Akira Fujimoto

ARB candesartan and CCB amlodipine in hypertensive patients: the CASE‑J trial

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was a comparative study of the angiotensin II receptor blocker (ARB), candesartan, and a calcium channel blocker (CCB), amlodipine, regarding the incidence of cardiovascular events in high-risk Japanese hypertensive patients. The study design was a prospective, multicenter, randomized, open-label, active-controlled, two-arm, parallel-group comparison study with a response-dependent dose titration and blinded assessment of the end point. The CASE-J trial enrolled 4728 patients, with a mean age of 63.8 years and a mean BMI of 24.6 kg/m2, who were randomly assigned to either candesartan- or amlodipine-based treatment regimens. Blood pressure was well controlled to the level of less than 140/80 mmHg in both of the treatment regimens. During 3.2 years of follow-up, primary cardiovascular events occurred in 134 patients in each of the two treatment-based regimens, resulting in no significant difference in the incidence of cardiovascular events between them (hazard ratio: 1.01; 95% confidence interval: 0.79–1.28; p = 0.969). In 404 patients with left ventricular hypertrophy, a significantly larger decrease in left ventricular mass index 3 years after enrollment was observed in candesartan-based (n = 205) than amlodipine-based (n = 199) regimens (-22.9 vs -13.4 g/m2, respectively; p = 0.023). Furthermore, new-onset diabetes occurred in fewer patients taking candesartan than in those taking amlodipine, resulting in a 36% relative risk reduction (p = 0.030). The CASE-J trial demonstrated that both an ARB, candesartan, and a CCB, amlodipine, equally suppressed the incidence of cardiovascular events. The ARB may confer more beneficial effects to hypertensive patients with left ventricular hypertrophy or for those at-risk of diabetes than CCB.

Is Pulse Pressure a Predictor of New-Onset Diabetes in High-Risk Hypertensive Patients? A subanalysis of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial

OBJECTIVE Hypertensive patients have an increased risk of developing diabetes. Accumulating evidence suggests a close relation between metabolic disturbance and increased arterial stiffness. Here, we examined the association between pulse pressure and the risk of new-onset diabetes in high-risk Japanese hypertensive patients. RESEARCH DESIGN AND METHODS The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial examined the effects of candesartan and amlodipine on the incidence of cardiovascular events in 4,728 high-risk Japanese hypertensive patients. In the present study, we analyzed the relationship between pulse pressure at baseline and new-onset diabetes in 2,685 patients without diabetes at baseline (male 1,471; mean age 63.7 years; mean BMI 24.8 kg/m2) as a subanalysis of the CASE-J trial. RESULTS During 3.3 ± 0.8 years of follow-up, 97 patients (3.6%) developed diabetes. In multiple Cox regression analysis, pulse pressure was an independent predictor for new-onset diabetes (hazard ratio [HR] per 1 SD increase 1.44 [95% CI 1.15–1.79]) as were male sex, BMI, and additional use of diuretics, whereas age and heart rate were not. Plots of HRs for new-onset diabetes considering both systolic and diastolic blood pressure (DBP) revealed that a higher pulse pressure with a lower DBP, indicating that the increased pulse pressure was largely due to increased arterial stiffness, was strongly associated with the risk of new-onset diabetes. CONCLUSIONS Pulse pressure is an independent predictor of new-onset diabetes in high-risk Japanese hypertensive patients. Increased arterial stiffness may be involved in the development of diabetes.

Role of diabetes and obesity in outcomes of the candesartan antihypertensive survival evaluation in Japan (CASE-J) trial

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial assessed cardiovascular outcomes in high-risk hypertensive patients receiving either candesartan or amlodipine. The aim of this study was to examine the role of pre-existing diabetes or obesity on these outcomes as a sub-analysis of the trial. We examined the influence of pre-existing diabetes on cardiovascular morbidity and mortality using a multivariate Cox regression model. The cardiovascular morbidity and mortality of candesartan and amlodipine were compared between subgroups with or without pre-existing diabetes or by body mass index (BMI) category, and new-onset diabetes was compared by BMI category. Pre-existing diabetes greatly increased the cardiovascular mortality and morbidity, regardless of the allocated drugs. Furthermore, all-cause mortality was significantly higher with amlodipine than with candesartan among patients with BMI ⩾27.5 kg m−2 (adjusted hazard ratio (HR)=0.32; range=0.13–0.75; P=0.009). New-onset diabetes occurred significantly less frequently with candesartan than with amlodipine, with an adjusted HR of 0.66 (P=0.043). Furthermore, the increase in new-onset diabetes was dependent on BMI among patients receiving amlodipine, whereas no such dependency was observed for candesartan (interaction P=0.016). In conclusion, preexisting diabetes increased the risk of experiencing a cardiovascular event among high-risk Japanese hypertensive patients. Candesartan treatment may suppress all-cause death and reduce the incidence of new-onset diabetes in patients with obesity.

Clinical significance of left ventricular hypertrophy and changes in left ventricular mass in high-risk hypertensive patients: a subanalysis of the Candesartan Antihypertensive Survival Evaluation in Japan trial.

Objective To evaluate the associations of left ventricular hypertrophy (LVH) and its changes with the incidence of cardiovascular events and the time-course of serum creatinine (sCr) levels in high-risk hypertensive patients who participated in the Candesartan Antihypertensive Survival Evaluation in Japan trial. Methods We analysed data of 1447 patients who underwent echocardiography at enrolment as an observational study irrespective of allocation. According to the left ventricular mass index (LVMI) at the baseline, they were divided into two groups (without LVH, LVMI < 125 g/m2; n = 607 and with LVH, LVMI ≥ 125 g/m2; n = 840) and four categories on the basis of LVMI at the baseline and 1 year: absence of LVH (n = 285), development of LVH (n = 97), regression of LVH (n = 155), and persistence of LVH (n = 418). Results During 3.3 ± 0.8 years, cardiovascular events occurred in 20 (3.3%) patients without LVH and in 67 (8.0%) patients with LVH (hazard ratio: 2.58; 95% confidence interval: 1.54–4.33; P < 0.001). Among the four categories, absence of LVH was associated with lower risk of cardiovascular events than persistence of LVH (hazard ratio: 0.30; 95% confidence interval: 0.13–0.71; P = 0.006), but development or regression of LVH was not. Only in persistence of LVH did the sCr level significantly increase over time (baseline vs. 3 years; 0.92 vs. 1.02 mg/dl, P < 0.001). Adjusted sCr level of absence and regression of LVH at 3 years was significantly lower than that of persistence of LVH (0.89 and 0.90 vs. 0.97 mg/dl, P < 0.001, P = 0.002, respectively), but that of development of LVH was not. Conclusion Protection against LVH is associated with a reduced risk of cardiovascular events and may be related to the preservation of renal function in high-risk hypertensive patients.

Relationship between the achieved blood pressure and the incidence of cardiovascular events in Japanese hypertensive patients with complications: a sub-analysis of the CASE-J trial

Various guidelines for hypertension specify that the target blood pressure (BP) should be below 140/90 mm Hg and that strict control is recommended for patients with cardiovascular risk factors. We examined the relationship between the achieved BP and the incidence of cardiovascular events in hypertensive patients with complications as a sub-analysis of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial. A total of 4703 patients were evaluated for efficacy in the CASE-J trial. In this sub-analysis, 4553 patients had at least one follow-up visit without any cardiovascular events. We examined the relationship between the achieved BP and cardiovascular events in hypertensive patients with type II diabetes mellitus (DM), chronic kidney disease (CKD) or left ventricular hypertrophy (LVH) at baseline. Possible baseline confounders were adjusted by using the multiple Cox regression model. A higher achieved BP was associated with an increased risk of cardiovascular events in hypertensive patients with complications (DM, CKD or LVH). In patients with LVH, who achieved systolic/diastolic BP (SBP/DBP) <130/75–79 mm Hg, the risk of cardiovascular events was reduced to the same level of SBP/DBP <130/75–79 mm Hg in those without LVH. However, the risks of cardiovascular events in patients with DM or CKD, who achieved SBP/DBP <130/75–79 mm Hg, were still significantly higher than in those without DM or CKD. In conclusion, this study extended the significance of BP control in hypertensive patients especially with complications. Further investigation in a large-scale clinical trial is needed to determine the optimal target BP for LVH patients.

Effects of renin-angiotensin system blockades on cardiovascular outcomes in patients with diabetes mellitus: a systematic review and meta-analysis

AIM To determine whether renin-angiotensin system (RAS) blockade is beneficial for cardiovascular outcomes in patients with diabetes mellitus (DM) using meta-analysis. METHODS The MEDLINE and Cochrane library databases were searched for randomized controlled trials published up to June 2010. We also reviewed reference lists from identified trials and review articles to identify any other relevant studies, and the ClinicalTrials.gov website to identify randomized controlled trials that were registered as completed but not yet published. A random-effects model was used to combine the estimates for risk ratios (RR). RESULTS Eligible studies were randomized controlled trials (including post hoc analyses) assessing the effects of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on cardiovascular events compared to controls in patients with DM. Nineteen clinical trials with 41,042 patients and 6039 cardiovascular events were identified. RAS blockade significantly reduced the risk of major cardiovascular events (RR 0.92, 95% confidence interval [CI] 0.84-1.00, I(2) statistic 53%) and myocardial infarction (RR 0.82, 95% CI 0.72-0.94, I(2)=55%). There were trends towards fewer strokes and lower all-cause mortality but these were not statistically significant. CONCLUSIONS The available evidence shows that treatment with RAS blockade can routinely be considered for diabetic patients to reduce major cardiovascular events.

Long-term effects of candesartan and amlodipine on cardiovascular mortality and morbidity in Japanese high-risk hypertensive patients: rationale, design, and characteristics of candesartan antihypertensive survival evaluation in Japan extension (CASE-J Ex).

Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the effects of the angiotensin II receptor blocker (ARB) candesartan and the calcium channel blocker (CCB) amlodipine on the incidence of cardiovascular (CV) events in Japanese high-risk hypertensive patients. After 3.2years follow-up, CV events rate was 17.6-17.7 per 1000 person-years in each group, which was much lower than we expected. Since it has not been known whether the same efficacy of two drugs is sustained beyond the current trial, a longer follow-up period will be needed. The Steering Committee of CASE-J trial decided to extend the trial for 3years as an observational study (CASE-J Ex). In CASE-J Ex, the primary end point is a composite of CV events and the secondary endpoints are all-cause death and new-onset diabetes. After Committees decision, 245 doctors agreed to participate in CASE-J Ex and 2236 patients (1141 with candesartan-based regimens and 1095 with amlodipine-based regimens) were re-enrolled. The baseline characteristics of CASE-J Ex participants were similar to CASE-J participants and still balanced well between candesartan and amlodipine. Recently, the interest of antihypertensive treatment has focused to differentiation of the effects of antihypertensive agents on the incidence of CV events as well as blood pressure lowering effect. CASE-J Ex will clarify the long-term effects of ARB and CCB on CV mortality and morbidity. Additionally, because the number of diabetic patients is increased, the evidences from CASE-J Ex will be valuable.

Long-term effects of candesartan and amlodipine on cardiovascular morbidity and mortality in Japanese high-risk hypertensive patients: the Candesartan Antihypertensive Survival Evaluation in Japan Extension Study (CASE-J Ex)

In the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, comparable efficacy was noted between candesartan and amlodipine in the incidence of cardiovascular (CV) morbidity and mortality during 3.2 years of follow up. Candesartan suppressed new-onset diabetes more effectively than amlodipine. In this observational study, we investigated whether or not the efficacy of the two drugs is sustainable for another 3 years beyond the experimental period of the CASE-J trial. Of the 4728 high-risk hypertensive patients initially enrolled in the CASE-J trial, 2232 agreed to further follow up. The primary endpoint was a composite of CV morbidity and mortality. The distribution of demographic characteristics for the 2232 patients in the CASE-J extension was similar to that in the initial 4703 patients in the CASE-J trial. Both drugs controlled blood pressure well over the relatively long period of time. The incidence of CV events was 15.5/1000 patient years in the candesartan group and 16.3/1000 patient years in the amlodipine group (Hazard ratio (HR)=0.95, 95% confidence interval (CI)=0.77–1.18; P=0.650). The incidence of new-onset diabetes was significantly lower in the candesartan group (9.5/1000 patient years) than in the amlodipine group (13.3/1000 patient years), representing a 29% risk reduction for new-onset diabetes (HR=0.71, 95% CI=0.51–1.00, P=0.0495). In conclusion, candesartan and amlodipine showed comparable efficacy against CV events beyond the experimental period of the CASE-J trial in high-risk hypertensive patients. In addition, the effects of candesartan on new-onset diabetes observed during the CASE-J trial were sustained in the CASE-J extension. The CASE-J extension, which covered a 3-year extension of follow-up from the original trial, corroborated the results of the CASE-J trial.

Fixed-dose combination therapy of candesartan cilexetil and amlodipine besilate for the treatment of hypertension in Japan

Hypertension is one of the most prevalent disorders and the largest contributor to global mortality. The aim of antihypertensive treatment is to reduce the risk of cardiovascular morbidity and mortality by lowering increased blood pressure (BP) to target levels. Despite progress in antihypertensive drug development, BP control remains suboptimal. Accumulating evidence has shown that fixed-dose combination therapy is better in terms of BP control than increasing the dose of one drug or its corresponding combination. Fixed-dose combinations of an angiotensin receptor blocker, candesartan cilexetil, and a calcium channel blocker, amlodipine besilate (candesartan/amlodipine 8/2.5 or 8/5 mg), were approved in Japan for once-daily oral administration in hypertensive patients. Recent data showed that a fixed-dose combination of candesartan and amlodipine lowered BP safely and rapidly, providing a potential opportunity to improve the rate of BP control. Further studies are needed to determine whether this will lead to improvements in long-term clinical outcomes.

841 OPTIMAL BLOOD PRESSURE TO PREVENT CARDIOVASCULAR EVENTS IN THE ELDERLY HIGH-RISK HYPERTENSIVE PATIENTS: SUBANALYSIS OF THE CASE-J EX STUDY

Objective: Various treatment guidelines for hypertension recommend that blood pressure (BP) of hypertensive patients should be maintained below 140/90 mmHg. The CASE-J trial and its extension (CASE-J Ex) compared the efficts of ARB candesartan with those of CCB amlodipine on the incidence of cardiovascular events in the high-risk hypertensive patients. The present study was aimed to examine the optimal BP in the elderly high-risk hypertensive patients for the prevention of cardiovascular events as a subanalysis of the CASE-J Ex study. Method: In the CASE-J Ex study, 4,728 high-risk hypertensive patients were randomly assigned to receive either Candesartan- or Amlodipine-based treatment. We examined the relationship between the incidence of cardiovascular events and the achieved BP in each age category (<65; n = 2,176, 65- < 75; n = 1,658, ≥75; n = 719) by using the multiple Cox regression analysis with adjustment for possible confounders. Results: The mean follow-up period was 4.5 years and the follow-up rate was 97.9%. In the patients aged 65 to 74 years old, the risk of cardiovascular events significantly increased at the level of achieved systolic BP ≥ 140 mmHg and achieved diastolic BP ≥ 85 mmHg, respectively. On the contrary, in patients aged 75 to 84 years old, the risk significantly increased at the level of achieved systolic BP ≥ 150 mmHg and achieved diastolic BP ≥ 85 mmHg, respectively. Conclusion: The present study confirmed our prevois finding that for the very elderly high-risk hypertensive patients target blood pressure should be less than 150/85 mmHg.