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Hypertension remains a global health concern because of suboptimal blood pressure control despite advancements in antihypertensive treatments. Chronotherapy, defined as evening or bedtime administration of medication based on biological rhythms, is emerging as a potential strategy to improve blood pressure control and treatment outcomes. Clinical trials have investigated the potential effects of nighttime administration of antihypertensive medication in the improvement of 24 hours blood pressure control and reduction of cardiovascular risk. Implementing chronotherapy in clinical practice could have significant implications in enhancing blood pressure control and improving clinical outcomes in patients with hypertension, particularly those with resistant hypertension. However, recent trials have reported contradictory results, causing confusion in real-world practice. Herein we review, analyze, and critique the current evidence and propose suggestions regarding the clinical application and future directions of chronotherapy.

Background/aims: To examine the prevalence and clinical characteristics of apparent treatment-resistant hypertension among ambulatory hypertensive patients., Methods: We enrolled adult ambulatory hypertensive patients at 13 well-qualified general hospitals in Korea from January to June 2012. Apparent resistant hypertension was defined as an elevated blood pressure > 140/90 mmHg with the use of three antihypertensive agents, including diuretics, or ≥ 4 antihypertensives, regardless of the blood pressure. Controlled hypertension was defined as a blood pressure within the target using three antihypertensives, including diuretics., Results: Among 16,915 hypertensive patients, 1,172 (6.9%) had controlled hypertension, and 1,514 (8.9%) had apparent treatment-resistant hypertension. Patients with apparent treatment-resistant hypertension had an earlier onset of hypertension (56.8 years vs. 58.8 years, p = 0.007) and higher body mass index (26.3 kg/m2 vs. 24.9 kg/m2, p < 0.001) than those with controlled hypertension. Drug compliance did not differ between groups. In the multivariable analysis, earlier onset of hypertension (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97 to 0.99; p < 0.001) and the presence of comorbidities (OR, 2.06; 95% CI, 1.27 to 3.35; p < 0.001), such as diabetes mellitus, ischemic heart disease, heart failure, and chronic kidney disease, were independent predictors. Among the patients with apparent treatment-resistant hypertension, only 5.2% were receiving ≥ 2 antihypertensives at maximally tolerated doses., Conclusion: Apparent treatment-resistant hypertension prevalence is 8.9% among ambulatory hypertensive patients in Korea. An earlier onset of hypertension and the presence of comorbidities are independent predictors. Optimization of medical treatment may reduce the rate of apparent treatment-resistant hypertension.

Although both angiotensin receptor blockers (ARBs) and dihydropyridine calcium channel blockers (CCBs) are all suitable for the initiation of antihypertensive treatment, studies investigating efficacy and safety between ARBs and CCBs are limited, and there is no previous study comparing their clinical outcomes during long-term follow-up periods in real world setting. We compared cardiovascular (CV) events between ARBs and CCBs in 464,948 hypertensive adults using the Korean National Health Insurance Service database during a 3-year follow-up. The patients with hypertension without heart failure, ischemic heart disease, cerebrovascular disease, or peripheral artery disease were enrolled. The CV events between only single prescription of CCBs and ARBs were finally compared. The primary endpoint for this study was the first occurrence of a major adverse CV events, defined as the composite of all-cause death, cardiac death, nonfatal myocardial infarction, or nonfatal stroke. ARB was significantly more administered in male and patients with higher income, diabetes mellitus, chronic kidney diseases, and higher Charlson comorbidity index. The primary endpoints occurred in 10,526 patients (5.2%) in the ARB group and in 19,363 patients (7.3%) in the CCB group (p < 0.001) during a 3-year follow-up (HR 0.96, 95% CI 0.93-0.98). All the components of CV events including all-cause death, cardiac death, nonfatal myocardial infarction, and nonfatal stroke occurred more frequently in the CCB group. With multivariable models adjusting age, sex, income, diabetes, chronic kidney disease, and Charlson comorbidity index, the primary endpoints less frequently developed in the ARB group than in the CCB group (HR 0.957, 95% CI 0.933-0.983, p < 0.001). After the propensity-score matching, baseline characteristics were similar and still showed significantly better primary endpoints in ARB group than CCB group (5.3% vs. 5.8%, p < 0.001). In this nationwide population-based simple hypertension study, administration of ARBs showed superior protection against CV events than CCBs during a 3-year follow-up. Our results suggest that ARBs could be preferred over CCBs as the initial choice of antihypertensive treatment regardless of age in real-world practice.

Introduction: We investigate the safety and efficacy of telmisartan plus S-amlodipine single-pill combination in a real-world population., Methods: A total of 44,715 patients who had hypertension and received a telmisartan/S-amlodipine single-pill combination at least once were included for safety and efficacy evaluation from 2852 primary to tertiary hospitals in Korea from August 2013 to December 2019. They were followed up for 3-6 months in terms of safety and efficacy of blood pressure (BP) lowering., Results: A total of 44,715 patients were included for safety analysis and 41,579 for efficacy analysis. Mean duration of taking the drug was 175.86 ± 48.45 days. A total of 28,096 (62.8%) patients were on telmisartan 40 mg plus S-amlodipine 2.5 mg combination followed by 80/2.5 mg (8664, 19.4%) and 40/5 mg of the drug (7136, 16.0%). Adverse events, total adverse drug reactions, and serious adverse drug reactions were found in 808 patients (1.81%), 352 (0.79%), and 1 (0.002%), respectively. Dizziness and headache were most common (134 [0.30%] and 81 [0.18%]) among all adverse events. Total edema and leg edema were rarely reported, 38 (0.08%) and 25 (0.06%), respectively. Systolic BP (SBP) and diastolic BP (DBP) was lowered from 143.1 ± 16.1/88.1 ± 11.8 mmHg to 129.6 ± 11.4/80.1 ± 9.0 mmHg (difference - 13.5/- 7.9 mmHg, P < 0.0001 for both). Target BP goal attainment rate defined as SBP < 140 mmHg and DBP < 90 mmHg was 74.6% (95% confidence interval [CI] 74.2-75.0) and BP response rate (defined as SBP < 140 mmHg or ≥ 20 mmHg reduction; DBP < 90 mmHg or ≥ 10 mmHg reduction) was 94.5% (95% CI 94.3-94.7)., Conclusion: Telmisartan plus S-amlodipine single-pill combination was safe and effective in patients with hypertension in a large real-world population.

We investigated whether self-blood pressure monitoring (SBPM) can improve the control rate of blood pressure (BP), adherence of antihypertensive medications, and the awareness of the importance of BP control in hypertensive patients. A total of 7751 patients who visited the outpatient clinics of private and university hospitals in Korea were given automatic electronic BP monitors and were recommended to measure their BP daily at home for 3 months. Changes in office BP, attainment of target BP, adherence to taking antihypertensive drugs, and awareness of BP were compared before and after SBPM. Patients and physicians were surveyed on their perception of BP and SBPM. Mean BP significantly decreased from 142/88 to 129/80 mm Hg (P < .001), and attainment of the target BP increased from 32% to 59% (P < .001) after SBPM. Drug non-adherence, which was defined as patient's not taking medication days per week, decreased significantly from 0.86 days to 0.53 days (P < .001). The rate of awareness of the BP goal increased from 57% to 81% (P < .001). Patients estimated that their mean BP was 125/81 mm Hg, but their actual mean BP was 142/88 mm Hg. Awareness about the importance of SBPM increased from 90% to 98%. The rate of SBPM ≥ once per week further increased, from 34% to 96%. In conclusion, SBPM is associated with reduced BP, better BP control rate, greater drug adherence, and improved perception of BP by the patients., (©2019 Wiley Periodicals, Inc.)

The objective of this study was to evaluate the association between sodium intake and blood pressure (BP) control in hypertensive patients taking antihypertensive medications by using 24-hour urine collection and 24-hour ambulatory BP. This is a cross-sectional community-based study and conducted in 2011 and 2012. A total of 1128 participants were recruited from five cities in Korea. Among them, 740 participants who had complete 24-hour urine collection and valid 24-hour ambulatory BP data were included in this study. Participants were divided into four groups: normotensives (NT, n = 441), untreated hypertensive patients (UTHT, n = 174), controlled hypertensive patients (CHT, n = 62), and uncontrolled hypertensive patients (UCHT, n = 63). UCHT and CHT groups showed higher mean age than NT and UTHT groups. UCHT and UTHT groups showed higher 24-hour systolic BP (SBP) and diastolic BP (DBP) than NT and CHT groups. UCHT group had the highest level of 24-hour urine sodium. Multivariate analysis adjusted with age, gender, body mass index, estimated glomerular filtration rate, and use of diuretics showed higher level of 24-hour urine sodium in UCHT group than that in CHT group. Multivariate logistic regression analysis revealed independent association of the amount of 24-hour urine sodium with uncontrolled BP in hypertensive patients on antihypertensive drug treatment. Higher level of 24-hour urine sodium excretion in uncontrolled hypertensive patients suggests that excessive sodium intake could be associated with blunted BP lowering efficacy of antihypertensive medications., (©2019 Wiley Periodicals, Inc.)

Background: The efficacy of a combination of a calcium channel blocker (CCB) plus chlorthalidone (diuretic) versus a CCB plus an angiotensin receptor blocker (ARB) in patients not responding to CCB monotherapy has not been evaluated previously. We plan to compare the efficacy and safety of S-amlodipine (CCB) plus chlorthalidone versus S-amlodipine plus telmisartan (ARB) combinations among hypertension patients unresponsive to amlodipine monotherapy., Methods/design: This study is a prospective, randomized, double-blind, multicenter, parallel, non-inferiority phase 4 study. Hypertension patients who have been treated with amlodipine (5 mg) or S-amlodipine (2.5 mg) monotherapy for ≥2 weeks and whose mean diastolic blood pressure (DBP) is greater than 90 mmHg will be randomized to either S-amlodipine (2.5 mg) plus chlorthalidone (25 mg) or S-amlodipine (2.5 mg) plus telmisartan (40 mg) therapy. The primary efficacy endpoint is mean sitting DBP change after 12 weeks of treatment. The study objective is to prove the non-inferiority of the former combination (test drug) as compared to the latter one (control) with a non-inferiority margin of 3 mmHg in mean DBP change. The secondary endpoints are 6-week DBP change, 6- and 12-week sitting systolic BP (SBP) change, and the attainment of the target BP (SBP < 140 mmHg or DBP < 90 mmHg). Urine albumin, albumin/creatinine ratio (ACR), pulse wave velocity, central BP, 24-h ambulatory BP monitoring, and body fluid composition analysis will be performed at each hospital's discretion. The sample size was estimated as 170 in total with 1:1 randomization., Discussion: This is the first study comparing the efficacy of a CCB plus chlorthalidone versus a CCB plus an ARB in patients who are not responding to CCB single therapy. The study result will help clinicians to choose between chlorthalidone and telmisartan in CCB-unresponsive patients., Trial Registration: ClinicalTrials.gov , NCT03226340. Registered on 2 December 2015.

Purpose: To evaluate the blood pressure (BP) lowering efficacy and safety of CKD-828, a fixed-dose combination of S-amlodipine (the more active isomer of amlodipine besylate, which is calcium channel blocker) and telmisartan (long acting angiotensin receptor blocker), in patients with hypertension inadequately controlled with S-amlodipine monotherapy., Patients and Methods: Eligible patients (N=187) who failed to respond after 4-week S-amlodipine 2.5 mg monotherapy (sitting diastolic blood pressure [sitDBP] ≥90 mmHg) to receive CKD-828 2.5/40 mg (n=63), CKD-828 2.5/80 mg (n=63), or S-amlodipine 2.5 mg (n=61) for 8 weeks. The primary efficacy endpoint, mean sitDBP change from baseline to Week 8, was compared between the combination (CKD-828 2.5/40 mg and CKD-828 2.5/80 mg) and S-amlodipine monotherapy groups. The safety was assessed based on adverse events, vital signs, and physical examination findings., Results: After the 8-week treatment, changes in sitDBP/systolic BP (SBP) were -9.67±6.50/-12.89±11.78, -10.72±6.19/-13.79±9.41, and -4.93±7.26/-4.55±11.27 mmHg in the CKD-828 2.5/40 mg ( P <0.0001/ P <0.0001), CKD-828 2.5/80 mg ( P <0.0001/ P <0.0001), and S-amlodipine 2.5 mg ( P <0.0001/ P =0.0027) groups, respectively, which were all significant BP reductions. At Week 8, the CKD-828 2.5/40 mg (sitDBP/SBP: P =0.0002/ P <0.0001) and CKD-828 2.5/80 mg (sitDBP/SBP: P =0.0001/ P <0.0001) showed superior BP-lowering effects to S-amlodipine 2.5 mg ( P <0.001). At Week 4, all groups showed significant antihypertensive effects but both CKD-828 combinations (CKD-828 2.5/40 mg and CKD-828 2.5/80 mg) exhibited superior BP-lowering effects to that of S-amlodipine 2.5 mg (sitDBP/SBP: P =0.0028/ P =0.0001 and P <0.0001/ P =0.0012, respectively). The adverse event incidence was significantly lower in the CKD-828 2.5/40 mg (9.52%, P =0.0086) than in the S-amlodipine 2.5 mg group (27.87%) and increasing the telmisartan dose induced no unexpected adverse events, suggesting the safety of CKD-828., Conclusion: CKD-828 is an effective and safe option for patients with inadequate responses to S-amlodipine monotherapy., Competing Interests: The authors report no conflicts of interest in this work.

Purpose: A fixed-dose combination of a stain and an antihypertensive drug may be useful for the treatment of patients with hypertension and hyperlipidemia. It may also improve patient drug compliance to help control risk factors of cardiovascular disease. This study was designed to evaluate the blood pressure-lowering and cholesterol-lowering effect of a fixed-dose combination of irbesartan-atorvastatin compared with monotherapy by either agent over an 8-week treatment period., Methods: Patients with comorbid hypertension and hypercholesterolemia were screened for this randomized, double-blind, Phase III study. Eligible study patients were randomly assigned to test groups receiving a combination of irbesartan 300 mg and atorvastatin 40 mg or 80 mg (IRB300 + ATO40 and IRB300 + ATO80). Comparator groups comprised monotherapy groups with irbesartan 300 mg (IRB300) or atorvastatin 40 mg (ATO40) or atorvastatin 80 mg (ATO80), or placebo. Patients who were eligible at screening were subjected to a 4- to 6-week washout period before commencing 8 weeks of therapy per their assigned group. The primary efficacy end points were percent change in LDL-C and sitting diastolic blood pressure (DBP) levels from baseline to end of therapy. Tolerability profiles of combination therapy were compared with other groups., Findings: A total of 733 patients with comorbid hypertension and hypercholesterolemia were screened for this study; 230 eligible patients were randomized to treatment. The mean age of patients was 58.9 (8.5) years, and their mean body mass index was 25.8 (3.2) kg/m 2 . More than two thirds (70.9%) of the study patients were male. Mean LDL-C and sitting DBP levels at baseline were 149.54 (29.19) mg/dL and 92.32 (6.03) mm Hg, respectively. Percent reductions in LDL-C after 8 weeks were 46.74% (2.06%) in the IRB300 + ATO40 group and 48.98% (2.12%) in the IRB300 + ATO80 group; these values were 47.13% (3.21%) and 48.30% (2.98%) in the ATO40 and ATO80 comparator groups. Similarly, a reduction in sitting DBP after 8 weeks was -8.50 (1.06) mm Hg in the IRB300 + ATO40 group and 10.66 (1.08) mm Hg in the IRB300 + ATO80 group compared with 8.40 (1.65) mm Hg in the IRB300 group. The incidence rate for treatment-emergent adverse events was 22.27% and was similar between the monotherapy and combination groups., Implications: A once-daily combination product of irbesartan and atorvastatin provided an effective, safe, and more compliable treatment for patients with coexisting hypertension and hyperlipidemia. ClinicalTrials.gov identifier: NCT01442987., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Carotid intima-media thickness (cIMT) is an established surrogate marker of atherosclerosis. However, cIMT may not reflect the whole arterial changes occurring in various pathologic conditions, such as hypertension. The aim of this study was to evaluate whether vascular properties of carotid artery (CA) in patients with hypertension differ from those of patients with diabetes and controls before the progression of cIMT., Methods: Vascular properties of CA were assessed in 402 consecutive asymptomatic subjects who have normal cIMT (131 with hypertension, 151 with diabetes mellitus, and 120 controls). Conventional carotid stiffness indices calculated from vessel diameter and blood pressure, and parameters from velocity-vector imaging (VVI), including vessel area, fractional area change (FAC), radial velocity, circumferential strain, and strain rate were measured to assess the differences between the groups., Results: In univariate analysis, both patients with hypertension and diabetes showed higher elastic modulus, lower distensibility coefficients and FAC of VVI than those of controls. However, when adjusting for baseline covariates, only FAC (odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.70-0.97, p = 0.025) and vessel area (OR = 2.84, 95% CI = 1.64-4.91, p < 0.001) discriminated CA of patients with hypertension from those of controls. Also, patients with hypertension showed larger vessel area than diabetes (OR = 2.58, 95% CI = 1.75-3.80, p < 0.001) independent of baseline covariates. No significant vascular parameter was found to discriminate patients with diabetes from controls after adjustments., Conclusion: Despite normal cIMT, the CA of hypertensive patients was stiffer than those of controls and positive remodeling preceded the wall thickening independent of baseline covariates., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)