Chronotherapy With Valsartan/Hydrochlorothiazide Combination in Essential Hypertension: Improved Sleep-Time Blood Pressure Control With Bedtime Dosing

Abstract

Administration of angiotensin receptor blockers at bedtime results in greater reduction of nighttime blood pressure than dosing upon awakening, independent of the terminal half-life of each individual medication. To obtain blood pressure (BP) target goals most patients require treatment with more than one hypertension medication. However, the potential differing effects on BP regulation of combination therapy depending on the time-of-day of administration have scarcely been investigated. Accordingly, the authors prospectively evaluated the administration-time-dependent BP-lowering efficacy of valsartan/hydrochlorothiazide (HCTZ) combination therapy. The authors conducted a randomized, open-label, blinded-endpoint trial on 204 subjects with essential hypertension (95 men/109 women), 49.7 ± 11.1 (mean ± SD) yrs of age. The BP of participants in this trial was not properly controlled with respect to published ambulatory BP criteria after initially randomized to valsartan monotherapy (160 mg/day), whether routinely ingested upon awakening by one group or at bedtime by another group for 12 wks. Thus, HCTZ (12.5 mg/day) was added to valsartan as a single-pill formulation, maintaining the original treatment-time, i.e., upon awakening or at bedtime, of participants of the two groups, for another 12 wks. BP was measured by ambulatory monitoring for 48 h at inclusion and after each 12-wk span of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately define the beginning and end of daytime activity and nocturnal sleep so that the respective BP means for every participant at each evaluation could be precisely determined. Combination therapy resulted in a similar statistically significant reduction of the 48-h BP mean from baseline for both treatment-time groups (17.0/11.5 mm Hg in systolic/diastolic BP after combination therapy on awakening; 17.9/12.1 mm Hg reduction after combination treatment at bedtime; p > .542 between groups). The awake BP mean was reduced to a comparable extent in both treatment-time groups (p > .682). However, bedtime compared to morning dosing better reduced the asleep means of systolic BP (20.1 vs. 16.0 mm Hg; p = .015) and pulse pressure (6.5 vs. 4.0 mm Hg; p = .007 between groups). Accordingly, the proportion of subjects with a baseline non-dipper BP profile was significantly reduced from 59% to 23% only after bedtime combination treatment (p < .001). Moreover, the proportion of subjects with properly controlled ambulatory BP after combination therapy was significantly greater with bedtime than upon-awakening treatment (55 vs. 40%, p = .037). The improved efficacy in lowering the asleep BP mean, increased sleep-time relative BP decline, and greater proportion of controlled patients suggest that valsartan/HCTZ combination should be preferably administered at bedtime for treatment of subjects with essential hypertension requiring combination therapy to achieve proper BP control. (Author correspondence: [email protected])

Keywords:

• Ambulatory blood pressure monitoring
• Asleep blood pressure
• Chronotherapy
• Combination therapy
• Dipper
• Essential hypertension
• Hydrochlorothiazide
• Non-dipper
• Valsartan

ACKNOWLEDGMENTS

This independent investigator-promoted research was supported by unrestricted grants from Dirección General de Investigación, Ministerio de Ciencia e Innovación (SAF2006-06254-FEDER; SAF2009-07028-FEDER); Consellería de Economía e Industria, Dirección Xeral de Investigación e Desenvolvemento, Xunta de Galicia (09CSA018322PR; INCITE07-PXI-322003ES; INCITE08-E1R-322063ES; INCITE09-E2R-322099ES); and Vicerrectorado de Investigación, University of Vigo.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.