Differential effectiveness of ARB plus CCB therapy and high-dose ARB therapy in high-risk elderly hypertensive patients: subanalysis of the OSCAR study.

The OSCAR study was a multicenter prospective randomized study that examined the relative benefit of combined ARB (olmesartan 20 mg per day) plus calcium channel blocker (CCB) therapy vs. high-dose ARB monotherapy (olmesartan 40 mg per day) for prevention of cardiovascular events in elderly Japanese hypertensive patients. The present subanalysis of patients enrolled in the OSCAR study (n = 1078) was performed to assess whether baseline eGFR coupled with cardiovascular disease (CVD) could predict the relative benefit of these two treatments. Patients with baseline CVD (n = 769) and patients without baseline CVD (n = 309) were divided into two groups based on baseline eGFR; (i) patients with eGFR of < 60 ml min(-1) 1.73 m(-)(2) and (ii) those with eGFR of ⩾ 60 ml min(-1) 1.73 m(-2). There was a significant treatment-subgroup interaction among these four subgroups in relation to the incidence of primary outcome events(P = 0.007 for interaction). In patients with CVD and with eGFR of <60 ml min(-1) 1.73 m(-2), ARB plus CCB therapy was associated with a lower incidence of primary events than high-dose ARB therapy and the difference of the relative risk was statistically significant (hazard ratio: 3.525, 95% confidence interval (CI): 1.676-7.412, P < 0.001). The greater benefit of ARB plus CCB therapy vs. high-dose ARB therapy in this subgroup was associated with less visit-to-visit variability of systolic BP and diastolic BP. In conclusion, baseline eGFR coupled with baseline CVD seems to be a predictor of the relative efficacy of ARB plus CCB therapy vs. high-dose ARB therapy in the elderly hypertensive patients. ARB plus CCB therapy appears to be superior to high-dose ARB therapy for preventing cardiovascular events in the patients with CVD and with eGFR of <60 ml min(-1) 1.73 m(-2).

Sex differences in response to angiotensin II receptor blocker-based therapy in elderly, high-risk, hypertensive Japanese patients: a subanalysis of the OSCAR study.

The OlmeSartan Calcium Antagonists Randomized (OSCAR) study is a multicenter, prospective, randomized, open-label, blinded, end point study of elderly hypertensive Japanese patients that compared the efficacy of a high-dose angiotensin II receptor blocker (ARB) treatment to an ARB plus calcium channel blocker (CCB) combination. In this pre-specified subgroup analysis, we compared the response to such therapy according to sex. A total of 1164 patients (515 (44%) men and 649 (56%) women) were included, and each gender was split into two nearly equal treatment groups. The primary end point was a composite of cardiovascular events and non-cardiovascular death. The baseline characteristics between the two treatment groups in each sex were similar, except for some variables. Male patients had lower systolic and higher diastolic blood pressure than female patients (156.8/85.7 vs. 158.5/84.2 mm Hg). At the end of the study, the mean systolic pressure was higher in the ARB group (134.4 mm Hg) than in the ARB plus CCB group (131.5 mm Hg; P=0.03) for men but not for women (135.4 vs. 133.4 mm Hg; P=0.12). For men, the primary outcome events tended to be higher in the ARB group than in the ARB plus CCB group (hazard ratio (HR)=1.66; P=0.055) but not for women (HR=0.97; P=0.92). This difference in men was due to cardiovascular events (HR=1.86; P=0.03). The interaction between sex and treatment group was not significant (P=0.17). These findings suggest that, in addition to blood pressure control, appropriate patient risk assessment is important for the treatment of hypertension, especially in male patients, as opposed to possible sex differences in treatment effects.

An angiotensin II receptor blocker-calcium channel blocker combination prevents cardiovascular events in elderly high-risk hypertensive patients with chronic kidney disease better than high-dose angiotensin II receptor blockade alone.

The OSCAR study was a multicenter, prospective randomized open-label blinded end-point study of 1164 Japanese elderly hypertensive patients comparing the efficacy of angiotensin II receptor blocker (ARB) uptitration to an ARB plus calcium channel blocker (CCB) combination. In this prospective study, we performed prespecified subgroup analysis according to baseline estimated glomerular filtration rate (eGFR) with chronic kidney disease (CKD) defined as an eGFR <60 ml/min per 1.73 m(2). Blood pressure was lower in the combined therapy than in the high-dose ARB cohort in both groups with and without CKD. In patients with CKD, significantly more primary events (a composite of cardiovascular events and noncardiovascular death) occurred in the high-dose ARB group than in the combination group (30 vs. 16, respectively, hazard ratio 2.25). Significantly more cerebrovascular and more heart failure events occurred in the high-dose ARB group than in the combination group. In patients without CKD, however, the incidence of primary events was similar between the two treatments. The treatment-by-subgroup interaction was significant. Allocation to the high-dose ARB was a significant independent prognostic factor for primary events in patients with CKD. Thus, the ARB plus CCB combination conferred greater benefit in prevention of cardiovascular events in patients with CKD compared with high-dose ARB alone. Our findings provide new insight into the antihypertensive strategy for elderly hypertensive patients with CKD.

Angiotensin II receptor blocker-based therapy in Japanese elderly, high-risk, hypertensive patients.

BACKGROUND: It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker + calcium channel blocker combination therapy is better in elderly hypertensive patients with high cardiovascular risk. The objective of the study was to compare the efficacy of these treatments in elderly, high-risk Japanese hypertensive patients. METHODS: The OlmeSartan and Calcium Antagonists Randomized (OSCAR) study was a multicenter, prospective, randomized, open-label, blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease. Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were randomly assigned to receive 40 mg/d olmesartan (high-dose angiotensin II receptor blocker) or a calcium channel blocker + 20 mg/d olmesartan (angiotensin II receptor blocker + calcium channel blocker). The primary end point was a composite of cardiovascular events and noncardiovascular death. RESULTS: During a 3-year follow-up, blood pressure was significantly lower in the angiotensin II receptor blocker + calcium channel blocker group than in the high-dose angiotensin II receptor blocker group. Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker + calcium channel blocker group. More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker + calcium channel blocker group (58 vs 48 events, hazard ratio [HR], 1.31, 95% confidence interval, 0.89-1.92; P=.17). In patients with cardiovascular disease at baseline, more primary events occurred in the high-dose angiotensin II receptor blocker group (HR, 1.63, P=.03); in contrast, fewer events were observed in the subgroup without cardiovascular disease (HR, 0.52, P=.14). This treatment-by-subgroup interaction was significant (P=.02). CONCLUSION: The angiotensin II receptor blocker and calcium channel blocker combination lowered blood pressure more than the high-dose angiotensin II receptor blocker and reduced the incidence of primary end points more than the high-dose angiotensin II receptor blocker in patients with cardiovascular disease. The addition of a second antihypertensive agent is more effective at lowering blood pressure than simply doubling the dose of an existing agent.

Salt-induced hemodynamic regulation mediated by nitric oxide.

Excess daily salt intake impairs vasodilatation and enhances vasoconstriction, resulting in reduction of regional blood flow and elevation of blood pressure in healthy individuals and hypertensive patients with either salt sensitivity or not tested for salt sensitivity or not evaluated for salt sensitivity. The mechanism may involve decreased production of nitric oxide via endothelial nitric oxide synthase (eNOS), impaired bioavailability of nitric oxide, and elevated plasma levels of asymmetric dimethylarginine (ADMA). Experimental animals, irrespective of salt sensitivity, although less extensive in those with salt-resistance, fed a high-salt diet have deteriorated endothelial functions; the mechanisms involved include an impairment of eNOS activation, a decrease in eNOS expression, and an increase in oxidative stress and ADMA. The imbalance of interactions between nitric oxide and angiotensin II is also involved in salt sensitivity. Deficiency of nitric oxide formed via neuronal NOS and inducible NOS may contribute to salt-induced hypertension. Reduced daily salt intake, therefore, would be the most rational prophylactic measure against the development of hypertension.

Comparative pharmacodynamics of olmesartan and azelnidipine in patients with hypertension: a population pharmacokinetic/pharmacodynamic analysis.

SUMMARY: The objectives of this study were to identify the factors influencing antihypertensive response to the angiotensin receptor blocker, olmesartan medoxomil, or the calcium channel blocker, azelnidipine, and to discuss the possibility of utilizing them as predictors for drug selection prior to therapy. A two-way crossover study of olmesartan medoxomil and azelnidipine was conducted in 29 patients with mild to moderate essential hypertension. The 24-hour ambulatory blood pressure measurements (ABPM) and plasma drug concentrations were obtained on the first and at the end of each treatment period, and were analyzed using population pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. The population PK/PD models considering circadian variations in baseline blood pressure well described the observed plasma drug concentrations and 24-hour ABPM profiles. Pre-treatment plasma renin activity (PRA) was identified as a significant covariate on the maximum drug effect (E(max)) of olmesartan, whereas azelnidpine E(max) was independent of patient background characteristics investigated. No patient was found to have a high E(max) to one agent who also had a high E(max) to the other. In conclusion, the effects of olmesartan medoxomil and azelnidipine were modestly correlated with pharmacokinetic profiles, and the pre-treatment PRA level could be a useful determinant of responsiveness in selecting olmesartan medoxomil and azelnidipine.

Rationale, design and patient baseline characteristics of OlmeSartan and calcium antagonists randomized (OSCAR) study: a study comparing the incidence of cardiovascular events between high-dose angiotensin II receptor blocker (ARB) monotherapy and combination therapy of ARB with calcium channel blocker in Japanese elderly high-risk hypertensive patients (ClinicalTrials. gov no. NCT00134160).

Higher doses of angiotensin II receptor blockers (ARBs) are expected to exert more protective effects against cardiovascular diseases. However, the significance of treatment of hypertension with high-dose ARB remains to be defined. The OlmeSartan and Calcium Antagonists Randomized (OSCAR) Study was designed to determine whether high-dose ARB monotherapy is superior to the combination therapy of ARB plus calcium channel blocker (CCB) in the prevention of cardiovascular morbidity/mortality in Japanese elderly high-risk hypertensive patients. The OSCAR study is a multicenter, active-controlled, two-arm parallel group comparison, using the prospective randomized open-blinded end-point method. In the 'Step 1' period, elderly hypertensive patients with diabetes or cardiovascular disease received monotherapy with ARB olmesartan medoxomil at a dose of 20 mg day(-1). If the target blood pressure control (less than 140/90 mm Hg) was not achieved by ARB monotherapy, the patients were randomized to receive either (1) the increased dose of olmesartan at 40 mg day(-1) (high-dose ARB monotherapy) or (2) the addition of a CCB (amlodipine or azelnidipine) to 20 mg day(-1) olmesartan (ARB plus CCB combination) in the 'Step 2' period. The follow-up duration will be 3 years. The primary end points will be the composite of fatal and non-fatal cardiovascular events, and death from any cause. Recruitment for the OSCAR study (around 1200 patients) was completed by the end of May 2007. The OSCAR study is the first large clinical trial comparing the efficacy of high-dose ARB monotherapy with that of an ARB plus CCB combination therapy in elderly high-risk hypertensive patients.

Antihypertensive efficacy of olmesartan medoxomil and candesartan cilexetil in achieving 24-hour blood pressure reductions and ambulatory blood pressure goals.

BACKGROUND: For patients with hypertension, effective 24-hour blood pressure (BP) control is vital to ensure protection against the early morning surge in BP and the associated increased risk of cardiovascular events. The aim of this analysis was to assess the 24-hour antihypertensive efficacy of olmesartan medoxomil (20mg once daily) compared with candesartan cilexetil (8mg once daily), with particular emphasis on BP control during the early morning period. METHODS: This is an additional analysis of a previously reported randomised, double-blind study in which 635 patients with mainly mild to moderate hypertension were randomised to 8 weeks of treatment with either olmesartan medoxomil 20 mg/day or candesartan cilexetil 8 mg/day. Changes from baseline during the last 4 and 2 hours of ambulatory BP measurement (ABPM) after 1, 2 and 8 weeks of treatment were compared between the two groups. In addition, the proportions of patients who achieved various ABPM goals, including those suggested by the European Society of Hypertension/European Society of Cardiology (ESH/ESC) [<125/80mm Hg] and the Japanese Society of Hypertension (JSH) [<135/80mm Hg], over 24 hours, during the daytime and at the last 4 and 2 hours of ABPM measurement were also compared. RESULTS: After 8 weeks, significantly greater proportions of patients treated with olmesartan medoxomil 20mg achieved 24-hour and daytime ABPM goals recommended by the guidelines of the ESH/ESC (25.6% and 18.3%, respectively) and JSH (37.5% and 26.6%, respectively) compared with candesartan cilexetil 8mg (24-hour ESH/ESC goal = 14.9%, p < 0.001; 24-hour JSH goal = 26.6%, p = 0.003; daytime ESH/ESC goal = 9.6%, p = 0.002; daytime JSH goal = 16.4%, p = 0.002). During the last 4 hours of 24-hour ABPM, the proportions of patients who achieved the ESH/ESC and JSH ABPM goals were significantly greater with olmesartan medoxomil (33.3% and 39.1%, respectively) than with candesartan cilexetil (22.9%, p < 0.001 and 31.6%, p = 0.047, respectively). Similarly, during the last 2 hours of 24-hour ABPM, the proportions of patients who achieved these BP goals were either significantly greater (JSH) or approached statistical significance (ESH/ESC) with olmesartan medoxomil (26.9% and 19.9%, respectively) compared with candesartan cilexetil (19.6%, p = 0.028 and 14.3%, p = 0.061, respectively). CONCLUSION: Compared with candesartan cilexetil 8mg, greater proportions of olmesartan medoxomil-treated patients (20mg) achieved ESH/ESC and JSH ABPM goals over 24 hours. The superior BP control of olmesartan medoxomil was also reflected in the larger proportions of olmesartan medoxomil-treated patients who achieved the ESH/ESC and JSH ABPM goals during the early morning surge period. This not only demonstrates that olmesartan medoxomil 20mg provides superior 24-hour BP reduction, but also suggests that olmesartan medoxomil may provide greater protection against the increased risk of cardiovascular events associated with the early morning BP surge period.

Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial.

BACKGROUND: Evidence-based treatment for hypercholesterolaemia in Japan has been hindered by the lack of direct evidence in this population. Our aim was to assess whether evidence for treatment with statins derived from western populations can be extrapolated to the Japanese population. METHODS: In this prospective, randomised, open-labelled, blinded study, patients with hypercholesterolaemia (total cholesterol 5.69-6.98 mmol/L) and no history of coronary heart disease or stroke were randomly assigned diet or diet plus 10-20 mg pravastatin daily. The primary endpoint was the first occurrence of coronary heart disease. Statistical analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00211705. FINDINGS: 3966 patients were randomly assigned to the diet group and 3866 to the diet plus pravastatin group. Mean follow-up was 5.3 years. At the end of study, 471 and 522 patients had withdrawn, died, or been lost to follow-up in the diet and diet plus pravastatin groups, respectively. Mean total cholesterol was reduced by 2.1% (from 6.27 mmol/L to 6.13 mmol/L) and 11.5% (from 6.27 mmol/L to 5.55 mmol/L) and mean LDL cholesterol by 3.2% (from 4.05 mmol/L to 3.90 mmol/L) and 18.0% (from 4.05 mmol/L to 3.31 mmol/L) in the diet and the diet plus pravastatin groups, respectively. Coronary heart disease was significantly lower in the diet plus pravastatin group than in the diet alone group (66 events vs 101 events; HR 0.67, 95% CI 0.49-0.91; p=0.01). There was no difference in the incidence of malignant neoplasms or other serious adverse events between the two groups. INTERPRETATION: Treatment with a low dose of pravastatin reduces the risk of coronary heart disease in Japan by much the same amount as higher doses have shown in Europe and the USA.

Relation of serum total cholesterol and other factors to risk of cerebral infarction in Japanese men with hypercholesterolemia.

BACKGROUND: Risk factors for cerebral infarction have not been well clarified, except for hypertension (HT), and few studies have examined the risk factors in the elderly. METHODS AND RESULTS: Clinical and behavioral risk factors for cerebral infarction were examined in 4,349 Japanese men aged 45-74 years with a serum total cholesterol (TC) concentration of 220 mg/dl or greater who participated in the Kyushu Lipid Intervention Study. A total of 81 men developed definite cerebral infarction in a 5-year follow-up period. The Cox proportional hazards model was used with serum TC at baseline and during the follow-up, serum high-density lipoprotein-cholesterol (HDL-C), HT, diabetes mellitus (DM), and other factors as covariates. Serum TC during the follow-up, not at baseline, was positively associated with cerebral infarction, showing a stronger association in the elderly (>or=65 years old) than in the middle-aged (<65 years old). Statin use was related to a moderate decrease in the risk of cerebral infarction when follow-up TC was not considered, but the decrease was almost nullified after adjustment for follow-up TC. A low concentration of serum HDL-C, diabetes mellitus, hypertension, and angina pectoris were each related to an increased risk. No clear association was observed for body mass index, smoking or alcohol use. CONCLUSIONS: Lowering cholesterol is important in the prevention of cerebral infarction in men with moderate hypercholesterolemia. A low concentration of HDL-C, DM, and HT are independent predictors of cerebral infarction.

Nifedipine retard was as effective as angiotensin converting enzyme inhibitors in preventing cardiac events in high-risk hypertensive patients with diabetes and coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) subgroup analysis.

We stratified findings from the Japan Multicenter Investigation for Cardiovascular Diseases-B according to whether or not the patients had diabetes and compared the incidence of cardiac events occurring over a 3-year period between treatment with nifedipine retard and angiotensin converting enzyme (ACE) inhibitor. The primary endpoint was the overall incidence of cardiac events (cardiac death or sudden death, myocardial infarction, hospitalization for angina pectoris or heart failure, serious arrhythmia, and coronary interventions), and the secondary endpoints were a composite of other events (cerebrovascular accidents, worsening of renal dysfunction, non-cardiovascular events, and total mortality). The results showed no significant difference in the incidence of the primary endpoint between the nifedipine group (n=199) and the ACE inhibitor group (n=173) in diabetic patients: 15.08% vs. 15.03%, relative risk 1.06, p=0.838. Also in nondiabetic patients, no significant difference was observed between the former (n=629) and the latter (n=649): 13.67% vs. 12.33%, relative risk 1.04, p=0.792. Similar results were obtained for the incidence of the secondary endpoints: in diabetic patients, 5.03% vs. 5.20%, relative risk 0.89, p=0.799; in nondiabetic patients, 2.70% vs. 2.47%, relative risk 1.07, p=0.842. Achieved blood pressure levels were 138/76 and 136/77 mmHg in the nifedipine group and 140/78 and 138/79 mmHg in the ACE inhibitor group in diabetic and nondiabetic patients, respectively. This study showed that nifedipine retard was as effective as ACE inhibitors in reducing the incidence of cardiac events in extremely high-risk hypertensive patients with complications of diabetes and coronary artery disease.

Relation of serum total cholesterol and other risk factors to risk of coronary events in middle-aged and elderly Japanese men with hypercholesterolemia: the Kyushu Lipid Intervention Study.

BACKGROUND: The role of serum total cholesterol (TC) in the development of coronary heart disease (CHD) may differ in different age groups. METHODS AND RESULTS: The relation of serum TC and other risk factors to CHD events was examined in middle-aged (<65 years) and elderly (> or =65 years) men separately in the Kyushu Lipid Intervention Study (KLIS). Subjects were 4,349 men aged 45-74 years with serum TC of 220 mg/dl or greater who had no history of myocardial infarction, coronary angioplasty, or stroke. There were 123 CHD events (ie, myocardial infarction, coronary bypass surgery, coronary angioplasty, cardiac death, and sudden death) in a 5-year follow-up period. The Cox proportional hazards model was used with baseline and follow-up serum TC, baseline high-density lipoprotein (HDL) cholesterol, hypertension, diabetes mellitus, and other factors as covariates. Serum TC concentration during the follow-up, not at baseline, was associated with an increased risk of CHD events, especially in elderly men. High concentrations of serum HDL cholesterol were associated with a modest, statistically nonsignificant decrease in the risk among middle-aged men. An increased risk of CHD events associated with diabetes mellitus was greater in middle-aged men. Hypertension and smoking were not measurably related to the risk in either middle-aged or elderly men. CONCLUSIONS: Both the serum TC concentration during follow-up and diabetes mellitus are important predictors of CHD events in Japanese men with moderately elevated serum TC.

Role of prehypertension in the development of coronary atherosclerosis in Japan.

BACKGROUND: Hypertension is an important risk factor of coronary heart disease. A new guidelines for hypertension prevention and management in The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in the United States recommended lifestyle modification or medical treatment for subjects with prehypertension. However, whether prehypertension increases the risk of coronary atherosclerosis in the Japanese population is still unknown. METHODS: A cross-sectional study in a clinical setting was conducted. The subjects were 705 patients (417 males and 288 females) aged 30 years and older who underwent a first-time coronary angiography for suspected or known coronary heart disease at 5 major cardiology departments in the Fukuoka metropolitan area between September 1996 and August 1997. RESULTS: Compared to subjects with normal blood pressure, those with prehypertension had an increased risk of coronary atherosclerosis even after adjusting for other factors. CONCLUSION: Prehypertension may be an important clinical entity which requires treatment in the Japanese population.

Comparison of nifedipine retard with angiotensin converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) randomized trial.

The Japan Multicenter Investigation for Cardiovascular Diseases-B was performed to investigate whether nifedipine retard treatment was associated with a significantly higher incidence of cardiac events than angiotensin converting enzyme inhibitor treatment in Japanese patients. The study used a prospective, randomized, open, blinded endpoint (PROBE) design. Patients were enrolled at 354 Japanese hospitals specializing in cardiovascular disease. The subjects were 1,650 outpatients aged under 75 years who had diagnoses of both hypertension and coronary artery disease. There were 828 patients subjected to intention-to-treat analysis in the nifedipine retard group and 822 patients in the angiotensin converting enzyme inhibitor group. The patients were randomized to 3 years of treatment with either nifedipine retard or angiotensin converting enzyme inhibitor. The primary endpoint was the overall incidence of cardiac events (cardiac death or sudden death, myocardial infarction, hospitalization for angina pectoris or heart failure, serious arrhythmia, and coronary interventions). The primary endpoint occurred in 116 patients (14.0%) from the nifedipine retard group and 106 patients (12.9%) from the angiotensin converting enzyme inhibitor group (relative risk, 1.05; 95% confidence interval, 0.81-1.37; p = 0.75). In the Kaplan-Meier estimates, there were no significant differences between the two groups (log-rank test: p = 0.86). The incidence of cardiac events and mortality did not differ between the nifedipine retard and angiotensin converting enzyme inhibitor therapies. Nifedipine retard seems to be as effective as angiotensin converting enzyme inhibitors in reducing the incidence of cardiac events and mortality.