening, in subjects with essential hypertension. However, no study has yet investigated the potential differing effects depending of the time of administration of combination therapy. Accordingly, we investigated the administration-time-dependent antihypertensive efficacy of valsartan-hydrochlorothiazide (HCTZ) combination. Methods: We studied 204 hypertensive subjects (95 men), 49.7 ± 11.1 years of age, randomly assigned to receive valsartan (160 mg/day) monotherapy either on awakening or at bedtime for 12 weeks. Due to uncontrolled ambulatory BP, HCTZ (12.5 mg/day) was added to valsartan as a single-pill formulation, maintaining the original circadian time of treatment, for another 12 weeks. BP was measured every 20-min from 07:00 to 23:00 h and every 30-min at night for 48 h before treatment and after each period of 12 weeks of therapy. Results: Combination treatment resulted in a statistically significant reduction of the 24 h BP mean from baseline, similar for both treatment-time groups (P > 0.542). The efficacy of valsartan/HCTZ on the awake BP mean was also similar for the two treatment-groups (P > 0.682). Results, however, reveal a greater efficacy with bedtime dosing in regulating asleep systolic BP (P = 0.015) as well as asleep pulse pressure (PP; P = 0.007 between groups). Accordingly, there was a significant (P < 0.001) increase in sleep-time relative systolic BP decline only when valsartan/HCTZ was consistently ingested at bedtime. The proportion of non-dipping was reduced from 59 to 23% only after bedtime dosing (P < 0.001). Conclusions: In patients not properly controlled with valsartan monotherapy, the addition of 12.5 mg/day HCTZ efficiently reduces BP for the entire 24 h of the day independently of dosing time. Bedtime administration, however, may be preferred, mainly in the elderly and patients with diabetes, due to the associated increase in sleep-time relative systolic BP decline and the decrease in ambulatory PP, both relevant markers of cardiovascular risk.