C-reactive Protein Levels and Cardiovascular Outcomes After Febuxostat Treatment in Patients with Asymptomatic Hyperuricemia: Post-hoc Analysis of a Randomized Controlled Study.

PURPOSE: Inflammation plays an important role in the initiation and progression of atherosclerosis, leading to poor clinical outcomes. Hyperuricemia is associated with the activation of the Nod-like receptor protein 3 inflammasome. Here, we investigated whether inhibition of inflammation using febuxostat lowered the risk of cardiovascular events. METHODS: This is a post-hoc analysis of the randomized trial, Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED). In total, 1067 patients (736 men and 331 women) were included in the analysis. We compared the serial changes in high-sensitivity C-reactive protein (hs-CRP) levels between febuxostat and non-febuxostat groups and assessed the correlation between the changes in uric acid (UA) and hs-CRP levels after febuxostat treatment. We also determined whether febuxostat could reduce a hard endpoint, defined as a composite of cardiovascular events and all-cause mortality. RESULTS: Serum UA levels in the febuxostat group were significantly lower than those in the non-febuxostat group after randomization (p < 0.05). However, hs-CRP levels were comparable between the two groups during the study. No significant correlation was observed between the changes in UA and hs-CRP levels after febuxostat treatment. The hard endpoints did not differ significantly between the two groups. In patients with baseline hs-CRP levels > 0.2 mg/dL or those administered 40 mg of febuxostat, the drug did not reduce hs-CRP levels or decrease the hard endpoint. CONCLUSION: Febuxostat reduced the UA levels but did not affect the CRP levels, and therefore may fail to improve cardiovascular outcomes after treatment. TRIAL REGISTRATION: ClinicalTrial.gov (NCT01984749). https://clinicaltrials.gov/ct2/show/NCT01984749.

Optimal uric acid levels by febuxostat treatment and cerebral, cardiorenovascular risks: post hoc analysis of a randomized controlled trial.

OBJECTIVES: Hyperuricaemia is recognized as an independent risk marker for cardiovascular and renal diseases. However, uric acid is a powerful free-radical scavenger, and the optimal level of serum uric acid (SUA) determining outcomes is unknown. This study explored whether interventional treatments for excessive SUA reduction were harmful and what constituted the optimal lowering of SUA levels for the prevention of events in patients with asymptomatic hyperuricaemia. METHODS: This was a post hoc analysis of a randomized trial (Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy [FREED]) in which 1070 older patients with asymptomatic hyperuricaemia were enrolled and allocated to febuxostat (n = 537) or non-febuxostat treatment group (n = 533). We assessed the relationship between the endpoint (withdrawal or study completion) SUA levels and clinical outcomes. Primary endpoint was defined as a composite of all-cause mortality, cerebral and cardiorenovascular events. RESULTS: In the febuxostat group, patients achieving SUA levels ≤4 mg/dl (hazard ratio: 2.01 [95% CI: 1.05, 3.87]), >4 to ≤5 mg/dl (2.12 [1.07, 4.20], >6 to ≤7 mg/dl (2.42 [1.05, 5.60]), and >7 mg/dl (4.73 [2.13, 10.5]) had significantly higher risks for a primary composite event than those achieving SUA levels >5 to ≤6 mg/dl (P = 0.003 [log-rank test]). This J-shaped relationship applied to patients with renal impairment (P = 0.007 [Gray's test]) and was not significant in the non-febuxostat treatment group (P = 0.212 [log-rank test]). CONCLUSION: Optimal SUA level by febuxostat treatment is 5-6 mg/dl for reducing all-cause mortality, cerebral, cardiovascular and renal events. Excessive SUA reduction may be harmful in older hyperuricaemic populations. TRIAL REGISTRATION: ClinicalTrial.gov, https://clinicaltrials.gov, NCT01984749.

Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy.

AIMS: To compare the occurrence of cerebral, cardiovascular, and renal events in patients with hyperuricaemia treated with febuxostat and those treated with conventional therapy with lifestyle modification. METHODS AND RESULTS: This multicentre, prospective, randomized open-label, blinded endpoint study was done in 141 hospitals in Japan. A total of 1070 patients were included in the intention-to-treat population. Elderly patients with hyperuricaemia (serum uric acid >7.0 to ≤9.0 mg/dL) at risk for cerebral, cardiovascular, or renal disease, defined by the presence of hypertension, Type 2 diabetes, renal disease, or history of cerebral or cardiovascular disease, were randomized to febuxostat and non-febuxostat groups and were observed for 36 months. Cerebral, cardiovascular, and renal events and all deaths were defined as the primary composite event. The serum uric acid level at endpoint (withdrawal or completion of the study) in the febuxostat (n = 537) and non-febuxostat groups (n = 533) was 4.50 ± 1.52 and 6.76 ± 1.45 mg/dL, respectively (P < 0.001). The primary composite event rate was significantly lower in the febuxostat group than in non-febuxostat treatment [hazard ratio (HR) 0.750, 95% confidence interval (CI) 0.592-0.950; P = 0.017] and the most frequent event was renal impairment (febuxostat group: 16.2%, non-febuxostat group: 20.5%; HR 0.745, 95% CI 0.562-0.987; P = 0.041). CONCLUSION: Febuxostat lowers uric acid and delays the progression of renal dysfunction. REGISTRATION: ClinicalTrials.gov (NCT01984749).

Differences between rosuvastatin and atorvastatin in lipid-lowering action and effect on glucose metabolism in Japanese hypercholesterolemic patients with concurrent diabetes. Lipid-lowering with highly potent statins in hyperlipidemia with type 2 diabetes patients (LISTEN) study ­.

BACKGROUND: Little is known about the differences between standard-dose statins effects on glucose level and lipids in Japanese patients with diabetes mellitus (DM). METHODS AND RESULTS: The 1,049 patients were randomly assigned to either the rosuvastatin group or atorvastatin group. There were no significant differences between the 2 groups in the effect on non-high-density lipoprotein cholesterol (non-HDL-C) and HbA1c at 12 months. However, physicians tended to switch to more intensive therapy for DM in the atorvastatin group. CONCLUSIONS: Rosuvastatin 5 mg and atorvastatin 10 mg have a similar lowering effect on non-HDL-C, but might be different in terms of adverse effect on glucose levels.

Validity of salt intake assessment system based on a 24-h dietary recall method using a touch panel computer.

BACKGROUND: An electronic system for salt intake assessment using a 24-h dietary recall method has been developed in Japan. We evaluated the validity of this salt intake system for assessing salt intake. METHODS: We prospectively obtained data on estimated salt intake using 24-hour urinary sodium excretion (24-hUNaCl) and salt intake by the salt intake assessment system from 203 consecutive outpatients with essential hypertension (age: 67.8 ± 10.7 years; 53.7% men). RESULTS: Mean values were 9.7 ± 2.9 g/day for 24-hUNaCl and 9.1 ± 2.9 g/day for the salt intake assessment system before corrections. The salt intake estimated by the present system was significantly correlated with 24-hUNaCl (r = 0.66, p < 0.0001). After corrections for habitual use of discretionary seasonings, habitual intake of salty foods, and physical activity, correlation coefficients between salt intake and 24-hUNaCl increased from 0.60 to 0.66 in men <65 years, from 0.80 to 0.81 in men ≥ 65 years, from 0.64 to 0.75 in women <65 years, and from 0.52 to 0.59 in women ≥ 65 years. After further correction for regional differences in average salt intake, the correlation coefficient reached 0.72 in all patients. CONCLUSION: After correction for dietary habits, lifestyle factors, and differences in average salt intake by region, this system may be a useful tool in Japan to encourage salt restriction in the clinical treatment of hypertension and improve public health in terms of salt restriction overall.

Impacts of Febuxostat on Cerebral and Cardiovascular Events in Elderly Patients with Hyperuricemia: Post Hoc Analysis of a Randomized Controlled Trial.

A recent meta-analysis found no benefit of uric acid-lowering therapy including febuxostat on death, cardiovascular events, or renal impairment. However, there may be populations that benefit from febuxostat in reducing mortality and cerebral and cardiovascular events. The aim of the present study was to examine the clinical benefit of febuxostat in elderly patients stratified by age using Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED) data. FREED was a randomized study involving patients aged 65 years or older with hyperuricemia and risk factors for cerebral, cardiovascular, or renal diseases. A total of 1,070 patients were included in this post hoc analysis, divided into 2 age groups: 65-74 years and ≥ 75 years. Patients were randomized into febuxostat and non-febuxostat groups, with uric acid levels monitored for 36 months. The primary composite end point included cerebral, cardiovascular, and renal events. In patients aged between 65 and 74 years, febuxostat significantly reduced the risk of future cerebral and cardiorenovascular events. However, no effects of febuxostat were found in the older population aged ≥ 75 years. Heterogeneity in potential interactions between the age and febuxostat treatment was particularly observed in non-fatal cerebral and cardiovascular events and all-cause death. Patients aged ≥ 75 years exhibited more pre-existing factors associated with cerebral and cardiorenovascular events than those aged 65-74 years. The effectiveness of febuxostat varies by age group, with potential benefits for patients aged 65-74 years. The effects of febuxostat are complex and it is important to consider patient characteristics in its clinical use.

Febuxostat and renal outcomes: post-hoc analysis of a randomized trial.

Effect of urate-lowering on renal outcomes in patients at high-risk for cardiovascular disease with hyperuricemia without gout is not known. We conducted a post hoc analysis of a randomized trial (Febuxostat for Cerebral and　CaRdiorenovascular Events PrEvEntion StuDy [FREED]). The FREED trial enrolled 1070 asymptomatic, hyperuricemic elderly patients with at least one risk factor for cardiovascular disease, divided into febuxostat (n = 537) and non-febuxostat (n = 533) groups. We compared the effect of these treatments on renal outcomes including 40% decline in estimated glomerular filtration rate, new onset of microalbuminuria and development or worsening macroalbuminuria. The relative risk of developing or worsening macroalbuminuria was 56% lower in the febuxostat group (hazard ratio, 0.44; 95% CI, 0.24-0.82; P = 0.0098). However, the risks for other outcomes were comparable. In patients with asymptomatic hyperuricemia without gout, febuxostat reduces the risk of development or worsening of macroalbuminuria.

White-coat effect on orthostatic hypotension: a nationwide survey of Japanese general practitioners.

OBJECTIVE: The relationship between the white-coat effect (WCE), defined as white-coat hypertension under treatment, and the frequency of orthostatic hypotension (OH) is not known. We conducted an orthostatic test in patients with WCE to determine the frequency of OH. METHODS: This was a cross-sectional study of 5631 patients with hypertension visiting general practitioners nationwide, in which 4305 patients with hypertension recorded their home blood pressure (BP) and consented to the orthostatic test. Patients with hypertension were divided into four groups: controlled hypertension (CHT), masked hypertension (MHT), sustained hypertension (SHT), and WCE. The orthostatic test was performed, and BP and pulse rate were measured immediately and 1 min after orthostasis. RESULTS: The OH frequencies immediately after standing in CHT, WCE, SHT, and MHT patients were 7, 11.7, 12.1, and 6.6%, respectively, and those at 1 min after standing were 7.1, 13.1, 11.6 and 6.9%, respectively (Chi-square test, P < 0.01, respectively). Logistic regression analysis was performed to examine the relationship between WCE and the frequency of OH. The frequency of OH immediately after standing was significantly increased [adjusted odds ratio (AOR), 1.702; 95% confidence interval (CI), 1.246-2.326; P < 0.01]. The frequency of OH at 1 min after standing was also significantly higher (AOR, 1.897; 95% CI, 1.396-2.578; P < 0.01). CONCLUSION: When the standing test was performed for patients with WCE, the frequency of OH increased. Thus, it is important to recognize the possibility of OH in patients with WCE to avoid adverse events associated with excessive hypotension.

Differences in Dental Care Referral for Diabetic Patients Between General Practitioners and Diabetes Specialists in Japan, Analyzed from NSAID-Study 3.

INTRODUCTION: Periodontal disease is a common inflammation worldwide and is not only the foremost cause of tooth loss but also a cause of deterioration of glycemic control in patients with diabetes mellitus. In addition, effective glycemic management improves the control of periodontitis infection. The aim of this study was to clarify whether awareness of the need to refer their patients with diabetes to dentists differs between general practitioners and diabetes specialists. This was achieved by secondary analysis of data from the 2018 Nationwide Survey on Actual Intervention for Type 2 Diabetes Mellitus (T2DM) by Japanese Practitioners (NSAID Study). METHODS: Data from 380 general practitioners and 79 diabetes specialists who participated in the NSAID study and responded to the question of whether they referred T2DM patients to the dentist were analyzed in this study. RESULTS: The proportion of general practitioners who referred T2DM patients to dentists was significantly lower than that of diabetes specialists (35.4% vs. 64.1%, respectively). CONCLUSION: This result suggests that the general practitioners who participated in this study were less cognizant of oral hygiene in patients with diabetes than those who specialized in diabetes. It is also necessary to increase the opportunities for education of physicians who provide diabetic care to promote appropriate dental referrals.

Periodontal disease is a common inflammation worldwide and not only causes tooth loss but also the deterioration of glycemic control in patients with diabetes. In addition, effective glycemic management improves the control of periodontitis infection. Physicians who care for diabetes patients need to be aware of the increased risk and need for improved oral hygiene and to refer their patients to dentists. This study aims to clarify whether awareness of the need to refer their patients with diabetes to dentists differs between general practitioners and diabetes specialists. Responses from 380 general practitioners and 79 diabetes specialists are analyzed in this study. The proportion of general practitioners who refer type 2 diabetes patients to dentists is shown to be significantly lower than that of diabetes specialists. It is necessary to increase the opportunities for education of physicians who provide diabetic care to promote appropriate dental referrals.

Cross sectional study on proportion of sulfonylureas among various oral antidiabetic drugs using for Japanese patients with type 2 diabetes, analyzed from NSAID Study-2.

AIM: We aimed to investigate the certainty of using sulfonylureas in Japanese patients with type 2 diabetes mellitus (T2DM) by analyzing data from the 2018 Nationwide Survey on Actual Intervention for T2DM by Japanese Practitioners (NSAID Study). METHODS: Of the 6525 and 1545 participants in the NSAID Study under the care of general practitioners (GP) and diabetes specialists (SP), respectively, we included 5423 (83.1%) and 1058 (68.5%) patients who were treated with only oral antidiabetic drugs (OADs) by GPs and SPs, respectively, in the analysis. RESULTS: Among the seven OAD classes in monotherapy, sulfonylureas were the third and fifth most prescribed OADs by GPs (7.1%) and SPs (6.4%), respectively. Sulfonylurea usage increased with combination therapy. Glimepiride was the most commonly prescribed sulfonylurea. Patients who used sulfonylureas had higher hemoglobin A1c (HbA1c) levels and lower body mass indices (BMIs) than patients who did not use sulfonylureas. CONCLUSION: The results of this study clearly demonstrated that, among the OADs, sulfonylureas were not frequently used in monotherapy, although the opportunity of using sulfonylurea increased with the number of OADs prescribed in combination therapies by both GPs and SPs in Japan. Moreover, low-dose glimepiride was the most-prescribed sulfonylurea for Japanese T2DM patients, especially for those who were lean and had higher HbA1c levels.

Direct comparison of the reproducibility of in-office and self-measured home blood pressures.

OBJECTIVE: The aim was to compare short-term and long-term reproducibilities of in-office unattended blood pressure (BP), namely automated office blood pressure (AOBP), conventionally measured attended office BP, and self-measured home BP. METHODS: A multicentre, clinical study was conducted in Japan, and 287 Japanese outpatients on antihypertensive drug medication were followed-up for 1 year. RESULTS: The intensity of drug treatment was sustained consistently throughout the study period (defined daily doses, 1.62-1.68; P = 0.12). The mean SBP differences between baseline and 1 month later, as well as baseline and 1 year later, were less than 1.5 mmHg, whereas the standard deviations of the differences for home, AOBP, and attended office measurements for the 1-year interval were 7.7, 14.5, and 15.3 mmHg, respectively. The coefficients of variation were significantly smaller for home BP than for AOBP among all patients at both 1-month and 1-year intervals (P < 0.0001). In the 1-month interval, partial correlation coefficients of home BP (r, 0.73/0.88 for systolic/diastolic measures) were significantly higher than of conventional BP (r, 0.47/0.69). However, the correlations converged to the modest level regardless of BP information (r, 0.49-0.54/0.63-0.73) when the 1-year interval was assessed. Results were confirmatory when patients on the same drug regimen (n = 167) were analysed. CONCLUSION: A higher reproducibility of home BP was demonstrated compared with in-office BP, including AOBP. However, the modest correlations for the 1-year interval support the importance of regular assessment of BP, regardless of in-office or home measurements for treatment of hypertension.

Effect of febuxostat on clinical outcomes in patients with hyperuricemia and cardiovascular disease.

BACKGROUND: We previously reported on the FREED study, which found that febuxostat reduced the risk of adverse clinical outcome in patients with asymptomatic hyperuricemia without gout. We have now investigated outcomes in subgroups of FREED patients with and without a history of cardiovascular disease (CVD). METHODS: We performed a post hoc subgroup analysis of 1070 patients randomized to the febuxostat or non-febuxostat group and followed for 36 months. RESULTS: At baseline, 234 patients (21.9%) had a history of CVD, including 86 patients with stroke (36.8%), 90 with coronary artery disease (38.5%), 74 with heart failure (31.6%), and 25 with vascular disease (10.7%). The risk for the primary composite endpoint, i.e., cerebral, cardiovascular, and renal events and all deaths, was higher in patients with CVD than in those without CVD (34.2% vs 23.7%; p < 0.001). Treatment with febuxostat lowered rates of the primary composite endpoint in patients with CVD (hazard ratio [HR] 0.601, 95% CI 0.384 to 0.940, p = 0.026), and these effects were consistently observed in subgroups with and without CVD (p = 0.227 for treatment by subgroup interaction). Furthermore, in the subgroup with CVD, all-cause mortality was significantly lower in the febuxostat group than in the non-febuxostat group (HR 0.160, 95% CI 0.047 to 0.547, p = 0.004), with a significant subgroup interaction (p = 0.007 for treatment by subgroup interaction). CONCLUSIONS: In patients with asymptomatic hyperuricemia without gout, febuxostat reduces the risk of the composite of cerebral, cardiovascular, and renal events and death in the secondary prevention setting.

Present status of sulfonylurea treatment for type 2 diabetes in Japan: second report of a cross-sectional survey of 15,652 patients.

Sulfonylureas are commonly used for the treatment of patients with type 2 diabetes mellitus (T2DM). However, some clinical concerns regarding their use have grown over the past decade. Thus, results of a previous Japan-wide cross-sectional survey of patients with type 2 diabetes mellitus (T2DM) were analyzed to determine the present status and problems associated with the use of sulfonylureas in the treatment of T2DM by general practitioners (GPs) and diabetes specialists. Of 15,652 patients across 721 clinics and hospitals from the previous survey, 15,350 were diagnosed as T2DM (14,312 by GPs and 1,038 by specialists). For each patient, data were collected for HbA1c levels, age, height, body weight, and treatment modality. Of T2DM patients being treated by GPs, 35.4% and 60.0% received sulfonylureas in entire oral drugs or as monotherapy, respectively, compared with 29.2% and 61.2% of patients, respectively, treated by specialists. Of the patients treated with sulfonylurea monotherapy, 1335 patients (35.2%) achieved HbA1c <6.5%, whereas HbA1c was >or=8.0% in 531 patients (14.0%). Patients with HbA1c levels >or=8.0% had a higher body mass index, used glibenclamide more frequently, and used higher doses of sulfonylureas than patients in whom HbA1c levels were <6.5%. In conclusion, the present study shows that sulfonylureas are central in the treatment of T2DM in Japan. However, careful consideration of suitable patients, agents, and doses is necessary to achieve appropriate glycemic control.

Nationwide Survey on Actual Interventions for Type 2 Diabetes by Japanese Practitioners (NSAID Study-1): Glycemic, Weight, and Blood Pressure Management.

INTRODUCTION: Considering the increase in the number of patients with diabetes, the quality of diabetes care provided by general practitioners (GP) is critical for preventing complications. We performed a nationwide survey to determine whether the diabetic management provided to patients with type 2 diabetes mellitus (T2DM) by Japanese practitioners is appropriate. METHODS: We randomly selected 463 clinics throughout Japan; 8070 patients with T2DM (6525 and 1545 under the care of GP and specialists [SP], respectively) were enrolled. We obtained information on hemoglobin A1c (HbA1c) levels, age, height, body weight, diabetes type and treatment modality, blood pressure (BP), and hypertension or dyslipidemia from each patient. Additionally, we surveyed the collaborations among physicians. RESULTS: The median HbA1c level of patients treated by GP was lower than that of patients treated by SP (6.8 [6.2-7.3], median [interquartile range] vs. 6.9 [6.5-7.5], p < 0.0001). The percentage of patients receiving insulin therapy was also higher (23.8%) among patients treated by SP than among those treated by GP (8.6%). Patients not receiving insulin therapy showed lower median HbA1c levels than those receiving insulin therapy, irrespective of the care provider. The mean body mass index of patients with HbA1c levels < 6.9% or > 9.0% cared for by SP was lower than that of those cared for by GP. The rate of target BP (< 140/90 mmHg) achievement was 73.2% and 73.3% among patients with T2DM and hypertension cared for by GP and SP, respectively. Furthermore, 88.2% of GP reported that consulting with SP was easy. CONCLUSION: The present study clearly demonstrated that many patients with T2DM are appropriately cared for by general practitioners instead of diabetes specialists in Japan, although the number of diabetes specialists is insufficient to cover all patients with diabetes.

Comparison of blood pressure values-self-measured at home, measured at an unattended office, and measured at a conventional attended office.

Self-measured blood pressure (BP) at home (HBP) has been commonly used in clinical practice. Although the unattended office BP (UBP), in which a patient is left alone before and during the measurement, has been investigated, the advantages of UBP over HBP or conventionally measured attended office BP obtained using automated devices (CBP) remain unclear. We performed a multicenter clinical study in Japan to compare the UBP, CBP, and HBP among 308 patients with hypertension at 3 clinics (women, 57.8%; mean age 71.8 years; under antihypertensive drug therapy, 96.4%). The patients measured HBP twice in the morning and twice in the evening for 5 days according to the Japanese Society of Hypertension guidelines. Using the Omron HEM-907 cuff-oscillometric device, the UBP and CBP were measured in line with the protocol in the Systolic blood PRessure INtervention Trial (SPRINT) and in accordance with the guidelines, respectively. Correlation coefficients were ≤0.16 for the comparison of UBP versus morning and evening HBP for the systolic measurement, whereas they were approximately 0.5 (P < 0.001) for the diastolic measurement. The difference between UBP minus HBP was small on average but varied among individuals (mean ± SD for UBP minus morning HBP: 0.9 ± 17.8/-4.5 ± 10.5 mmHg; UBP minus evening HBP: 5.7 ± 17.8/-0.1 ± 11.3 mmHg). In contrast, the measurement values of CBP and UBP were highly correlated (r ≥ 0.72), but the difference between CBP minus UBP was 10.4 ± 12.0/4.2 ± 6.5 mmHg. Based on the low correlations and wide range of differences, UBP cannot be used as an alternative to HBP.

Blood pressure differences between office and home settings among Japanese normotensive subjects and hypertensive patients.

This study attempted to clarify the differences in blood pressure (BP) between the office (clinic) and home settings in patients with controlled, sustained, masked or white-coat hypertension. The following formula was used: office mean systolic BP (omSBP)-mean morning home SBP (mmhSBP)/office mean diastolic BP (omDBP)-mean morning home DBP (mmhDBP). The paired t-test was used for statistical analysis. The omSBP-mmhSBP/omDBP-mmhDBP calculation yielded the following results: among normotensive subjects, -1.1±11.2/-1.7±8.5 mm Hg (mean SBP and mean DBP were higher at home than in the office; n=451, P=0.038 in SBP, P=0.000 in DBP); in controlled hypertensive patients, -0.42±10.9/-2.2±8.2 mm Hg (n=1362, P=0.160 in SBP, P=0.000 in DBP); among sustained hypertensive patients, 5.6±14.7/0.048±9.9 mm Hg (n=1370, P=0.000 in SBP, P=0.857 in DBP); in masked hypertensive patients, -15.3±12.9/-9.3±9.5 mm Hg (n=1308, both P=0.000); and among white-coat hypertensive patients, 23.7±13.2/8.2±9.1 mm Hg (n=580, both P=0.000). Our results showed a difference of 5 mm Hg in SBP among sustained hypertensive patients, as recommended by the Japanese Society of Hypertension Guidelines for the Management of Hypertension; however, in other hypertensive patient types, the differences in SBP and DBP between office and home measurements differed by >5 mm Hg. Office and home BP measurements should be interpreted cautiously, keeping in mind the clinical setting.

Rationale, design, and baseline characteristics of a study to evaluate the effect of febuxostat in preventing cerebral, cardiovascular, and renal events in patients with hyperuricemia.

BACKGROUND: Since uric acid is associated with cardiovascular and renal disease, a treatment to maintain blood uric acid level may be required in patients with hyperuricemia. This study aims to evaluate preventive effects of febuxostat, a selective xanthine oxidase inhibitor, on cerebral, cardiovascular, and renal events in patients with hyperuricemia compared to conventional treatment. METHODS AND RESULTS: This study is a prospective randomized open-label blinded endpoint study. Patient enrolment was started in November 2013 and was completed in October 2014. The patients will be followed for at least 3 years. The primary endpoint is a composite of cerebral, cardiovascular, and renal events, and all deaths including death due to cerebral, cardiovascular, and renal disease, new or recurring cerebrovascular disease, new or recurring non-fatal coronary artery disease, cardiac failure requiring hospitalization, arteriosclerotic disease requiring treatment, renal impairment, new atrial fibrillation, and all deaths other than cerebral or cardiovascular or renal disease. These events will be independently evaluated by the Event Assessment Committee under blinded information regarding the treatment group. The study was registered at ClinicalTrials.gov with the identifier NCT01984749.

Current status of antihypertensive prescription and associated blood pressure control in Japan.

The importance of tight blood pressure (BP) control has been established. We performed cross-sectional studies on the current status of BP control and the prescription and efficacy of antihypertensive drugs in hypertensive patients in Japan. The data were also evaluated in subgroups with or without diabetes mellitus (DM) and in winter and summer. Analyses were performed on the collected data of 12,437 treated hypertensive patients in winter and 5,972 in summer 2002. In winter, 50.3% of patients received calcium channel blockers (CCBs), 15.3% received angiotensin converting enzyme inhibitors (ACEIs) and 11.0% received angiotensin receptor blockers (ARBs). In the patients receiving monotherapy, 69% of patients received a CCB, 13% an ACEI and 11.0% an ARB. A total of 2,918 patients received combination therapy, and CCBs were the most frequently (89.6%) prescribed component of such therapy. Prescriptions of beta-blockers (BBs) decreased and those of CCBs and diuretics (D) increased with age (p<0.001). The rate of patients with adequately controlled BP less than 140/90 mmHg was 40.3% in the CCB group, 37.6% in the D group, and 36.9% in the BB group (p<0.001). In patients receiving combination therapy, those with CCB+D had the best rate of BP control (40.7%). The rate of patients with adequately controlled BP was lower in winter than in summer at both a target BP of 140/90 mmHg (36.2% vs. 43.8%, p<0.001) and a target BP of 130/85 mmHg in patients younger than 60 years old (15.5% vs. 18.6%, p<0.02). In diabetic patients, the target BP (130/80 mmHg) was achieved in only 11.3%, which was lower (p<0.05) than the rate in non-diabetic patients (13.1%). In conclusion, the present cross-sectional study showed that CCBs were the most frequently prescribed agent for the treatment of hypertension in Japan. The rate of adequate BP control was less than 50% and was even worse in patients with DM and in winter. Our results indicate that physicians should treat hypertension more intensively to achieve the target BP.

How does deep breathing affect office blood pressure and pulse rate?

Little is known about the relation between deep breathing (DB) and blood pressure (BP). We studied the relationship between DB and BP in a large Japanese population. The subjects were recruited from randomly selected clinics and hospitals that were members of a medical association, and divided into two groups. In one group, BP was measured before and after taking 6 DB over a period of 30 s, and in the other group BP was measured before and after a 30-s rest in a sitting position without DB. Before these measurements, all patients rested 10 min or more in the waiting room and another 2 min or more in the doctor's office. Analyses were performed on data collected from 21,563 subjects. In both groups, systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate (PR) were significantly reduced after DB or a 30-s rest compared with the baseline measurements (p < 0.001). SBP reductions were greater in the DB group than in the 30-s rest group (normotensives: -6.4 +/- 8.3 vs. -3.0 +/- 7.4 mmHg, p < 0.001; untreated hypertensives: -9.6 +/- 10.2 vs. -5.9 +/- 9.1 mmHg, p < 0.001; treated hypertensives: -8.3 +/- 9.6 vs. -4.4 +/- 8.3 mmHg, p < 0.001). Greater BP reductions were found in patients with a higher baseline BP in both the DB and 30-s rest groups. In conclusion, the present study showed a baseline BP-dependent BP reduction by DB, suggesting that BP measurement should be done without DB in the office because DB lowers BP.

Comparison of effects of angiotensin II receptor blocker on morning home blood pressure and cardiorenal protection between morning administration and evening administration in hypertensive patients: the COMPATIBLE study.

Whether the time of administering the angiotensin receptor antagonist olmesartan influences antihypertensive and renoprotective effectiveness remains unclear. This study compared the effects of olmesartan on morning home blood pressure (MHBP), office BP (OBP) and renoprotective parameters between morning and evening administration. A total of 218 patients with primary hypertension were randomly assigned to receive olmesartan once daily in the morning (morning-dose group) or evening (evening-dose group), and 188 completed the study protocol (morning-dose group, n=95; evening-dose group, n=93). In both groups, morning home systolic BP, morning home diastolic BP, office systolic BP and office diastolic BP decreased significantly. There was no significant difference between the groups in MHBP or OBP after 6 months of treatment. The urinary albumin-to-creatinine ratio (UACR) decreased from 13.9 to 6.9 mg g(-1) (geometric means, P<0.001) in the morning-dose group and from 14.4 to 9.1 mg g(-1) (P<0.001) in the evening-dose group. The changes in UACR after treatment did not differ significantly between the groups. SV1+RV5 decreased significantly from baseline to 6 months in the morning-dose group (P<0.001) and the evening-dose group (P<0.01), and did not differ significantly between the groups. In conclusion, olmesartan effectively decreased MHBP, OBP, SV1+RV5 and UACR regardless of whether the drug was administered in the morning or in the evening. Our results suggest that olmesartan can be prescribed once daily, either in the morning or in the evening.