Comparison between valsartan and amlodipine regarding cardiovascular morbidity and mortality in hypertensive patients with glucose intolerance: NAGOYA HEART Study

It has not been fully examined whether angiotensin II receptor blocker is superior to calcium channel blocker to reduce cardiovascular events in hypertensive patients with glucose intolerance. A prospective, open-labeled, randomized, controlled trial was conducted for Japanese hypertensive patients with type 2 diabetes mellitus or impaired glucose tolerance. A total of 1150 patients (women: 34%; mean age: 63 years; diabetes mellitus: 82%) were randomly assigned to receive either valsartan- or amlodipine-based antihypertensive treatment. Primary outcome was a composite of acute myocardial infarction, stroke, coronary revascularization, admission attributed to heart failure, or sudden cardiac death. Blood pressure was 145/82 and 144/81 mm Hg, and glycosylated hemoglobin was 7.0% and 6.9% at baseline in the valsartan group and the amlodipine group, respectively. Both of them were equally controlled between the 2 groups during the study. The median follow-up period was 3.2 years, and primary outcome had occurred in 54 patients in the valsartan group and 56 in the amlodipine group (hazard ratio: 0.97 [95% CI: 0.66-1.40]; P=0.85). Patients in the valsartan group had a significantly lower incidence of heart failure than in the amlodipine group (hazard ratio: 0.20 [95% CI: 0.06-0.69]; P=0.01). Other components and all-cause mortality were not significantly different between the 2 groups. Composite cardiovascular outcomes were comparable between the valsartan- and amlodipine-based treatments in Japanese hypertensive patients with glucose intolerance. Admission because of heart failure was significantly less in the valsartan group.     

Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension. Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators

The comparative antihypertensive efficacy and tolerability of the angiotensin II receptor blocker candesartan cilexetil and the calcium channel blocker amlodipine were evaluated in an 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration study in 251 adult patients (45% women, 16% black) with mild hypertension (stage 1). Following a 4- to 5-week placebo run-in period, patients with sitting diastolic blood pressure (BP) of 90 to 99 mm Hg received candesartan cilexetil 16 mg (n = 123) or amlodipine 5 mg (n = 128) once daily. After 4 weeks of double-blind treatment, patients were uptitrated to candesartan cilexetil 32 mg or amlodipine 10 mg once daily. There were no significant differences between the candesartan cilexetil and amlodipine regimens for reducing BP; mean systolic BP/diastolic BP reductions were -15.2/-10.2 mm Hg versus -15.4/-11.3 mm Hg, respectively (p = 0.88/0.25). Overall, 79% of patients on candesartan cilexetil and 87% of those on amlodipine were controlled (diastolic BP <90 mm Hg). A total of 3.3% of patients on candesartan cilexetil discontinued treatment, compared with 9.4% of patients on amlodipine, including 2.4% versus 4.7% for adverse events and 0% versus 1.6% for peripheral edema, respectively. Peripheral edema, the prespecified primary tolerability end point, occurred with significantly greater frequency in patients on amlodipine (22.1%; mild 8.7%, moderate 11.8%, severe 1.6%) versus patients on candesartan cilexetil (8.9%; mild 8.1%, moderate 0.8%) (p = 0.005). Candesartan cilexetil and amlodipine are both highly effective in controlling BP in patients with mild hypertension. Candesartan cilexetil offers a significant tolerability advantage with respect to less risk of developing peripheral edema.     

An angiotensin receptor blocker reduces the risk of congestive heart failure in elderly hypertensive patients with renal insufficiency.

We examined the efficacy of candesartan in reducing cardiovascular events in hypertensive patients with coexisting chronic kidney disease and cardiovascular diseases. This open-label, prospective study was conducted from 1999 to 2002, and 141 hypertensive subjects 60 to 75 years old with non-diabetic chronic renal insufficiency were enrolled. Before randomization of the patients, we examined their past medical history and found that 69 patients had been hospitalized due to myocardial infarction (MI) or stroke. Therefore, the patients were divided into 2 groups, one with previous histories of MI or stroke and the other with no previous history of Ml or stroke. The patients were randomized to receive either the angiotensin receptor blocker candesartan or conventional treatment. The mean duration of follow-up was 3.1 +/- 0.4 years. The primary outcome was a primary cardiovascular event (MI, stroke, or heart failure) verified by hospitalization. At the end of the study, in the patients with past history of cardiovascular diseases, blood pressure was reduced from 146.4 +/- 7.2/79.2 +/- 5.1 to 34.4 +/- 6.1/72.3 +/- 4.0 mmHg in the candesartan group and from 145.3 +/- 5.1/80.1 +/- 3.8 to 133.4 +/- 5.8/73.8 +/- 4.2 mmHg in the conventional treatment group. In the patients without past history of cardiovascular diseases, blood pressure was reduced from 143.2 +/- 4.3/78.3 +/- 4.8 to 133.8 +/- 5.3/ 73.1 +/- 3.8 mmHg in the candesartan group and from 143.9 +/- 6.8/78.1 +/- 4.2 to 132.6 +/- 5.4/74.5 +/- 4.4 mmHg in the conventional treatment group at the end of the study. There were no significant differences between the candesartan group and the conventional treatment group in the reduction of blood pressures. Among patients with a past history of cardiovascular disease, the serum creatinine concentration increased from 1.49 +/- 0.38 to 1.58 +/- 0.42 by candesartan treatment and from 1.50 +/- 0.32 to 1.89 +/- 0.37 by conventional treatment. On the other hand, in patients with no past history of cardiovascular disease, the serum creatinine concentration increased from 1.44 +/- 0.42 to 1.46 +/- 0.40 by candesartan treatment and from 1.46 +/- 0.44 to 1.51 +/- 0.38 by conventional treatment. Although, there was no significant difference in the incidence of cardiovascular events between the 2 groups with the candesartan-based and conventional-based antihypertensive treatment, in patients without cardiovascular events (12/36 vs. 7/34: these figures indicate events per total participated persons per 3 years; following figures are the same as this), treatment with candesartan reduced the incidence of cardiovascular events in the patients with past history of cardiovascular diseases (20/33 vs. 32/ 38). In particular, candesartan-based treatment reduced the incidence of congestive heart failure by 66.4% in these patients. In conclusion, this prospective, open-labeled randomized study suggests that 1) previous history of cardiovascular diseases is a major risk factor for cardiovascular events; and 2) candesartan is effective for reduction of cardiovascular events in hypertensive patients with coexisting chronic kidney disease and cardiovascular diseases, especially for prevention of congestive heart failure.     

Effects of up-titration of candesartan versus candesartan plus amlodipine on kidney function in type 2 diabetic patients with albuminuria

In the present study, we tested the hypothesis that up-titrating the dose of an angiotensin receptor blocker (ARB) is superior to combined treatment with an ARB and a calcium channel blocker for the same degree of blood pressure (BP) reduction, with respect to urinary albumin excretion in diabetic patients treated with a standard dose of the ARB. Hypertensive patients with type 2 diabetes mellitus and albuminuria (≥30?mg?g(-1) creatinine) were enroled in the study, and were either started on or switched to candesartan (8?mg per day) monotherapy. After a 12-week run-in period, baseline evaluations were performed and patients with BP ≥130/80?mm?Hg were randomly assigned to receive either candesartan (12?mg per day) or candesartan (8?mg per day) plus amlodipine (2.5?mg per day) for a further 12 weeks. The primary end-point was a reduction in urinary albumin levels. Although there was no significant difference in the BP reduction between the two groups, the reduction in urinary albumin was greater in the up-titrated than the combination therapy group (-40±14% vs -9±38%, respectively; P<0.0001). Thus, up-titration of candesartan more effectively reduces urinary albumin excretion than combined candesartan plus amlodipine in hypertensive patients with diabetes for the same degree of BP reduction.     

Effects of candesartan on cardiovascular outcomes in Japanese hypertensive patients.

In recent years, angiotensin receptor blockers (ARBs) have begun to represent a markedly larger percentage of the antihypertensive agents used in Japan. However, it remains uncertain whether ARBs are effective for protecting against hypertension-related organ damage in the general Japanese population. In the present report, we describe the results of a single blind, randomized, prospective study conducted in 1999-2002 and employing a total of 2,048 essential hypertensive subjects (sitting blood pressure 140-180/90-110 mmHg) aged 35-79 years. Subjects were randomly assigned to receive the ARB candesartan, 2 to 12 mg daily, or conventional antihypertensive drugs other than angiotensin converting enzyme inhibitors or ARBs. We used Cox regression analysis to compare the two regimens. The primary outcome was assessed by hospitalization due to stroke, myocardial infarction, and congestive heart failure. Blood pressure was reduced from 162.1/91.1 to 140.1/78.9 mmHg in the candesartan group and from 165.9/95.9 to 138.4/81.1 mmHg in the conventional therapy group. The main outcomes were as follows: there was a 39% reduction in hospitalization for stroke (5.8 vs. 9.4 cases: relative risk [RR]: 0.61; 95% confidence interval [CI]: 0.41-0.84; p<0.05) and a 57% reduction in hospitalization for myocardial infarction (RR: 0.44; CI: 0.21-0.84; p<0.05) with the candesartan-based treatment compared with the conventional treatment. In spite of a significant difference in the total incidence of both stroke and myocardial infarction, there was no significant reduction in the incidence of congestive heart failure (15% reduction: 4.3 vs. 5.0; RR: 0.85; CI: 0.57-1.26). Further analysis in stratifying the subjects with or without a past history of cardiovascular diseases including stroke and myocardial infarction revealed that candesartan reduced the incidence of stroke (61% reduction; RR: 0.39; CI: 0.15-0.43; p<0.01) and congestive heart failure (49% reduction; RR: 0.51; CI: 0.23-0.92; p<0.05) but not myocardial infarction (RR: 0.74; CI: 0.36-1.48; p=0.1) in hypertensive patients with a past history. However, conventional treatment was superior to candesartan-based treatment in reducing the incidence of stroke in the patients without a past history of cardiovascular diseases (66% reduction; RR: 0.34; CI: 0.16-0.69; p<0.05). This is the first demonstration that an ARB-based antihypertensive treatment was superior to the conventional treatment for reducing the risk of stroke and myocardial infarction in Japanese hypertensive patients, especially in the patients with a past history of cardiovascular diseases.     

The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial

BACKGROUND: The prognostic benefits of blood pressure lowering treatment in elderly hypertensive patients were established more than a decade ago, but are less clear in those with mildly to moderately elevated blood pressure. OBJECTIVE: To assess whether candesartan-based antihypertensive treatment in elderly patients with mildly to moderately elevated blood pressure confers a reduction in cardiovascular events, cognitive decline and dementia. DESIGN: Prospective, double-blind, randomized, parallel-group study conducted in 1997-2002. SETTING AND PARTICIPANTS: The study was of 4964 patients aged 70-89 years, with systolic blood pressure 160-179 mmHg, and/or diastolic blood pressure 90-99 mmHg, and a Mini Mental State Examination (MMSE) test score >or= 24. A total of 527 centres in 15 countries participated in the study. INTERVENTION: Patients were assigned randomly to receive the angiotensin receptor blocker candesartan or placebo, with open-label active antihypertensive therapy added as needed. As a consequence, active antihypertensive therapy was extensively used in the control group (84% of patients). Mean follow-up was 3.7 years. MAIN OUTCOME MEASURES: The primary outcome measure was major cardiovascular events, a composite of cardiovascular death, non-fatal stroke and non-fatal myocardial infarction. Secondary outcome measures included cardiovascular death, non-fatal and fatal stroke and myocardial infarction, cognitive function measured by the MMSE and dementia. RESULTS: Blood pressure fell by 21.7/10.8 mmHg in the candesartan group and by 18.5/9.2 mmHg in the control group. A first major cardiovascular event occurred in 242 candesartan patients and in 268 control patients; risk reduction with candesartan was 10.9% [95% confidence interval (CI), -6.0 to 25.1, P = 0.19]. Candesartan-based treatment reduced non-fatal stroke by 27.8% (95% CI, 1.3 to 47.2, P = 0.04), and all stroke by 23.6% (95% CI, -0.7 to 42.1, P = 0.056). There were no significant differences in myocardial infarction and cardiovascular mortality. Mean MMSE score fell from 28.5 to 28.0 in the candesartan group and from 28.5 to 27.9 in the control group (P = 0.20). The proportions of patients who had a significant cognitive decline or developed dementia were not different in the two treatment groups. CONCLUSIONS: In elderly hypertensive patients, a slightly more effective blood pressure reduction during candesartan-based therapy, compared with control therapy, was associated with a modest, statistically non-significant, reduction in major cardiovascular events and with a marked reduction in non-fatal stroke. Cognitive function was well maintained in both treatment groups in the presence of substantial blood pressure reductions. Both treatment regimens were generally well tolerated.     

Angiotensin II Receptor Blocker-based Therapy in Japanese Elderly, High-risk, Hypertensive Patients

BackgroundIt 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.MethodsThe 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.ResultsDuring 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).ConclusionThe 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.     

Efficacy of candesartan cilexetil alone or in combination with amlodipine and hydrochlorothiazide in moderate-to-severe hypertension. UK and Israel Candesartan Investigators

This multicenter study evaluated the efficacy of candesartan cilexetil, an angiotensin II type 1 receptor antagonist, used alone or in combination with amlodipine or in combination with amlodipine and hydrochlorothiazide in the treatment of patients with moderate-to-severe essential hypertension. After a 2-week, single-blind, placebo run-in period, patients entered a 12-week, open-label, dose-titration period. The candesartan cilexetil dose was increased from 8 to 16 mg once daily; amlodipine (5 mg once daily), hydrochlorothiazide (25 mg once daily), and additional medication were also added sequentially if necessary. Patients then entered a final 4-week, parallel-group, double-blind, randomized, placebo-controlled withdrawal period of candesartan alone. A total of 216 patients were recruited. After a 2-week run-in period on placebo tablets, mean sitting blood pressure (BP) was 175/108 mm Hg. At the end of the 12-week dose-titration/maintenance period, mean sitting BP fell to 141/88 mm Hg. In 67 patients who were randomized to placebo and had their candesartan withdrawn, there was a highly significant increase in mean systolic/diastolic BP (13/6 mm Hg) compared with those patients who continued with candesartan (ANCOVA, P:<0.0001). In conclusion, candesartan cilexetil is an effective BP-lowering drug when used alone or in combination with amlodipine or amlodipine plus hydrochlorothiazide in the treatment of moderate-to-severe essential hypertension. The drug was well tolerated throughout the investigation period.     

Effects of candesartan and lisinopril on the fibrinolytic system in hypertensive patients

The effects of the angiotensin II receptor blocker candesartan and the angiotensin-converting enzyme inhibitor lisinopril on the fibrinolytic system were investigated in a double-blinded, prospective, randomized study. Seventy-seven hypertensive patients taking candesartan (n=41) and lisinopril (n=36) with a systolic blood pressure >130 mm Hg and/or a diastolic blood pressure >80 mm Hg obtained by 24-hour ambulatory blood pressure measurement were included in the study. Blood pressure, plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the molar ratio of PAI-1/tPA were determined before treatment and 6 weeks later. Blood pressure decreased in both groups (candesartan, 155/85 mm Hg to 140/84 mm Hg; P<.05; lisinopril, 152/85 mm Hg to 138/83 mm Hg; P<.05). The fibrinolytic balance was significantly different between treatment groups (molar ratio of PAI-1/tPA: candesartan, 3.66 [2.2;] lisinopril, 5.44 [2.6;] P<.05). In contrast to lisinopril, the balance between coagulation and fibrinolytic activity shifted toward fibrinolysis during candesartan treatment.     

Cardiovascular effects of combination of perindopril, candesartan, and amlodipine in hypertensive rats

The combination therapy with ACE inhibitors, angiotensin II type 1 (AT(1)) receptor antagonists, or calcium channel antagonists may exert more beneficial effects on cardiovascular diseases than monotherapy. Perindopril, candesartan cilexetil, or amlodipine alone or the combination of low doses of each agent was administered orally to stroke-prone spontaneously hypertensive rats (SHRSP) for 4 weeks to compare the hypotensive or cardiovascular effects. Although perindopril (2 mg/kg), candesartan cilexetil (2 mg/kg), or amlodipine (3 mg/kg) alone caused comparable hypotensive effects in SHRSP, monotherapy with perindopril or candesartan decreased left ventricular (LV) weight; mRNA levels for atrial natriuretic factor, skeletal alpha-actin, and collagen types I and III; and aortic weight and platelet-derived growth factor-beta receptor tyrosine phosphorylation to a greater extent than monotherapy with amlodipine. Although monotherapy with a low dose (0.2 mg/kg) of perindopril or candesartan cilexetil did not significantly reduce the LV mRNA levels and aortic platelet-derived growth factor-beta receptor phosphorylation of the SHRSP, combination therapy at such a low dose normalized these parameters more potently than the use of amlodipine (3 mg/kg) alone. Although perindopril or candesartan cilexetil alone at 0.05 mg/kg did not decrease the blood pressure of the SHRSP, such a low dose of combination therapy decreased LV weight and atrial natriuretic factor mRNA levels of the SHRSP to a greater extent than amlodipine alone or amlodipine combined with perindopril or candesartan cilexetil. Our results provide evidence that suggests the combination of an ACE inhibitor and an AT(1) receptor antagonist may be more effective in the treatment of cardiac and vascular diseases than the combination of a calcium channel blocker with an ACE inhibitor or an AT(1) receptor antagonist or monotherapy with each agent.     

初始低剂量氨氯地平加替米沙坦或复方阿米洛利联合治疗对高血压患者血压控制率影响的阶段报告

目的 探讨以氨氯地平为基础的联合治疗方案,对高血压患者血压达标及对心血管事件的影响.方法 2007年10月至2008年10月,在全国180家医疗机构,入选50～79岁伴心血管病危险因素的高血压患者13 542例.采用多中心随机开放对照盲终点评估的临床试验方法,患者随机分为低剂量氨氯地平(商品名:安内真2.5 mg/d,苏州东瑞制药有限公司产品)+复方阿米洛利(商品名:安利亚半片/d,苏州东瑞制药有限公司产品)组或氨氯地平+替米沙坦(商品名:安内强40 mg/d,苏州东瑞制药有限公司产品)组,计划治疗随访4年.主要研究终点是心血管病复合事件.结果氨氯地平+复方阿米洛利组(n=6776)和氨氯地平+替米沙坦组(n=6766)患者基线临床特征相似:平均年龄均为(61.5 ±7.7)岁,脑血管病史占19%、冠心病病史占12%,糖尿病占18%,血脂异常占 42%,平均血压水平为157/93 mm Hg(1 mm Hg=0.133 kPa).治疗第8周氨氯地平+复方阿米洛利组与氨氯地平+替米沙坦组血压分别降至(133.0±11.0)/(81.0±7.6)mm Hg与(132.9±11.6)/(80.6± 7.9)mm Hg;血压控制率分别达72.1%和72.6%.结论早期资料分析提示本研究患者多为高危人群,随机分配良好;以氨氯地平为基础的联合降压治疗血压控制率较高.     

Candesartan-based therapy and risk of cancer in patients with systemic hypertension (Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease [HIJ-CREATE] substudy)

The aim of the present study was to clarify the influence of candesartan-based therapy on subsequent carcinogenesis and cancer death in patients with coronary artery disease with hypertension in a substudy of a multicenter, prospective, randomized, controlled trial. That trial compared the effects of candesartan-based therapy with those of non-angiotensin receptor blocker (ARB)-based standard therapy on major adverse cardiovascular events. Hypertensive patients with coronary artery disease were randomly assigned to receive either candesartan-based (n = 1,024) or non-ARB-based pharmacotherapy, including angiotensin-converting enzyme inhibitors (n = 1,025). During a median follow-up of 4.2 years, 1,606 adverse events (798 in the candesartan group and 808 in the non-ARB standard group) were reported. Among them, new cancer occurred in 5.37% of subjects in the candesartan group and 5.66% of subjects in the standard therapy group (hazard ratio 0.95, 95% confidence interval 0.65 to 1.38). Cancer deaths occurred in 1.66% in the candesartan group and 2.44% in the standard therapy group, respectively (hazard ratio 0.74, 95% confidence interval 0.39 to 1.39). Kaplan-Meier estimates of survival without new cancer and cancer deaths demonstrated that candesartan-based therapy does not accelerate the occurrence of new cancer (log-rank, p = 0.84) or cancer death (p = 0.39) compared to standard therapy. Advanced age and male gender were independently and significantly correlated with the subsequent incidence of cancer. In conclusion, the results of the present study suggest that candesartan-based therapy is not associated with either carcinogenesis or cancer death compared to non-ARB standard therapy.     

Effects of low-dose angiotensin II receptor blocker candesartan on cardiovascular events in patients with coronary artery disease

Objectives

The purpose of this study was to investigate the effects of angiotensin II receptor blockers on the prevention of cardiovascular events in patients with coronary artery disease (CAD).

Background

Angiotensin II may contribute to the pathogenesis of CAD. Long-term clinical trials have shown that blockade of the renin-angiotensin system can reduce cardiovascular events in patients with acute myocardial infarction complicated by heart failure.

Methods

Patients with a history of coronary intervention and no significant coronary stenosis on follow-up angiography 6 months after intervention were randomly assigned into a candesartan group (n = 203; baseline treatment plus candesartan 4 mg/d) or a control group (n = 203; baseline treatment alone). The primary end point was a composite of revascularization, nonfatal myocardial infarction, or cardiovascular death. The secondary end point was hospitalization for cardiovascular causes.

Results

There were no changes in blood pressure and in other coronary risk factors in either group during a mean follow-up of 24 months. Primary end point risk was significantly lower in the candesartan group (n = 12) than in control group patients (n = 25) (P = .03). Candesartan treatment reduced primary end point risk (5.9% vs 12.3% for control subjects; relative risk, 0.47; 95% CI, 0.24 to 0.93). The incidence of all events including secondary end points and noncardiovascular death was significantly lower in the candesartan group than in control group patients (23 vs 40 cases) (P = .02).

Conclusions

Relatively low-dose candesartan, which did not alter blood pressure levels, reduces cardiovascular risk in high-risk patients with CAD.     

Rationale and design of the KYOTO HEART study: effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high risk of cardiovascular events

It remains to be determined whether the evidence in Western countries for blockade of the renin-angiotensin System in cardiovascular diseases could be directly applied to East Asian races including the Japanese population as a long-term strategy. The KYOTO HEART Study (KHS) is designed to investigate the add-on effect of valsartan versus conventional anti-hypertensive treatment on cardiovascular morbidity and mortality in Japanese hypertensive patients with uncontrolled blood pressure and with high cardiovascular risk. Over 3000 high-risk Japanese patients with uncontrolled hypertension were randomised to receive either additional treatment with valsartan or conventional non-angiotensin receptor blocker therapies, and the follow-up period will be at least 3 years. The primary end point is a composite of defined cardio- or cerebro-vascular events. Secondary end points include all causes of mortality, worsening of cardiac function, new onset or worsening of arrhythmias or diabetes mellitus. The KHS will provide new evidence for the management of blood pressure in hypertensive patients with high risk.     

Combination therapy for hypertension in the elderly: a sub-analysis of the Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) Trial

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial demonstrated that the calcium-channel blocker benidipine-based combination therapies with an angiotensin-receptor blocker (ARB), a β-blocker, or a thiazide diuretic (thiazide) were similarly effective in preventing cardiovascular events and achieving the target blood pressure (BP; <140/90?mm?Hg). We further evaluated the efficacy and safety of these combination therapies in older (65 years) and younger (<65 years) hypertensive patients. In this sub-analysis of the COPE trial 3293 patients (153365 years old and 1760 <65 years old) were randomly assigned to receive benidipine-based therapy with an ARB, a β-blocker or a thiazide. In each group, the average BP did not differ among the three treatment groups. The incidence of the primary cardiovascular composite end point in the older group was higher than in the younger group (12.7 vs. 8.3 per 1000 person-years, P=0.023). The primary composite cardiovascular end point, achievement (%) of target BP, and cardiovascular hard composite end points were similar among the three treatment groups. However, the hazard ratios and 95% confidence intervals in older patients were 2.74 (1.08-6.96; β-blocker vs. thiazide, P=0.022) for fatal and non-fatal stroke, and 2.47 (1.03-5.91; β-blocker vs. ARB, P=0.043) for new-onset diabetes. Thus, benidipine combined with an ARB, a β-blocker, or a thiazide was similarly effective in preventing cardiovascular events and achieving the target BP in both older and younger hypertensive patients. Further studies will be necessary to evaluate the usefulness of benidipine combined with a β-blocker in terms of the incidence of stroke and new-onset diabetes in older patients.     

Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis in the Elderly (SCOPE)

OBJECTIVES: The aim of this study was to test the hypothesis that the angiotensin II type 1 receptor blocker (ARB) candesartan can reduce the risk of stroke in elderly patients with isolated systolic hypertension (ISH). BACKGROUND: Isolated systolic hypertension is the predominant form of hypertension in the elderly, and stroke is the most common cardiovascular (CV) complication. METHODS: In the Study on Cognition and Prognosis in the Elderly (SCOPE), 4,964 patients age 70 to 89 years were randomly assigned to double-blind candesartan or placebo with open-label antihypertensive therapy (mostly thiazide diuretics) added as needed to control blood pressure. Of the 4,964 patients, 1,518 had ISH (systolic blood pressure >160 mm Hg and diastolic blood pressure <90 mm Hg). The present study is a predefined subgroup analysis of outcome results in the ISH patients. RESULTS: Of the ISH patients, 754 were randomized to the candesartan group and 764 to the control group. Over the study period, blood pressure was reduced by 22/6 mm Hg in the candesartan group and by 20/5 mm Hg in the control group (difference between treatments 2/1 mm Hg; p = 0.101 and 0.064). A total of 20 fatal/non-fatal strokes occurred in the candesartan group (7.2/1,000 patient-years) and 35 in the control group (12.5/1,000 patient-years); relative risk (RR) was 0.58 (95% confidence interval 0.33 to 1.00), that is, a RR reduction of 42% (p = 0.050 unadjusted, p = 0.049 adjusted for baseline risk). There were no marked or statistically significant differences between the treatment groups in other CV end points or all-cause mortality. CONCLUSIONS: In elderly patients with ISH, antihypertensive treatment based on the ARB candesartan resulted in a significant 42% RR reduction in stroke in comparison with other antihypertensive treatment, despite little difference in blood pressure reduction.     

Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: the VALUE trial

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and increases cardiovascular risk in hypertensive patients. Therefore, in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) a prespecified objective was to compare the effects of valsartan and amlodipine on new-onset AF. METHODS: A total of 15 245 hypertensive patients at high cardiovascular risk received valsartan 80-160 mg/day or amlodipine 5-10 mg/day combined with additional antihypertensive agents. Electrocardiograms were obtained every year and analyzed centrally for evidence of left ventricular hypertrophy and new-onset AF. RESULTS: At baseline, AF was diagnosed in 2.6% of 7649 valsartan recipients and 2.6% of 7596 amlodipine recipients. During antihypertensive treatment the incidence of at least one documented occurrence of new-onset AF was 3.67% with valsartan and 4.34% with amlodipine [unadjusted hazard ratio 0.843, [95% confidence interval (CI): 0.713, 0.997], P = 0.0455]. The incidence of persistent AF was 1.35% with valsartan and 1.97% with amlodipine [unadjusted hazard ratio 0.683 (95% CI: 0.525, 0.889), P = 0.0046]. CONCLUSIONS: Valsartan-based treatment reduced the development of new-onset AF, particularly sustained AF in hypertensive patients, compared with amlodipine-based therapy. These findings suggest that angiotensin II receptor blockers may result in greater benefits than calcium antagonists in hypertensive patients at risk of new-onset AF.     

Efficacy of candesartan cilexetil as add-on therapy in hypertensive patients uncontrolled on background therapy: a clinical experience trial

A large-scale, 8-week, open-label, clinical experience trial evaluated the efficacy of the angiotensin II receptor (AT₁ subtype) blocker candesartan cilexetil (16 to 32 mg once daily) either alone or as add-on therapy in 6465 hypertensive patients. The study population was 52% female and 16% African American with a mean age of 58 years. It included 5446 patients who had essential hypertension (HBP) and 1014 patients who had isolated systolic hypertension (ISH). These patients had either untreated or uncontrolled hypertension (systolic blood pressure [SBP] 140 to 179 mm Hg or diastolic blood pressure [DBP] 90 to 109 mm Hg inclusive at baseline) despite a variety of antihypertensive medications including diuretics, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, and α- or β-blockers, either singly or in combination. The mean baseline blood pressure for the HBP group was 156/97 mm Hg. Candesartan cilexetil as monotherapy (in 51% of HBP patients) reduced mean SBP/DBP by 18.7/13.1 mm Hg. As add-on therapy (in 49% of HBP patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.8/11.3 mm Hg), calcium antagonists (16.6/11.2 mm Hg), β-blockers (16.5/10.4 mm Hg), ACE inhibitors (15.3/10.0 mm Hg), α-blockers (16.4/10.4 mm Hg). The mean baseline blood pressure for the ISH group was 158/81 mm Hg. Candesartan cilexetil, as monotherapy (in 34% of ISH patients), reduced SBP/DBP by 17.0/4.4 mm Hg. As add-on therapy (in 66% of ISH patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.4/5.1 mm Hg), calcium antagonists (15.6/3.6 mm Hg), β-blockers (14.0/4.8 mm Hg), ACE inhibitors (13.4/4.3 mm Hg), and α-blockers (11.6/4.5 mm Hg). The further blood pressure lowering effects of candesartan cilexetil as add-on therapy were seen regardless of age, sex, and race. Overall, 6.8% of the 6465 patients withdrew because of adverse events, most commonly headache (6.3%) and dizziness (5.0%). Orthostatic hypotension was infrequent; 0.2% with candesartan cilexetil alone, and 0.8% with candesartan cilexetil as add-on therapy. Thus, candesartan cilexetil either alone or as add-on therapy was highly effective for the control of systolic or diastolic hypertension regardless of demographic background when used in typical clinical practice settings.     

Effects of valsartan and amlodipine on home blood pressure and cardiovascular events in Japanese hypertensive patients: a subanalysis of the VART

The Valsartan Amlodipine Randomized Trial (VART) was performed to compare the beneficial effects of valsartan and amlodipine on cardiovascular events in Japanese hypertensive patients. In this subanalysis of the VART, we assessed the relationship between home blood pressure (HBP) levels and cardiovascular events in the enrolled patients. We enrolled 1021 patients with mild-to-moderate hypertension in the VART. The participants were allocated randomly to either the valsartan group or the amlodipine group. The primary end point was a composite of all-cause death, sudden death, cerebrovascular events, cardiac events, vascular events and renal events. A total of 621 patients (valsartan group: 305 and amlodipine group: 316) completed the measurements of HBP (morning and evening) throughout the trial. Both the agents evenly and significantly lowered morning HBP and evening HBP throughout the trial. There was no significant difference in the primary end point between the two groups. However, we observed significant decreases in the left ventricular mass index and urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group. There were no significant differences in HBP levels and the main outcome of the cardiovascular events between the valsartan and amlodipine groups. However, in the valsartan group, significant improvements in left ventricular hypertrophy and microalbuminuria were observed.     

The Study on COgnition and Prognosis in the Elderly (SCOPE) - major CV events and stroke in subgroups of patients

The Study on COgnition and Prognosis in the Elderly (SCOPE) assessed the effect of candesartan on cardiovascular outcomes in elderly patients with mild to moderate hypertension. Patients were randomized to candesartan 8-16 mg daily (n = 2477) or placebo (n =2460). Due to extensive add-on therapy, blood pressure reduction was only about 3/2 mmHg greater in the candesartan group than in the control group. Nevertheless, non-fatal stroke was reduced by 28% (p = 0.04) in the candesartan group compared to the control group, and there was a non-significant 11% reduction in major cardiovascular events (p = 0.19). This report provides results in pre-specified subgroups of patients (age, gender, diabetes, history of stroke, smoking and cardiovascular risk at randomization). Reductions in major cardiovascular events and stroke with candesartan-based therapy were indicated in all subgroups. A significant interaction between treatment and subgroups was found for one pair of subgroups only; the reduction in major cardiovascular events with candesartan was greater in patients with a previous stroke (64% reduction, p = 0.004) than in those without (5% reduction, p > 0.20). In conclusion, this analysis indicated consistent favourable effects of candesartan-based therapy on major cardiovascular events and stroke across the different subgroups of patients. However, the benefit was particularly pronounced in patients who entered the study with a previous stroke.