Katsutoshi Hiramatsu

Rationale, study design, baseline characteristics and blood pressure at 16 weeks in the HONEST Study

On the basis of the studies that investigated the relationship between baseline clinic blood pressure (CBP) or home blood pressure (HBP) values and cardiovascular (CV) events, HBP has been reported to have a stronger prognostic ability. However, few studies have compared the prognostic ability of on-treatment CBP and HBP. The relationship between on-treatment HBP, measured twice in the morning and twice at bedtime, and CV events was investigated in over 20 000 patients in the HONEST (Home blood pressure measurement with Olmesartan Naive patients to Establish Standard Target blood pressure) Study, a prospective, 2-year observational study of treatment with an angiotensin receptor blocker, olmesartan (OLM), in OLM-naive hypertensive patients. This report summarizes the study protocol, the baseline characteristics of the patients and CBP and HBP at 16 weeks. A total of 22 373 patients were registered across Japan; baseline data from 22 162 patients were collected. Baseline HBP (mean±s.d.) in the morning (the first measurement) was 151.6±16.4/87.1±11.8 mm Hg and at bedtime was 144.3±16.8/82.8±11.9 mm Hg, whereas CBP was 153.6±19.0/87.1±13.4 mm Hg. At 16 weeks, morning HBP was 135.0±13.7/78.8±9.9 mm Hg and bedtime HBP was 129.7±13.8/74.7±10.1 mm Hg, whereas CBP was 135.6±15.4/77.6±10.9 mm Hg. The follow-up period for each patient ends on 30 September 2012. The HONEST Study is expected to provide evidence showing the relationship between baseline and on-treatment CBP and HBP levels (both first and second measurements) and CV events.

Relationship between achieved blood pressure, dietary habits and cardiovascular disease in hypertensive patients treated with olmesartan: the OMEGA study

We investigated the relationship between cardiovascular disease (CVD) and the achieved blood pressure, dietary habits and the presence/absence of metabolic syndrome (MetS) in hypertensive patients treated with olmesartan medoxomil. A prospective cohort study with a 3-year follow-up was conducted in 14 721 olmesartan-naive outpatients (mean age: 64.9 years, 49.6% women) with essential hypertension. The association of CVD with achieved blood pressure, dietary habits and MetS was investigated by Cox proportional hazards analysis. There were 3059 patients (31.8%) with MetS (Japanese criteria) among 9625 evaluable patients. The mean baseline blood pressure was 157.4/88.8 mm Hg, which decreased to 134.0/76.1 mm Hg during treatment (P<0.0001). The annual incidence of CVD was 7.15 per 1000 persons during the study period. When the achieved blood pressure was stratified according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009), the risk of CVD increased significantly along with the severity of hypertension (P<0.0001), especially the risk of stroke. Investigation of dietary habits revealed a significant association between salt intake and the risk of stroke. Higher salt intake was associated with a significantly higher risk of stroke than lower salt intake (hazard ratio, 1.897; 95% confidence interval, 1.003–3.590). Blood pressure was well controlled in both patients with and without MetS, and there was no significant difference in the incidence of events between the two groups. In conclusion, the severity of hypertension (achieved blood pressure) is associated with the incidence of CVD, and the results of this study suggest that tight blood pressure control and salt restriction are important for preventing stroke.

The Use of Olmesartan Medoxomil as Monotherapy or in Combination With Other Antihypertensive Agents in Elderly Hypertensive Patients in Japan

The efficacy and safety of the angiotensin receptor blocker olmesartan medoxomil (OLM) was assessed in 550 elderly Japanese hypertensive patients who were followed for 24 weeks in daily clinical practice. Patients were given OLM alone or in combination with other antihypertensive drugs at the discretion of the investigators. After 24 weeks of treatment, systolic and diastolic blood pressure (BP) significantly decreased from baseline (P<.0001). When patients were classified as either young‐old (65–74 years) or older‐old (75 years and older), with either isolated systolic hypertension (ISH) or systolic‐diastolic hypertension (SDH), the reduction of diastolic BP in ISH patients was significantly smaller than that in SDH patients (5.0 vs 15.2 mm Hg; P<.0001), indicating that OLM did not cause excessive reduction of diastolic BP in ISH patients. Treatment was well tolerated in all groups. In conclusion, the medication was safe and effective in reducing BP levels in ISH patients aged 75 years and older, as well as in other elderly hypertensive patients.

Effect of the angiotensin II receptor antagonist olmesartan on morning home blood pressure in hypertension: HONEST Study at 16 weeks

Morning home blood pressure (BP) levels are more closely associated with cardiovascular risk than clinic BP levels. However, control of morning home BP has been worse than that of clinic BP in clinical practice. We examined the effects of olmesartan-based treatment using data (n=21 341) from the first 16 weeks of the Home BP measurement with Olmesartan Naive patients to Establish Standard Target blood pressure (HONEST) study, a prospective observational study for olmesartan-naive patients with essential hypertension. After 16-week olmesartan-based treatment, the clinic and morning home systolic BP (SBP) lowered from 151.6±16.4 and 153.6±19.0 mm Hg to 135.0±13.7 and 135.5±13.7 mm Hg, respectively (P<0.0001). The achievement percentage of target morning home SBP (<135 mm Hg) in all patients, those with diabetes mellitus (DM), and those with chronic kidney disease (CKD) increased from 13.5, 16.4 and 17.2% to 50.8, 47.9 and 48.8%, respectively, and the proportion of patients with well-controlled hypertension (clinic SBP<140 mm Hg and morning home SBP<135 mm Hg) increased from 7.9, 9.2 and 10.2% to 38.9, 34.5 and 36.3%, respectively. After 16-week olmesartan-based treatment, the proportion of patients with masked and white coat hypertension changed from 11.8 to 24.2% and 5.6 to 11.9%. In conclusion, both clinic and morning home BP in all, DM and CKD patients improved with 16-week olmesartan-based treatment in the ‘real world’, and the results showed a sustained 24-hour BP-lowering effect of olmesartan. Decrease in clinic and home BP resulted in an increased rate of masked and white coat hypertension, and further management is needed in those patients.

Risk factors for primary prevention of cardiovascular disease and risk reduction by lipid control: the OMEGA study risk factor sub-analysis.

Abstract To identify risk factors for cardiovascular disease (CVD) in hypertensive patients with no history of CVD being treated with antihypertensive drugs, we examined subgroup data (n = 13 052) from the prospective, observational Olmesartan Mega Study to Determine the Relationship between Cardiovascular Endpoints and Blood Pressure Goal Achievement (OMEGA) study. Risk factors for CVD, stroke and coronary heart disease (CHD) were examined using a Cox proportional hazards model. In addition, the effect of statin therapy at baseline on CHD prevention was analyzed in dyslipidemic patients. The factors significantly related to CVD were female (hazard ratio [HR] = 0.637, 95% confidence interval [CI] 0.428–0.948), older age (65–69 years: HR = 2.165, 95% CI 1.214–3.861; 70–74 years: HR = 2.324, 95% CI 1.294–4.174; ≥75 years: HR = 2.448, 95% CI 1.309–4.578), family history of CHD (HR = 1.993, 95% CI 1.249–3.179), diabetes (HR = 2.287, 95% CI 1.700–3.078), current smoking (HR = 2.289, 95% CI 1.512–3.466) and alcohol drinking socially (HR = 0.589, 95% CI 0.379–0.913). Diabetes was a risk factor for both stroke and CHD, while age, family history of CHD, and sodium intake score were risk factors for stroke alone. Sex, dyslipidemia, smoking and exercise habits were risk factors for CHD alone. The risk of CHD in dyslipidemic patients on statin treatment was comparable to the risk in patients without dyslipidemia (HR = 1.134, 95% CI 0.604–2.126). However, in dyslipidemic patients not on statin treatment, the HR increased to 1.807 (95% CI 1.156–2.825). In conclusion, some risk factors for CVD in hypertensive patients being treated with antihypertensive drugs with no history of CVD differed between CHD and stroke. These results suggest the importance of managing dyslipidemia with a statin for primary prevention of CHD, as well as the importance of hypertension therapy.

Artist® tablets (carvedilol) for hypertensive patients in Japan: results of a drug use survey.

AbstractBackground: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14.4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a drug use survey, which we conducted as a post-marketing survey. Objective: This prospective post-marketing drug use survey was conducted to assess the safety and efficacy of the β-adrenergic receptor antagonist (β-blocker) Artist® Tablets (carvedilol) in patients with hypertension in Japan. Patients: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. Methods: This was a prospective survey conducted over 3 years from October 1993 to September 1996. The standard observation period for the patients was defined as 12 weeks of treatment with carvedilol. Results: We collected data on 4961 patients at 561 medical institutions who had not been previously treated with carvedilol; 4574 patients were included in the safety analysis and 4422 in the efficacy analysis. The incidence of adverse drug reactions (the proportion of patients with adverse drug reactions) was 4.31% (197 of 4574 patients), which is less than that shown in the pre-approval clinical trial of carvedilol (6.85%[68 of 993]). The most common adverse drug reactions were bradycardia, dizziness, hypotension, headache, and feeling light-headed.After 12 weeks’ treatment with carvedilol, systolic/diastolic blood pressure (SBP/DBP) was reduced from 168.2 ± 18.6/95.7 ± 11.3mmHg at baseline to 144.3 ± 17.3/83.4 ± 10.8mmHg. Patients were classified according to which antihypertensive drug they had been using when carvedilol treatment was initiated. Coadministered agents were calcium channel blockers (CCBs), angiotensinconverting enzyme inhibitors (ACEIs), diuretics, and a-adrenergic receptor antagonists (α-blockers). At 12 weeks, the change in SBP/DBP in the monotherapy group was −22.7/−12.2mmHg and that of each combination therapy subgroup, CCB, ACEI, diuretic, and b-blocker, was −26.1/−12.7mmHg, −25.4/−11.9mmHg, −26.3/−13.0mmHg, and −24.4/−11.5mmHg, respectively. The achievement rates for target BP (<140/90mmHg) were 29.5% in the monotherapy group, 34.8% in the CCB group, 31.3% in the ACEI group, 31.8% in the diuretic group, and 32.4% in the β-blocker group. There was no significant difference in the achievement of target BP among the four combination therapy subgroups (p = 0.475). These results indicate that carvedilol exerts reasonable BP reduction regardless of whether it is used as monotherapy or in combination therapy, and that the effect is not influenced by the coadministered drug. Moreover, carvedilol was also effective in reducing BP levels in elderly patients (≥65 years) and in patients with diabetes mellitus or renal diseases. Conclusions: The results of this study reflect the results of clinical trials up to the time of approval and it was confirmed that carvedilol is a highly useful drug in the treatment of hypertension.

Enhanced Blood Pressure–Lowering Effect of Olmesartan in Hypertensive Patients With Chronic Kidney Disease–Associated Sympathetic Hyperactivity: HONEST Study

To investigate the blood pressure (BP)–lowering effect of olmesartan in relation to chronic kidney disease (CKD)–associated sympathetic nerve activity, a subanalysis was performed using data from the first 16 weeks of the Home BP Measurement With Olmesartan‐Naive Patients to Establish Standard Target Blood Pressure (HONEST) study, a prospective observational study of hypertensive patients. Essential hypertensive patients who took no antihypertensive agent at baseline were classified based on baseline morning home systolic BP (MHSBP) in quartiles. In each class, patients were further classified based on baseline morning home pulse rate (MHPR). A subgroup analysis in patients with/without chronic kidney disease (CKD) was performed. A total of 5458 patients (mean age, 63.0 years; 51.6% women) were included. In the 4th quartile of baseline MHSBP (≥165 mm Hg), patients with MHPR ≥70 beats per minute had a greater BP reduction (by 3.2 mm Hg) than those with MHPR <70 beats per minute after 16 weeks of olmesartan‐based treatment (P=.0005). An even greater BP reduction (by 6.6 mm Hg) was observed in patients with CKD than in patients without CKD in this group (P=.0084). Olmesartan was more effective in hypertensive patients with high MHSBP and MHPR ≥70 beats per minute, especially in patients with CKD. Olmesartan may have enhanced BP‐lowering effects by improving renal ischemia in hypertensive CKD patients with potential increased sympathetic nerve activity.

Blood Pressure-Lowering Effects of Angiotensin Receptor Antagonist Monotherapy and in Combination with Other Anti-Hypertensive Drugs in Primary Care Settings in Japan

Combination therapy with multiple anti-hypertensives is required to achieve target blood pressure (BP) control and is recommended as the first-line therapy in hypertension. Although angiotensin receptor blockers (ARBs) may be combined with other anti-hypertensives, it is unclear how the effects of ARBs are influenced by co-administered anti-hypertensives. We investigated the effect of olmesartan medoxomil (OLM) when it is given alone (monotherapy) or concomitantly with other anti-hypertensives in 6507 OLM-naïve Japanese in “real world” clinical practice. After a 12-week treatment, BP was significantly reduced from baseline in both the monotherapy group and the combination therapy group (P < 0.0001). The BP-lowering efficacy after treatment and achievement rates of target BP were similar in both groups. In the combination therapy group, no significant difference of achieved BP level was detected between patients taking Calcium channel blockers and any other class of anti-hypertensive drugs. This study suggests that ARBs such as OLM-elicits BP-lowering efficacy as either a first- or second-line agent and its effects are minimally influenced by co-administered anti-hypertensives.

Estimating Antihypertensive Effects of Combination Therapy in an Observational Study Using Marginal Structural Models

The evaluation of the antihypertensive effect of multiple antihypertensive drugs using data from an observational study requires adjustment for time-dependent confounders. Marginal structural models (MSMs) have been proposed to address this type of confounding through inverse probability weighting. Generally, the probabilities are estimated using logistic regression models that assume linearity between the logistic link and the predictors, but the linearity might be inaccurate. In this article, we proposed MSMs to assess the blood pressure-lowering effects of combination therapy with olmesartan medoxomil (OLM) plus calcium channel blockers (CCB) (OLM+CCB) in an observational study of OLM, and extended estimation methods of the probabilities for the MSMs using generalized additive models (GAMs). The estimation using GAMs was suggested to improve the balance of the distributions of confounder values between the therapy groups in the pseudo-population. We obtained estimated changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) for OLM+CCB combination therapy after 12 wk compared with OLM monotherapy of -4.3 mmHg (95% confidence interval (CI): -7.7 and -0.9 mmHg) and -2.9 mmHg (95% CI: -5.1 and -0.7 mmHg), respectively. The estimated target BP (SBP<140 mmHg and DBP<90 mmHg) achievement rates for OLM+CCB combination therapy and OLM monotherapy were 62.0 and 46.7%, respectively. The results of the MSMs were closer to those in the randomized controlled trial, such as the combination of OLM and amlodipine besylate in controlling high blood pressure study, than those of conventional methods. The proposed MSMs provided useful information to evaluate the effects of combination therapy of antihypertensive drugs in the context of an observational study.

Artist® Tablets (Carvedilol) for Hypertensive Patients in Japan

AbstractBackground: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14-4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a long-term special survey that we conducted as a post-marketing survey. Objective: The results of a prospective post-marketing survey that was conducted to assess the safety and efficacy of the b-adrenergic receptor antagonist (β-blocker) Artist® tablets 10 mg, 20mg (carvedilol) in patients with hypertension in Japan, were investigated in order to examine the safety and efficacy of the drug during long-term treatment (18 months). Patients: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. Methods: We performed this survey as a prospective cohort study (special survey) utilizing a centralized registration method over 3 years (starting from April 1994), for an observation period of 18 months of carvedilol treatment. Results: Sixty-one medical institutions across Japan collected 380 case report forms of patients who received long-term administration of carvedilol, with 363 and 341 cases evaluated for safety and efficacy, respectively. The discontinuation rate was 7.2% and the incidence of adverse drug reactions was 5.23% (19 of 363) in the safety population. There was no significant change in fasting plasma glucose levels from baseline (118.1 ± 46.5mg/dL) to after carvedilol treatment (114.6 ± 43.3 mg/dL) [n = 141; p = 0.310].In 341 evaluable patients in the efficacy population, decreases in both blood pressure and pulse rate were statistically significant at all assessment points in comparison with baseline data (p < 0.001). Similarly, in hypertensive patients with diabetes mellitus, decreases in blood pressure were statistically significant at all assessment points in comparison with baseline data (p < 0.001). Conclusions: The results of this study show that carvedilol exerted stable antihypertensive effects leading to favorable blood pressure control throughout long-term treatment, without showing any safety concerns. It was concluded that there were no clinically significant issues in terms of safety or efficacy with the long-term treatment of carvedilol in patients with hypertension.