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The relationship between periodontitis and hypertension remains controversial. This study aimed to investigate the association of periodontitis, missing teeth, and oral hygiene behaviors with the incidence of hypertension.A total of 104,349 participants were selected from the National Health Insurance System-Health Screening (NHIS-HEALS) cohort. Incident hypertension and periodontitis were diagnosed based on the patients' clinical records and health examinations. A multivariable Cox proportional hazards regression analysis was performed after adjusting for socioeconomic factors, coexisting disease, and health behaviors.The mean age of the participants was 51.1 years (range, 40-79 years) at baseline, and 55.1% were men. A total of 52,855 incident hypertension cases were identified during the median follow-up period of 9.6 years. Among the participants, periodontitis (hazard ratio [HR]: 1.02; 95% confidence interval [95% CI]: 1.00-1.04), number of missing teeth (for ≥15 group, HR: 1.40; 95% CI: 1.29-1.52), dental scaling (HR: 0.93; 95% CI: 0.91-0.95), and toothbrushing frequency (for ≥3 group, HR: 0.85; 95% CI: 0.83-0.88) were significantly associated with incident hypertension after full adjustments for covariates. While periodontitis was significantly associated with incident hypertension (HR: 1.04; 95% CI: 1.02-1.06) in the middle-aged group (40-64 years), the effect was insignificant in the older group (≥65 years).Oral inflammation could contribute to the incidence of hypertension; thus, efforts to reduce oral inflammation should be encouraged. Future intervention studies are warranted to determine whether oral health care could be beneficial in the management of hypertension.

Background: The introduction of a fixed-dose combination (FDC) is expected to improve treatment compliance. Methods: There were 181 subjects who were randomized to three groups: ezetimibe–rosuvastatin 10/20 mg + telmisartan 80 mg, ezetimibe–rosuvastatin 10/20 mg, and telmisartan 80 mg. The primary outcomes were change in mean sitting systolic blood pressure (MSSBP) and percentage change in low-density-lipoprotein cholesterol (LDL-C) compared to baseline at week 8. Results: The least-square mean (SE) in MSSBP changes between the ezetimibe–rosuvastatin 10/20 mg + telmisartan 80 mg group and the ezetimibe–rosuvastatin 10/20 mg group were −25.81 (2.34) mmHg and −7.66 (2.45) mmHg. There was a significant difference between the two groups (−18.15 (2.83) mmHg, 95% CI −23.75 to −12.56, p < 0.0001). Changes in least-square mean (SE) in LDL-C between the ezetimibe–rosuvastatin 10/20 mg + telmisartan 80 mg group and the telmisartan 80 mg group were −63.82 (2.87)% and −2.48 (3.12)%. A significant difference was observed between the two groups (−61.34 (3.33)%, 95% CI −67.91 to −54.78, p < 0.0001). No serious adverse events were observed. Conclusions: Ezetimibe–rosuvastatin plus telmisartan treatment is effective and safe when compared to either ezetimibe–rosuvastatin or telmisartan.

Background To assess the efficacy and safety of a combination therapy involving fimasartan, amlodipine, and rosuvastatin in patients with essential hypertension and dyslipidemia who fail to respond to fimasartan monotherapy. Methods This phase III, randomized, double-blind, multicenter study was conducted in adults aged 19–70 years. Patients who voluntarily consented were screened for eligibility to enroll in the study. Patients who failed to respond to 4 weeks of fimasartan monotherapy were randomized with a 1:1:1 ratio to the fimasartan 60 mg/amlodipine 10 mg + rosuvastatin 20 mg (FMS/ALD + RSV) as study group, fimasartan 60 mg/amlodipine 10 mg (FMS/ALD) as control 1 group, and fimasartan 60 mg + rosuvastatin 20 mg (FMS + RSV) as control 2 group. The primary efficacy endpoints were the change in the sitting systolic blood pressure and the rate of change in the low-density lipoprotein cholesterol (LDL-C) level from baseline to 8 weeks. The adverse events, adverse drug reactions, physical examination findings, laboratory test results, electrocardiograms, and vital signs were evaluated to assess safety in the study. Results Of 138 randomized patients, 131 were conducted efficacy analysis, and 125 completed the study. For the change in LDL-C and sitting SBP (SiSBP) as primary efficacy assessments, the change in LDL-C at week 8 was significantly reduce in the FMS/ALD + RSV group than in the control 1 group (P P Conclusions The fimasartan/amlodipine + rosuvastatin combination therapy can effectively and safely lower blood pressure and improve lipid levels in patients with essential hypertension and dyslipidemia who fail to respond adequately to fimasartan monotherapy. Trial registration NCT03156842, Registered 17 May 2017

Purpose We compared the efficacy and safety of third-standard-dose triple and third-standard-dose dual antihypertensive combination therapies in patients with mild to moderate hypertension. Methods This was a phase II multicenter, randomized, double-blind, parallel-group trial. After a 4-week placebo run-in period, 245 participants were randomized to the third-dose triple combination (ALC group; amlodipine 1.67 mg + losartan potassium 16.67 mg + chlorthalidone 4.17 mg) or third-dose dual combination (AL group; amlodipine 1.67 mg + losartan potassium 16.67 mg, LC group; losartan potassium 16.67 mg + chlorthalidone 4.17 mg, AC group; amlodipine 1.67 mg + chlorthalidone 4.17 mg) therapy groups and followed up after 8 weeks. Results The mean systolic blood pressure (BP) reduction was − 18.3 ± 13.2, -13.0 ± 13.3, -16.3 ± 12.4, and − 13.8 ± 13.2 mmHg in the ALC, AL, LC, and AC groups, respectively. The ALC group showed significant systolic BP reduction compared to the AL and AC groups at weeks 4 (p = 0.010 and p = 0.018, respectively) and 8 (p = 0.017 and p = 0.036, respectively). The proportion of systolic BP responders was significantly higher in the ALC group (42.6%) than in the AL (22.0%), LC (23.3%), and AC (27.1%) groups (p = 0.013, p = 0.021 and p = 0.045, respectively) at week 4. The proportion of systolic and diastolic BP responders was significantly higher in the ALC group (59.7%) than in the AL (39.3%) and AC (42.4%) groups (p = 0.022 and p = 0.049, respectively) at week 8. Conclusion Third-standard-dose triple antihypertensive combination therapy demonstrated early effective BP control compared to third-standard-dose dual combination therapies, without increasing adverse drug reactions in patients with mild-to-moderate hypertension. Trial Registration NCT04959305

Background/Aims: Ascertaining the prevalence of isolated nocturnal hypertension (INHT) in the general population and identifying the characteristics of patients with INHT may be important to determine patients who should receive 24- hour ambulatory blood pressure (BP) measurements. This study aimed to evaluate the prevalence and characteristics of INHT in the general population.Methods: Of 1,128 participants (aged 20 to 70 years), we analyzed 823 who had valid 24-hour ambulatory BP measurements and were not on antihypertensive drug treatment.Results: The prevalence of INHT in the study was 22.8%. Individuals with INHT had a higher office, 24-hour, and daytime and nighttime ambulatory systolic and diastolic BPs compared to individuals with sustained day-night normotension. INHT was more prevalent in individuals with masked hypertension (MH) than in those with sustained hypertension (59.8% vs. 15.6%, p < 0.001). Among individuals with INHT, 92.6% had MH. Among individuals with office BP-based prehypertension, 34.5% had both INHT and MH. The prevalence of INHT was highest in individuals with office BP-based prehypertension. INHT was an independent determinant of MH after adjustment for age, sex, body mass index, diabetes, low-density-lipoprotein cholesterol, 24-hour systolic and diastolic BP, systolic and diastolic BP dipping, and systolic and diastolic BP non-dipping.Conclusions: The present study showed that INHT is not uncommon and is a major determinant of MH. Our findings strongly suggest the use of 24-hour ambulatory BP measurement for individuals within the prehypertension range of office BP owing to the high prevalence of INHT and MH in this population.

PURPOSE We investigated whether the combination therapy of low-intensity rosuvastatin and ezetimibe is an useful alternative to moderate-intensity rosuvastatin monotherapy in patients requiring cholesterol-lowering therapy. METHODS This was a multicenter randomized, double-blind study to investigate the safety and efficacy of a fixed-dose combination of rosuvastatin 2.5 mg and ezetimibe 10 mg (R2.5+E10) compared to those of ezetimibe 10 mg monotherapy (E10), rosuvastatin 2.5 mg (R2.5), and rosuvastatin 5 mg monotherapy (R5) in patients with hypercholesterolemia. A total of 348 patients at 15 centers in Korea were screened, and 279 patients were randomized to different groups in the study. Clinical and laboratory examinations were performed at baseline and 4 and 8 weeks after intervention. The primary endpoint was the percentage change of low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up. FINDINGS Baseline characteristics were similar among the four groups. There were significant changes in lipid profiles at the 8-week follow-up. A greater decrease in the LDL cholesterol levels (primary endpoint) were found in the R2.5+E10 group (-45.7±18.6%) than in the E10 group (-16.7±14.7%, p

This study evaluated the association of body mass index (BMI) with adverse clinical outcomes during chronic maintenance antiplatelet monotherapy after percutaneous coronary intervention (PCI) with drug-eluting stents (DES).Methods and Results: Overall, 5,112 patients were stratified (in kg/mLower BMI is associated with a higher risk of primary composite outcomes, which is primarily related to the events of all-cause death or major bleeding during chronic maintenance antiplatelet monotherapy after PCI with DES.

Background Optimal antiplatelet monotherapy during the chronic maintenance period in patients who undergo coronary stenting is unknown. We aimed to compare head to head the efficacy and safety of aspirin and clopidogrel monotherapy in this population. Methods We did an investigator-initiated, prospective, randomised, open-label, multicentre trial at 37 study sites in South Korea. We enrolled patients aged at least 20 years who maintained dual antiplatelet therapy without clinical events for 6-18 months after percutaneous coronary intervention with drug-eluting stents (DES). We excluded patients with any ischaemic and major bleeding complications. Patients were randomly assigned (1:1) to receive a monotherapy agent of clopidogrel 75 mg once daily or aspirin 100 mg once daily for 24 months. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium (BARC) bleeding type 3 or greater, in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02044250. Findings Between March 26, 2014, and May 29, 2018, we enrolled 5530 patients. 5438 (98·3%) patients were randomly assigned to either the clopidogrel group (2710 [49·8%]) or to the aspirin group (2728 [50·2%]). Ascertainment of the primary endpoint was completed in 5338 (98·2%) patients. During 24-month follow-up, the primary outcome occurred in 152 (5·7%) patients in the clopidogrel group and 207 (7·7%) in the aspirin group (hazard ratio 0·73 [95% CI 0·59-0·90]; p=0·0035). Interpretation Clopidogrel monotherapy, compared with aspirin monotherapy during the chronic maintenance period after percutaneous coronary intervention with DES significantly reduced the risk of the composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and BARC bleeding type 3 or greater. In patients requiring indefinite antiplatelet monotherapy after percutaneous coronary intervention, clopidogrel monotherapy was superior to aspirin monotherapy in preventing future adverse clinical events. Funding ChongKunDang, SamJin, HanMi, DaeWoong, and the South Korea Ministry of Health and Welfare.

The potential cancer risk associated with long‐term exposure to angiotensin receptor blockers (ARBs) is still unclear. We assessed the risk of incident cancer among hypertensive patients who were treated with ARBs compared with patients exposed to angiotensin‐converting enzyme inhibitors (ACEIs), which are known to have a neutral effect on cancer development. Using the Korean National Health Insurance Service database, we analyzed the data of patients diagnosed with essential hypertension from January 2005 to December 2012 who were aged ≥40 years, initially free of cancer, and were prescribed either ACEI or ARB (n = 293,962). Cox proportional hazard model adjusted for covariates was used to evaluate the risk of incident cancer. During a mean follow‐up of 10 years, 24,610 incident cancers were observed. ARB use was associated with a decreased risk of overall cancer compared with ACEI use (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.72‐0.80). Similar results were obtained for lung (HR 0.73, 95% CI 0.64‐0.82), hepatic (HR 0.56, 95% CI 0.48‐0.65), and gastric cancers (HR 0.74, 95% CI 0.66‐0.83). Regardless of the subgroup, greater reduction of cancer risk was seen among patients treated with ARB than that among patients treated with ACEIs. Particularly, the decreased risk of cancer among ARB users was more prominent among males and heavy drinkers (interaction P, In this contemporary cohort involving a population of nearly 0.3 million Koreans, the use of ARBs was associated with a decrease in the risk of overall cancer compared with the use of angiotensin‐converting enzyme inhibitors during a mean follow‐up of 10 years. The current study provides appropriate long‐term safety data, given that more patients were exposed to ARBs.

The objective of this study was to compare the diagnostic accuracy of office blood pressure (BP) threshold of 140/90 and 130/80 mmHg for correctly identifying uncontrolled out‐of‐office BP in apparent treatment‐resistant hypertension (aTRH). We analyzed 468 subjects from a prospectively enrolled cohort of patients with resistant hypertension in South Korea (clinicaltrials.gov: NCT03540992). Resistant hypertension was defined as office BP ≥ 130/80 mmHg with three different classes of antihypertensive medications including thiazide‐type/like diuretics, or treated hypertension with four or more different classes of antihypertensive medications. We conducted different types of BP measurements including office BP, automated office BP (AOBP), home BP, and ambulatory BP. We defined uncontrolled out‐of‐office BP as daytime BP ≥ 135/85 mmHg and/or home BP ≥ 135/85 mmHg. Among subjects with office BP

Purpose We evaluated the efficacy and safety of nebivolol and rosuvastatin combination treatment in patients with hypertension and hyperlipidemia. Patients and Methods Eligible patients, after more than 4 weeks of therapeutic lifestyle change, were randomly assigned to three groups: 5 mg nebivolol plus 20 mg rosuvastatin (NEBI/RSV), 20 mg rosuvastatin (RSV), or 5 mg nebivolol (NEBI). Treatments lasted 8 weeks. Results Efficacy was analyzed using data from 276 patients. Sitting systolic and diastolic blood pressures differed between the NEBI/RSV and RSV groups (LSmean difference = -5.89 and -5.99 mmHg; 95% confidence interval [CI] = -9.88 to -1.90 mmHg and -8.13 to -3.84 mmHg, respectively). Reductions in the two pressures did not differ between the NEB/RSV and NEB groups. The percent reduction in low-density lipoprotein (LDL) cholesterol differed between the NEBI/RSV and NEBI groups (LSmean difference = -47.76%, 95% CI = -52.69 to -42.84%) but not between the NEBI/RSV and RSV groups. The blood pressure (BP) control rate was higher in the NEBI/RSV group than in the RVS group (51.09% vs 29.67%, p = 0.003). The LDL cholesterol goal achievement rate was higher in the NEBI/RSV group than in the NEBI group (85.87% vs 11.83%, p < 0.001). The incidence of adverse drug reactions in the NEBI/RSV, RSV, and NEBI groups was 8.51%, 7.45%, and 8.60%, respectively (p = 0.950). Conclusion Nebivolol plus rosuvastatin treatment is effective in reducing BP and LDL cholesterol levels and is safe in patients with hypertension and hypercholesterolemia without the loss of BP or the LDL cholesterol-lowering effect of each drug. Trial Registration CRIS registration number KCT0002148.

Single risk factors, such as hypertension and dyslipidemia, can combine to exacerbate the development and severity of cardiovascular disease. Treatment goals may be more effectively achieved if multiple disease factors are targeted with combination treatment. We enrolled 202 patients who were randomly divided into the following three groups: telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg, telmisartan 80 mg + rosuvastatin 20 mg, and telmisartan/amlodipine 80/5 mg. The primary efficacy variables were changes from baseline in mean sitting systolic blood pressure (MSSBP) between telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan 80 mg + rosuvastatin 20 mg at 8 weeks, and the percent changes from baseline in low‐density lipoprotein (LDL) cholesterol between telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan/amlodipine 80/5 mg at 8 weeks. The secondary efficacy variables were changes in MSSBP, mean sitting diastolic blood pressure (MSDBP), LDL cholesterol and other lipid levels at 4 weeks and 8 weeks, as well as observed adverse events during follow‐up. There were no significant differences between the three groups in demographic characteristics and no significant difference among the three groups in terms of baseline characteristics for the validity evaluation variables. The mean overall treatment compliance in the three groups was, respectively, 98.42%, 96.68%, and 98.12%, indicating strong compliance for all patients. The Least‐Square (LS) mean (SE) for changes in MSSBP in the two (telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan 80 mg + rosuvastatin 20 mg) groups were −19.3 (2.68) mm Hg and −6.69 (2.76) mm Hg. The difference between the two groups was significant (−12.60 (2.77) mm Hg, 95% CI −18.06 to −7.14, P

BACKGROUND AND OBJECTIVES The relationship between the hospital percutaneous coronary intervention (PCI) volumes and the in-hospital clinical outcomes of patients with acute myocardial infarction (AMI) remains the subject of debate. This study aimed to determine whether the in-hospital clinical outcomes of patients with AMI in Korea are significantly associated with hospital PCI volumes. METHODS We selected and analyzed 17,121 cases of AMI, that is, 8,839 cases of non-ST-segment elevation myocardial infarction and 8,282 cases of ST-segment elevation myocardial infarction, enrolled in the 2014 Korean percutaneous coronary intervention (K-PCI) registry. Patients were divided into 2 groups according to hospital annual PCI volume, that is, to a high-volume group (≥400/year) or a low-volume group (

Objectives We evaluated the association between cardiovascular risk factors and the magnitude of the difference in systolic blood pressure (SBP) between office and ambulatory measurements (masked effect) in untreated individuals without apparent hypertension-mediated organ damage (HMOD). Methods The inclusion criteria were 1) age ≥ 20 years, 2) blood pressure ≥ 140/90 mmHg at the outpatient clinic, and 3) not receiving antihypertensive medications. The difference between office and ambulatory SBP was calculated by subtracting the ambulatory daytime SBP from the office SBP. The association between the masked effect and SBP variability was analyzed in individuals without HMOD (no electrocardiographic left ventricular hypertrophy, spot urine albumin-to-creatinine ratio 2, n = 296). Results Among the cardiovascular risk factors, ambulatory BP variability was significantly correlated with the SBP difference. The standard deviation (SD) and coefficient of variation (cv) of 24-h SBP exhibited a significant negative linear association with the SBP difference in univariate and multivariate analyses adjusted for age, sex, presence of diabetes, and 24-h ambulatory SBP. A significant association was observed in patients with ambulatory daytime hypertension. In the multivariate analysis, individuals with a negative SBP difference > -5 mmHg exhibited a higher SD and cv of 24-h SBP than those with a negative SBP difference ≤ -5 mmHg or a positive SBP difference. Conclusions The results of our study suggest that the magnitude of the negative difference in office and ambulatory SBP may be a potential risk factor, even in individuals without apparent HMOD. Trial registration This trial is registered with ClinicalTrials.gov (NCT03855605).

The authors developed and validated a diagnostic algorithm using the optimal upper and lower cut‐off values of office and home BP at which ambulatory BP measurements need to be applied. Patients presenting with high BP (≥140/90 mm Hg) at the outpatient clinic were referred to measure office, home, and ambulatory BP. Office and home BP were divided into hypertension, intermediate (requiring diagnosis using ambulatory BP), and normotension zones. The upper and lower BP cut‐off levels of intermediate zone were determined corresponding to a level of 95% specificity and 95% sensitivity for detecting daytime ambulatory hypertension by using the receiver operator characteristic curve. A diagnostic algorithm using three methods, OBP‐ABP: office BP measurement and subsequent ambulatory BP measurements if office BP is intermediate zone; OBP‐HBP‐ABP: office BP, subsequent home BP measurement if office BP is within intermediate zone and subsequent ambulatory BP measurement if home BP is within intermediate zone; and HBP‐ABP: home BP measurement and subsequent ambulatory BP measurements if home BP is within intermediate zone, were developed and validated. In the development population (n = 256), the developed algorithm yielded better diagnostic accuracies than 75.8% (95%CI 70.1–80.9) for office BP alone and 76.2% (95%CI 70.5–81.3) for home BP alone as follows: 96.5% (95%CI: 93.4–98.4) for OBP‐ABP, 93.4% (95%CI: 89.6–96.1) for OBP‐HBP‐ABP, and 94.9% (95%CI: 91.5–97.3%) for HBP‐ABP. In the validation population (n = 399), the developed algorithm showed similarly improved diagnostic accuracy. The developed algorithm applying ambulatory BP measurement to the intermediate zone of office and home BP improves the diagnostic accuracy for hypertension.

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.

Aims We investigated the dose–response association of 24-hour urine sodium and potassium with 24-hour ambulatory blood pressure. Design Cross-sectional community-based study. Methods Among the 1128 participants in the community-based cross-sectional survey, 740 participants (aged 20–70 years) with complete 24-hour urine collection and valid 24-hour ambulatory blood pressure monitoring were included in the study. Participants were grouped into younger (Results In the older population, nighttime blood pressure linearly increased with 24-hour urine sodium and the sodium to potassium ratio. For 24-hour urine sodium, adjusted β was 0.171 (95% confidence interval (CI) 0.036–0.305) for nighttime systolic blood pressure and 0.144 (95% CI 0.012–0.276) for nighttime diastolic blood pressure. For the 24-hour urine sodium to potassium ratio, adjusted β was 0.142 (95% CI 0.013–0.270) for nighttime systolic blood pressure and 0.144 (95% CI 0.018–0.270) for nighttime diastolic blood pressure. The 24-hour blood pressure linearly increased with the 24-hour urine sodium to potassium ratio and adjusted β was 0.133 (95% CI 0.003–0.262) for 24-hour systolic blood pressure and 0.123 (95% CI 0.003–0.244) for 24-hour diastolic blood pressure. Daytime blood pressure and 24-hour systolic blood pressure showed a significant but non-linear association with 24-hour urine sodium among the older population. In the younger population, 24-hour urine sodium, potassium and the sodium to potassium ratio were not associated with ambulatory blood pressure. Conclusion In the older population, 24-hour urine sodium and the sodium to potassium ratio showed a linear and positive association with nighttime blood pressure, and 24-hour urine sodium was associated with 24-hour systolic blood pressure and daytime blood pressure in a non-linear fashion.

Soon Jun Hong,1,* Ki-Chul Sung,2,* Sang-Wook Lim,3 Seok-Yeon Kim,4 Weon Kim,5 Jinho Shin,6 Sungha Park,7 Hae-Young Kim,8 Moo-Yong Rhee9,10 On behalf of MH_APOLLO to read: HM_APOLLO1Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea; 2Department of Cardiology, Gangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul, Republic of Korea; 3Cardiology Division, Cardiac Center, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; 4Department of Cardiology, Seoul Medical Center, Seoul, Republic of Korea; 5Department of Internal Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul, Republic of Korea; 6Division of Cardiology, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea; 7Department of Cardiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 8Department of Health Policy and Management, College of Health Science & Department of Health Care Science, Graduate School, Korea University, Seoul, Republic of Korea; 9Cardiovascular Center, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi, Republic of Korea; 10College of Medicine, Dongguk University, Gyeongju-si, Gyeongbuk, Republic of Korea*These authors contributed equally to this workCorrespondence: Moo-Yong RheeCardiovascular Center, Dongguk University Ilsan Hospital, 27 Dongguk-Ro, Ilsandong-Gu, Goyang-si, Gyeonggi-do 10326, Republic of KoreaTel +82 31 961 5775Fax +82 31 961 7786Email mooyong_rhee@dumc.or.krPurpose: We evaluated the dose-responsiveness, efficacy, and safety of low-dose triple antihypertensive combination therapies in patients with mild-to-moderate hypertension.Patients and Methods: After a 1 to 2-week placebo run-in period, 248 patients were randomized to the half-dose triple combination (amlodipine 2.5 mg + losartan 25 mg + chlorthalidone 6.25 mg), third-dose triple combination (amlodipine 1.67 mg + losartan 16.67 mg + chlorthalidone 4.17 mg), quarter-dose triple combination (amlodipine 1.25 mg + losartan 12.5 mg + chlorthalidone 3.13mg), amlodipine 10mg, amlodipine 5mg, losartan 100mg, and placebo groups for 8 weeks. The primary outcome was the mean change in systolic blood pressure (SBP) from baseline to week 8.Results: The placebo-corrected SBP reductions of the half-dose, third-dose, quarter-dose combination, amlodipine 10 mg, amlodipine 5 mg and losartan 100 mg treatments were − 17.2, − 19.5, − 14.9, − 18.5, − 11.3 and − 9.9 mmHg, respectively. The BP control and response rates were significantly higher in the half-dose, third-dose, and quarter-dose combination groups than in the placebo group (all p < 0.01). Despite no intergroup differences in study drug-related adverse events, ankle circumference increased significantly in the amlodipine group compared to those in the combination treatment groups. The quarter-dose combination, amlodipine 5 mg, and losartan 100 mg groups showed similar SBP reduction and BP response rates. The SBP reduction and BP response rate in the third-dose and half-dose combination groups were not significantly different from those in the amlodipine 10 mg group but superior to those in the losartan 100 mg group.Conclusion: Low-dose triple combination therapies could be effective as antihypertensive therapies.Trial Registration: ClinicalTrials.gov identifier NCT03897868.Keywords: hypertension, blood pressure, combination therapy, low-dose, amlodipine, losartan, chlorthalidone

Among the 146 patients enrolled in the Korean FH registry, 83 patients who had undergone appropriate LLT escalation and were followed-up for ≥ 6 months were analyzed for pathogenic variants (PVs). The achieved percentage of expected low-density lipoprotein-cholesterol (LDL-C) reduction (primary variable) and achievement rates of LDL-C 2 = 0.045, p = 0.048). Among evolocumab users, PV-negative patients or those with only defective PVs revealed higher primary variable, whereas patients with at least one null PV showed lower primary variables. The adjusted response of patients with FH to LLT showed significant associations with PV positivity and 4-SNP score. These results may be helpful in managing FH patients with diverse genetic backgrounds.

Home and ambulatory blood pressure (BP) measurements are recommended for the diagnosis of hypertension. However, the clinical characteristics of individuals showing a diagnostic disagreement between their home and ambulatory BP measurements are unclear. Of the 470 individuals who were not on antihypertensive drug treatment with a BP &ge, 140/90 mmHg at an outpatient clinic, 399 who had valid office, home, and ambulatory BP results were included. Hypertension was diagnosed based on an average home BP &ge, 135/85 mmHg and/or an average daytime ambulatory BP &ge, 135/85 mmHg. The participants were divided into three groups: Agree-NT (home and ambulatory BP normotension), Disagree (home BP normotension and ambulatory BP hypertension, or home BP normotension and ambulatory BP hypertension), and Agree-HT (home and ambulatory BP hypertension). Eighty-four individuals (21.1%) were classified as the Disagree group. The mean serum creatinine, triglycerides, and electrocardiogram voltage in the Disagree group were intermediate between those observed in the Agree-NT and the Agree-HT group. In the Disagree group, the mean levels of office and home diastolic BP, all of the components of ambulatory BP, the aortic systolic BP, and the BP variabilities were found to be intermediate between those of the Agree-NT and the Agree-HT groups. These results indicate that individuals showing a diagnostic disagreement between their home and ambulatory BP may have cardiovascular risks that are intermediate between those with sustained home and ambulatory normotension and hypertension.

Purpose We evaluated the efficacy and safety of nebivolol and rosuvastatin combination treatment in patients with hypertension and hyperlipidemia. Patients and Methods Eligible patients, after more than 4 weeks of therapeutic lifestyle change, were randomly assigned to three groups: 5 mg nebivolol plus 20 mg rosuvastatin (NEBI/RSV), 20 mg rosuvastatin (RSV), or 5 mg nebivolol (NEBI). Treatments lasted 8 weeks. Results Efficacy was analyzed using data from 276 patients. Sitting systolic and diastolic blood pressures differed between the NEBI/RSV and RSV groups (LSmean difference = −5.89 and −5.99 mmHg; 95% confidence interval [CI] = −9.88 to −1.90 mmHg and −8.13 to −3.84 mmHg, respectively). Reductions in the two pressures did not differ between the NEB/RSV and NEB groups. The percent reduction in low-density lipoprotein (LDL) cholesterol differed between the NEBI/RSV and NEBI groups (LSmean difference = −47.76%, 95% CI = −52.69 to −42.84%) but not between the NEBI/RSV and RSV groups. The blood pressure (BP) control rate was higher in the NEBI/RSV group than in the RVS group (51.09% vs 29.67%, p = 0.003). The LDL cholesterol goal achievement rate was higher in the NEBI/RSV group than in the NEBI group (85.87% vs 11.83%, p < 0.001). The incidence of adverse drug reactions in the NEBI/RSV, RSV, and NEBI groups was 8.51%, 7.45%, and 8.60%, respectively (p = 0.950). Conclusion Nebivolol plus rosuvastatin treatment is effective in reducing BP and LDL cholesterol levels and is safe in patients with hypertension and hypercholesterolemia without the loss of BP or the LDL cholesterol-lowering effect of each drug. Trial Registration CRIS registration number KCT0002148.

Our study evaluated whether there were differences in the prevalence of white-coat hypertension (WH) and masked hypertension (MH) based on the 2018 ESC/ESH and 2017 ACC/AHA hypertension guidelines in Korea. The motivation was the lowering of the diagnostic threshold for hypertension in the 2017 ACC/AHA guidelines. Of 319 participants without antihypertensive drug history and with suspected hypertension based on outpatient clinic blood pressure (BP) measured by physicians, 263 participants (51.6 &plusmn, 9.6 years, 125 men) who had valid research-grade office BP and 24-h ambulatory BP measurements were enrolled. WH prevalence based on daytime ambulatory BP among normotensive individuals was lower with the ESC/ESH guidelines than the ACC/AHA guidelines (29.0% vs. 71.4%, p &lt, 0.001). However, MH prevalence based on daytime ambulatory BP among hypertensive individuals was higher based on the ESC/ESH guidelines (21.6% vs. 1.8%, p &lt, 0.001). Seventy percent of WH cases (2017 ACC/AHA guidelines) and 95.2% of MH cases (2018 ESC/ESH guidelines) occurred in individuals with systolic BP of 130&ndash, 139 mmHg and/or diastolic BP of 80&ndash, 89 mmHg. The diagnostic threshold of the 2017 ACC/AHA guidelines yielded a higher prevalence of WH compared to that of the 2018 ESC/ESH guidelines. However, the prevalence of MH was higher with the 2018 ESC/ESH guidelines than with the 2017 ACC/AHA guidelines. The high prevalence of WH and MH in people with a systolic BP of 130&ndash, 139 mmHg or diastolic BP of 80&ndash, 89 mmHg suggests the need for a more active out-of-office BP measurement in this patient group.

Purpose The aim of this study was to evaluate the safety and efficacy of combination treatment of rosuvastatin with ezetimibe in patients with primary hypercholesterolemia. Methods This multicenter, randomized, double-blind study comprised a main study and an extension study. In the main study, the efficacy and safety of a combination of rosuvastatin (5, 10, and 20 mg) with ezetimibe (10 mg) were compared with those of rosuvastatin (5, 10, and 20 mg) alone. The subjects who achieved the National Cholesterol Education Program Adult Treatment Panel III LDL-C goal in the main study and agreed to a further study were enrolled for the extension study. In the extension study, ezetimibe 10 mg was also administered to subjects who had received rosuvastatin (5, 10, and 20 mg) alone in the main study, and the same treatment was continued for subjects who had received a combination of rosuvastatin with ezetimibe in the main study. Findings At the end of the main study (week 8), LDL-C levels were significantly lower in subjects receiving combination therapy than in those receiving rosuvastatin monotherapy. Other lipid profiles also significantly improved in the combination therapy group. These improvements continued in the extension study. The combination therapy of rosuvastatin and ezetimibe was generally well tolerated. At the end of the main study, more subjects achieved the National Cholesterol Education Program Adult Treatment Panel III LDL-C goal in the combination therapy group than in the monotherapy group. The increased dosage of rosuvastatin was also well tolerated in the combination treatment. Implications Combination therapy of ezetimibe 10 mg with varying doses of rosuvastatin that are commonly used in the clinical field improved the lipid profile and allowed more subjects to reach the LDL-C goal in primary hypercholesterolemia compared with rosuvastatin monotherapy. In addition, the efficacy of the combination therapy was maintained for the extended period. Additional beneficial changes were also achieved with combination therapy even in patients who responded well to rosuvastatin monotherapy. ClinicalTrials.gov identifier: NCT03288038.

BACKGROUND: Data on treatment results of lipid‐lowering therapy (LLT) in familial hypercholesterolemia (FH) are limited, particularly in Asian patients. HYPOTHESIS: We sought to evaluate the target achievement rate and associated variables in Korean patients with FH after maximal statin‐based LLT. METHODS: We enrolled 146 patients with heterozygous FH, and 90 patients were finally analyzed. Patients were initially prescribed rosuvastatin 10 mg or atorvastatin 20 mg, and the regimen was adjusted to achieve the low‐density lipoprotein cholesterol (LDL‐C) target of 100 mg/dL. The primary evaluation point was the achievement rate of the LDL‐C targets at 12 months: LDL‐C < 100 mg/dL and ≥50% LDL‐C reduction. The associations between clinical variables and target achievement were also analyzed. RESULTS: At 12 months, 58% of patients were receiving high‐intensity regimens, whereas 46% were receiving combination therapy. The mean pre‐ and post‐treatment LDL‐C levels were 229 and 118 mg/dL, respectively. Twenty‐eight percent of patients achieved LDL‐C < 100 mg/dL, and 47% achieved ≥50% LDL‐C reduction. Pretreatment LDL‐C and high‐intensity regimens indicated a negative tendency toward the attainment of LDL‐C < 100 mg/dL. Conversely, pretreatment LDL‐C and diabetes mellitus were positively associated with a higher rate of ≥50% LDL‐C reduction. CONCLUSIONS: The target achievement of LDL‐C < 100 mg/dL was low, and 50% LDL‐C reduction was moderately achieved in Korean patients with FH receiving maximal statin‐based LLT. Pretreatment LDL‐C levels and diabetes mellitus were associated with target achievement. Our results provide rare and informative data on FH treatment in Asian patients.

Background Differences between the recently suggested outcome-driven diagnostic threshold of home blood pressure (HBP) measurements and the currently recommended diagnostic threshold of HBP measurements may cause a disagreement between 24-hour ambulatory blood pressure (ABP) and HBP measurements in the diagnosis of hypertension. We evaluated the agreement of various HBP diagnostic thresholds (135/85, 130/85, and 130/80 mm Hg) to ABP measurements, as a reference method. Methods Patients who were confirmed to have high BP (≥140/90 mm Hg) at the outpatient clinic were referred. HBP measurement was performed for 7 days in triplicates every morning and evening. The 24-hour ABP measurement was performed on the 8th day. Using 24-hour ABP measurement as a reference method, we analyzed HBP diagnostic thresholds at 135/85, 130/85, and 130/80 mm Hg. Results Among 319 patients, 256 patients (mean age, 51.8 ± 9.7 years; 119 men) with valid HBP measurements and 24-hour ABP measurements were enrolled. The threshold of 130/80 mm Hg showed the highest diagnostic sensitivity (P = 0.001) with diagnostic agreement by Kappa statistics. Using 130/80 mm Hg as a diagnostic threshold of hypertension, the prevalence of masked hypertension was significantly lower than 130/85 and 135/85 mm Hg (7.8, 15.2, and 18.4%, respectively, P = 0.002). Conclusions The present study suggests that lowering the diagnostic thresholds of HBP measurement from 135/85 mm Hg to 130/80 mm Hg may improve diagnostic accuracy for hypertension.

Background and purpose Based on the data of patients who measured office BP (OBP) in controlled condition, home BP (HBP), and 24-hour ambulatory BP (24hABP) for diagnosis of hypertension, we developed and validated a diagnostic algorithm for hypertension. Methods Patients who have high BP (≥140/90 mmHg) at the outpatient clinic were referred to measure OBP in controlled condition, HBP and 24hABP. The OBP was measured three times at each visit for 3 days in controlled condition by using a validated oscillometric device. HBP was measured for 7 days in triplicates every morning and evening. The 24hABP was measured on the 8th day. Same study protocol was used for development and validation population. Results In the development of algorithm, 319 patients were recruited and data of 256 patients (51.8±9.7 years, 119 men) with valid HBP and 24hABP measurements were analyzed. In the validation of algorithm, 300 patients were recruited and data of 257 patients (52.4±9.8 years, 126 men) with valid HBP and 24hABP measurements were analyzed. In the development population, the prevalence of masked hypertension was 19.5% (n=50) and most of them (n=47, 94%) was in the range of 130–139/80–89 mmHg. The BP in the range of 130–144/80–94 mmHg was defined as the grey zone of OBP, because prevalence of white-coat hypertension was lowered to 1.6% from 4.3% with threshold of 145/95 mmHg. The diagnostic sensitivity, specificity, positive and negative predictive value of OBP was improved to 97.4%, 76.5, 96.5% and 81.3% after excluding the grey zone of OBP (n=125). The diagnostic agreement between 24hABP and HBP in the grey zone of OBP was 64%. The diagnostic sensitivity, specificity, positive and negative predictive value of HBP were 88.8%, 74.7, 93.5% and 61.5% after excluding the grey zone of HBP (130–134/80–84 mmHg, n=28). Based upon these results, we developed a diagnostic algorithm for hypertension by using on out-of-office BP measurements to improved diagnostic accuracy of hypertension (Figure). In the validation population, the developed algorithm showed similar diagnostic accuracy. Diagnostic algorithm for hypertension Conclusion For accurate diagnosis of hypertension, OBP measurement according to guidelines and 24hABP measurement to grey zone of OBP is preferred. To improve diagnostic accuracy of HBP measurement, 24hABP measurement to grey zone of HBP is required. Acknowledgement/Funding Part of this study was supported by a grand from Dong-A ST Co. Ltd., Seoul, Korea.

Background Hypertension is an important risk factor for cardiovascular disease, even in the elderly. Fimasartan is a new non-peptide angiotensin II receptor blocker with a selective type I receptor blocking effect. The objective of this study is to confirm the safety and the non-inferiority of the blood pressure–lowering effect of fimasartan compared with those of perindopril, which has been proven safe and effective in elderly patients with hypertension. Methods This is a randomized, double-blind, active-controlled, two-parallel group, optional-titration, multicenter, phase 3 study comparing the efficacy and safety of fimasartan and perindopril arginine. The study population consists of individuals 70 years old or older with essential hypertension. The primary outcome will be a change in sitting systolic blood pressure from baseline after the administration of the investigational product for 8 weeks. The secondary outcomes will be a change in sitting diastolic blood pressure from baseline and changes in sitting systolic blood pressure and diastolic blood pressure from baseline after the administration of the investigational product for 4, 16, and 24 weeks. The sample size will be 119 subjects for each group to confer enough power to test for the primary outcome. Discussion Research to confirm the efficacy and safety of a new medicine compared with those of previously proven anti-hypertensive drugs is beneficial to guide physicians in the selection of therapeutic agents. If it is confirmed that the new drug is not inferior to the existing drug, the drug will be considered as an option in the treatment of hypertension in elderly patients. Trial registration ClinicalTrials.gov Identifier: NCT03246555, registered on July 25, 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3466-5) contains supplementary material, which is available to authorized users.

SPIRIT 2013 checklist: Recommended items to address in a clinical trial protocol and related documents. (DOC 124 kb)

The authors developed an equation to estimate 24‐hour urine sodium (24HUNa) using the average of three spot urine (SU) samples (morning‐first, morning, and evening) from 74 individuals and validated this equation using the average of three SU samples (morning‐first, daytime, and evening) from 174 additional individuals. Compared with previously published equations using a single SU sample, the currently developed equation using the average of three SU samples showed much lower bias from measured 24HUNa (−2.9 vs >10 mmol/24 h). The intraclass and concordance correlation coefficients of the proposed equation using the average of three SU samples were 0.909 and 0.832, respectively. The limits of agreement were −64.1–58.3 mmol/24 h and approximately 100 mmol/24 h for the currently developed and previously published equations, respectively. All equations showed a tendency to overestimate or underestimate 24HUNa in a manner dependent on the level of 24HUNa but irrespective of the number of SU samples considered. Nonetheless, among the currently tested equations, our equation using the average of three SU samples provided the best estimation of 24HUNa at a population level.

SummaryAim We aimed to compare the effects of fixed-dose combinations of ezetimibe plus rosuvastatin to rosuvastatin alone in patients with primary hypercholesterolemia, including a subgroup analysis of patients with diabetes mellitus (DM) or metabolic syndrome (MetS). Method This multicenter eight-week randomized double-blind phase III study evaluated the safety and efficacy of fixed-dose combinations of ezetimibe 10 mg plus rosuvastatin, compared with rosuvastatin alone in patients with primary hypercholesterolemia. Four hundred and seven patients with primary hypercholesterolemia who required lipid-lowering treatment according to the ATP III guideline were randomized to one of the following six treatments for 8 weeks: fixed-dose combinations with ezetimibe 10 mg daily plus rosuvastatin (5, 10, or 20 mg daily) or rosuvastatin alone (5, 10, or 20 mg daily). Results Fixed-dose combination of ezetimibe plus rosuvastatin significantly reduced LDL cholesterol, total cholesterol, and triglyceride levels compared with rosuvastatin alone. Depending on the rosuvastatin dose, these fixed-dose combinations of ezetimibe plus rosuvastatin provided LDL cholesterol, total cholesterol, and triglyceride reductions of 56%–63%, 37%–43%, and 19%–24%, respectively. Moreover, the effect of combination treatment on cholesterol levels was more pronounced in patients with DM or MetS than in non-DM or non-MetS patients, respectively, whereas the effect of rosuvastatin alone did not differ between DM vs non-DM or MetS vs non-MetS patients. Conclusion Fixed-dose combinations of ezetimibe and rosuvastatin provided significantly superior efficacy to rosuvastatin alone in lowering LDL cholesterol, total cholesterol, and triglyceride levels. Moreover, the reduction rate was greater in patients with DM or MetS.

Background We evaluated the association between sodium intake and plasma renin levels in the cross sectional study and meta-analysis of randomized controlled trials, whether there is a persistent elevation of plasma renin by longer-term sodium intake restriction. Methods Plasma renin activity (PRA) and 24-h urine sodium (24HUNa) excretion were measured from individuals randomly selected from a community. Simple and multiple linear regression analyses adjusted for age, 24-h systolic blood pressure, 24-h average heart rate, fasting blood glucose and gender were performed. For meta-analysis, 74 studies published from 1975 to mid-2014 were identified in a systematic literature search using EMBASE, CINAHL, and MEDLINE. Random effects meta-analyses and a meta-regression analysis were performed. Results Among the 496 participants recruited, 210 normotensive and 87 untreated hypertensive subjects were included in the analysis. There was no significant association between PRA and 24HUNa in the total population, or hypertensive and normotensive individuals. In the meta-analysis, the standard mean difference (SMD) of renin level by sodium intake reduction was 1.26 (95% CI: 1.08 to 1.44, Z=12.80, P 2 =87%). In the meta-regression analysis, an increase in a day of intervention was associated with a fall in SMD by −0.04 (95% CI: −0.05 to −0.02, Z=−5.27, P 2 =86%), indicating that longer duration of reduced sodium intake would lead to lesser SMD of renin level. Conclusions The present population based cross-sectional study and meta-analysis suggests that prolonged reduction in sodium intake is very unlikely associated with elevation of plasma renin levels.