Treatment-Time Regimen of Hypertension Medications Significantly Affects Ambulatory Blood Pressure and Clinical Characteristics of Patients With Resistant Hypertension

Abstract

Patients with resistant hypertension (RH) are at greater risk for stroke, renal insufficiency, and cardiovascular disease (CVD) events than are those for whom blood pressure (BP) is responsive to and well controlled by therapeutic interventions. Although all chronotherapy trials have compared the effects on BP regulation of full daily doses of medications when ingested in the morning versus at bedtime, prescription of the same medications in divided doses twice daily (BID) is frequent. Here, we investigated the influence of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and laboratory medicine parameters of RH patients evaluated by 48-h ambulatory BP monitoring (ABPM). This cross-sectional study evaluated 2899 such patients (1701 men/1198 women), 64.2 ± 11.8 (mean ± SD) yrs of age, enrolled in the Hygia Project. Among the participants, 1084 were ingesting all hypertension medications upon awakening (upon-awakening regimen), 1436 patients were ingesting the full daily dose of ≥1 of them at bedtime (bedtime regimen), and 379 were ingesting split doses of ≥1 medications BID upon awakening and at bedtime (BID regimen). Patients of the bedtime regimen compared with the other two treatment-time regimens had lower likelihood of microalbuminuria and chronic kidney disease; significantly lower albumin/creatinine ratio, glucose, total cholesterol, and low-density lipoprotein (LDL) cholesterol; plus higher estimated glomerular filtration rate and high-density lipoprotein (HDL) cholesterol. The bedtime regimen was also significantly associated with lower asleep systolic (SBP) and diastolic (DBP) BP means than the upon-awakening and BID regimens. The sleep-time relative SBP and DBP decline was significantly attenuated by the upon-awakening and BID regimens (p < .001), resulting in significantly higher prevalence of non-dipping in these two treatment-time regimen groups (80.5% and 77.3%, respectively) than in the bedtime regimen (54.4%; p < .001 between groups). Additionally, the prevalence of the riser BP pattern, associated with highest CVD risk, was much greater, 31.0% and 29.8%, respectively, among patients of the upon-awakening and BID-treatment regimens, compared with the bedtime regimen (17.6%; p < .001 between groups). Patients of the bedtime regimen also showed significantly higher prevalence of properly controlled ambulatory BP (p < .001) as a result of a greater proportion of them showing complete control of asleep SBP and DBP means. Our findings demonstrate significantly lower asleep SBP and DBP means and attenuated prevalence of blunted nighttime BP decline, i.e., lower prevalence of CVD risk markers, in RH patients ingesting the full daily dose of ≥1 hypertension medications at bedtime than in those ingesting all of them upon awakening or ≥1 of them as split doses BID. In RH, ingesting the same medications BID neither improves ambulatory BP control nor reduces the prevalence of non-dipping, and cannot be considered chronotherapy. Collectively, findings...

The possibility of resistant hypertension during the treatment of hypertensive patients

“…A previous study investigated the influence of the timing of hypertensive treatment on circadian BP patterns and the degree of BP control in order to clarify the relevant clinical and laboratory parameters of RH patients using 48-hour ABPM. 12 These findings demonstrated that bedtime-based hypertension medication regimens are recommended for the treatment of patients who have been mistakenly judged to be resistant to therapy by conventional cuff methods or after treatment with a morning-based treatment regimen. 12 It is suggested that we need to consider when patients should be administered anti-hypertensive drugs in order to achieve well-controlled BP levels.…”

“…12 These findings demonstrated that bedtime-based hypertension medication regimens are recommended for the treatment of patients who have been mistakenly judged to be resistant to therapy by conventional cuff methods or after treatment with a morning-based treatment regimen. 12 It is suggested that we need to consider when patients should be administered anti-hypertensive drugs in order to achieve well-controlled BP levels. Such decisions should be taken on the basis of ABPM measurements of the diurnal changes in BP, which should be taken into account before definitely diagnosing RH.…”

Evening Dosing of Antihypertensive Therapy to Reduce Cardiovascular Events: A Third Type of Evidence Based on a Systematic Review and Meta‐Analysis of Randomized Trials

“…A trial with twice-daily, thrice-daily, or 4-times-daily dosing was deemed to be insufficient to label it an EDT and was included as a UDT for the following reasons: (1) It was not clear that the last dose of the day was given in the evening; (2) twice-daily, thrice-daily, and 4-times-daily dosing would give the equivalent of one half, one third, and one fourth of the standard dose, respectively, for the last dose of the day; (3) in crosssectional data, twice-daily dosing and exclusively morning dosing have been associated with similar reductions in nondipping, microalbuminuria, and chronic kidney disease, and both of these types of dosings were inferior to evening dosing with respect to these conditions. 10 The hazard ratio (HR) of each trial was standardized to a 10 mm Hg reduction in systolic and a 5 mm Hg reduction in diastolic BP. For CAD, the pooled HRs for EDTs and UDTs were obtained by meta-analysis 11 (random-effects models were used throughout), yielding HR EDTs and HR UDTs , respectively.…”

Chronotherapy for Hypertension

“…Unfortunately, the study was not powered to provide absolute conclusions on the benefit of morning compared to bedtime administration by drug class or the benefits of particular drug combinations. Three cross-sectional studies exploring the efficacy of taking one or more antihypertensive medications at night indicate that bedtime antihypertensive medication reduces asleep SBP, DBP and prevalence of non-dipping, and improves 24-h BP control (82–84). A smaller RCT of ARB, found no significant effects of treatment timings on morning home BP or office BP based (85).…”