Candesartan Antihypertensive Survival Evaluation Research Articles

Long-term effects of antihypertensive therapy on cardiovascular events and new-onset diabetes mellitus in high-risk hypertensive patients in Japan.

During the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, patients with hypertension who received amlodipine had similar cardiovascular risks as those who received candesartan. We conducted a post-trial study, the Candesartan Antihypertensive Survival Evaluation in Japan 10-year follow-up (CASE-J 10). This study aimed to confirm the long-term cardiovascular effects of candesartan and amlodipine. Case report forms were sent to CASE-J investigators who agreed to participate in the CASE-J 10. All the available information was retrospectively collected. The primary endpoint was a time-to-first event for a composite of cerebrovascular, cardiac, renal, and vascular events, and sudden death. Secondary endpoints included new-onset diabetes (NOD), cardiovascular mortality, and all-cause mortality. For each endpoint, treatment effect was compared on an intention-to-treat basis, according to previous randomization categories. A total of 1313 patients' data have been updated. The 10-year Kaplan-Meier rates of the primary endpoint were 14.7% for candesartan and 14.8% for amlodipine. After adjusting for baseline characteristics, the rates for the primary endpoint were similar between the two treatments (hazards ratioadj = 0.99, 95% CI 0.82-1.20). Candesartan had a lower Kaplan-Meier rate of NOD than amlodipine (8.3 vs. 11.1%), and when adjusted for clinical factors, candesartan remained an independent predictor for NOD prevention (hazard ratioadj = 0.71, 95% CI 0.52-0.98). With more than 28 385 patient-years follow-up, we demonstrated that candesartan and amlodipine were comparable in reducing cardiovascular events in patients with high-risk hypertension. Additionally, our results may support candesartan's superiority in reducing NOD incidence compared with amlodipine even after the long-term follow-up.

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.

How to use marginal structural models in randomized trials to estimate the natural direct and indirect effects of therapies mediated by causal intermediates

Although intention-to-treat analysis is a standard approach, additional supplemental analyses are often required to evaluate the biological relationship among interventions, intermediates, and outcomes. Therefore, we need to evaluate whether the effect of an intervention on a particular outcome is mediated by a hypothesized intermediate variable. To evaluate the size of the direct effect in the total effect, we applied the marginal structural model to estimate the average natural direct and indirect effects in a large-scale randomized controlled trial (RCT). Method The average natural direct effect is defined as the difference in the probability of a counterfactual outcome between the experimental and control arms, with the intermediate set to what it would have been, had the intervention been a control treatment. We considered two marginal structural models to estimate the average natural direct and indirect effects introduced by VanderWeele (Epidemiology 2009) and applied them in a large-scale RCT - the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J trial) - that compared angiotensin receptor blockers and calcium-channel blockers in high-risk hypertensive patients. There were no strong blood pressure-independent or dependent effects; however, a systolic blood pressure reduction of about 1.9 mmHg suppressed all events. Compared to the blood pressure-independent effects of calcium channel blockers, those of angiotensin receptor blockers contributed positively to cardiovascular and cardiac events, but negatively to cerebrovascular events. There is a particular condition for estimating the average natural direct effect. It is impossible to check whether this condition is satisfied with the available data. We estimated the average natural direct and indirect effects through the achieved systolic blood pressure in the CASE-J trial. This first application of estimating the average natural effects in an RCT can be useful for obtaining an in-depth understanding of the results and further development of similar interventions.

Effects of candesartan versus amlodipine on home-measured blood pressure, QT dispersion and left ventricular hypertrophy in high-risk hypertensive patients

The GIFU substudy of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the long-term effects of candesartan and amlodipine on office- and home-measured blood pressure (BP), QTc dispersion and left ventricular mass index (LVMI) in high-risk Japanese patients with hypertension. We used a prospective, randomized, open-label design with blinded assessment of endpoints. Patients were assigned to candesartan-based therapy up to 12 mg/day (n = 100) or amlodipine-based therapy up to 10 mg/day (n = 101) and followed for 3 years. LVMI was assessed by echocardiography and QTc dispersion was obtained from electrocardiograms. Both candesartan and amlodipine lowered and controlled office- and home-measured BP levels with no significant between-treatment differences. In patients diagnosed with left ventricular hypertrophy (LVH) at baseline, both candesartan and amlodipine significantly regressed LVMI after 3 years. However, candesartan (41.7 ± 15.1 ms at baseline vs 32.9 ± 16.6 ms after 3 years, p < 0.01), but not amlodipine (41.4 ± 13.5 ms at baseline vs 41.5 ± 16.1 ms after 3 years), produced a significant reduction in QTc dispersion. Larger studies in patients treated for longer periods are needed to determine whether this candesartan effect will translate into improved prognosis in terms of cardiovascular mortality and morbidity.

Influence of Coronary Risk Factors on Coronary Events in Japanese High-Risk Hypertensive Patients - Primary and Secondary Prevention of Ischemic Heart Disease in a Subanalysis of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) Trial -

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the effects of candesartan and amlodipine on cardiovascular events in Japanese high-risk hypertensive patients. The aim of the present subanalysis was to evaluate the influence of coronary risk factors on coronary events in these patients as an observational study irrespective of allocated drugs. The adjusted hazard ratios (HRs) of the association of baseline risk factors including gender, age, allocated drugs, body mass index, systolic/diastolic blood pressure (SBP/DBP), diabetes mellitus (DM), hyperlipidemia (HL), smoking, left ventricular hypertrophy, previous ischemic heart disease (IHD), previous cerebrovascular events, and chronic kidney disease (CKD) with coronary events in 4,703 patients who were enrolled in the CASE-J trial, were examined. The coronary events occurred in 83 patients, and were significantly associated with previous IHD, DM, male sex, CKD, and low DBP. Significant predictors were previous IHD (HR, 3.89), DM (HR, 3.10), male sex (HR, 1.81), CKD (HR, 1.60), and low DBP (HR, 1.36), respectively. In 4,107 patients without previous IHD, DM (HR, 4.88), HL (HR, 2.67), and DBP (HR, 1.39) were significantly associated with the risk of coronary events, while male sex (HR, 3.03), CKD (HR, 2.44), and DM (HR, 2.15) were in 596 patients with previous IHD. DM is the important factor in both primary and secondary prevention of coronary events. Comprehensive risk management including surveillance of DM, CKD and HL is needed for preventing coronary events, in addition to blood pressure control.

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 >or=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.

Is Pulse Pressure a Predictor of New-Onset Diabetes in High-Risk Hypertensive Patients?

OBJECTIVEHypertensive 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 METHODSThe 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.RESULTSDuring 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.CONCLUSIONSPulse 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.

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

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. We analysed data of 1447 patients who underwent echocardiography at enrollment 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 > or = 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). 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. 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.

Effects of candesartan and amlodipine on cardiovascular events in hypertensive patients with chronic kidney disease: subanalysis of the CASE-J Study

We examined the effects of candesartan and amlodipine on cardiovascular events in hypertensive patients with chronic kidney disease (CKD) using the data from the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial. CKD was defined as proteinuria and/or decreased GFR (<60 ml per min per 1.73 m(2)) at enrollment. Among 2720 subjects with CKD, there were 1376 and 1344 patients in the candesartan and the amlodipine group, respectively. During a 3.2-year follow-up, cardiovascular event rate did not differ in the two groups (7.2% for candesartan and 7.6% for amlodipine). In the subgroup analysis based on the CKD stage, there were no significant differences in the incidence rates of cardiovascular events between the two groups in stages 1+2 and 3 CKD. In stage 4 CKD, however, candesartan reduced the incidence of cardiovascular events (55% risk reduction), particularly of renal events (81% risk reduction), compared with amlodipine. Furthermore, composite cardiovascular events were increased as the CKD stage progressed, and this effect was exaggerated in the presence of proteinuria. Finally, the new onset of diabetes was less in the candesartan-based regimen in stage 3 CKD. In conclusion, candesartan protected hypertensive patients with CKD more potently against renal events, particularly in moderately-to-severely impaired CKD. Furthermore, candesartan prevented a new onset of diabetes in CKD, which would be favorable for the long-term management of CKD.

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 Cardiac Complications on Cardiovascular Events in Japanese High-Risk Hypertensive Patients Subanalysis of the CASE-J Trial

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial compared the effects of candesartan and amlodipine on cardiovascular events in Japanese high-risk hypertensive patients. The present study aimed to clarify the effect of cardiac complications on cardiovascular events in patients enrolled in CASE-J. Cardiac complications were defined as left ventricular hypertrophy (LVH) and ischemic heart disease (IHD). The primary endpoint was a composite of sudden death, cerebrovascular, cardiac, renal and vascular events. The study group was divided into 2,030 and 2,673 patients with and without cardiac complications. During 3.2 follow-up years, cardiovascular events occurred for a rate of 13.6 per 1000 patient-years in patients without cardiac complications, and 23.1 per 1000 patient-years in patients with cardiac complications (adjusted hazard ratio (HR): 2.22; P<0.001). Furthermore, LVH was associated with the onset of cerebrovascular events (adjusted HR: 2.38; P<0.001), whereas IHD was associated with the onset of cardiovascular death (adjusted HR: 2.22; P<0.05), especially sudden death and other cardiac events. Cardiac complications are independent predictors for cardiovascular events in Japanese high-risk hypertensive patients. In particular, LVH is related to cerebrovascular events and IHD is related to cardiac death and other cardiac events.

Effects of Candesartan Compared With Amlodipine in Hypertensive Patients With High Cardiovascular Risks: Candesartan Antihypertensive Survival Evaluation in Japan Trial

Effects of Candesartan Compared With Amlodipine in Hypertensive Patients With High Cardiovascular Risks: Candesartan Antihypertensive Survival Evaluation in Japan Trial

Left Ventricular Hypertrophy, Ischemic Heart Disease and the Incidence of Cardiovascular Events in Japanese High-Risk Hypertensive Patients

lthough blood pressure (BP) is the main variable determining cardiovascular (CV) risk in hypertensive patients, recent guidelines emphasize that management of hypertension should be related to quantification of the total CV risk. 1 This concept is based on the fact that, when concomitantly present, BP and other risk factors augment the risk and lead to a greater CV risk than the sum of the individual components. 2 Article p 1080 The most common clinical variables that should be used in stratification are risk factors, target organ damage, dia betes and established CV or renal disease. High total CV risk is a subgroup of patients with a previous diagnosis of CV disease, besides the subgroups of patients with diabetes mellitus and with severely elevated single risk factors. 1 In addition, it is widely accepted that subclinical organ damage plays a crucial role in determining the CV risk of hypertensive patients. Of these, there has been further confirmation of the adverse prognostic role of left ventricular hypertrophy (LVH), together with evidence that it is fairly common in hypertensive patients. 3 Accordingly, evaluation of cardiac complications, such as previous CV disease and the presence of LVH, is useful for detecting hypertensive subjects at increased risk of CV disease. However, whether each component cardiac complication has separate implications on the outcome of long-term CV events in hypertensive patients is not known with certainty. Ueshima et al, reporting in this issue of the Journal, 4 provide the interesting piece of information that each of 2 cardiac complications, LVH and ischemic heart disease (IHD), has a different effect on the incidence of future CV events in Japanese high-risk hypertensive patients. By using enrolled participants of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, the authors evaluated 2,030 and 2,673 high-risk hypertensive patients with and without cardiac complications. The incidence of CV events, represented as a composite of sudden death, cerebrovascular, cardiac, renal and vascular events, was compared between patients with and without the complication of LVH and/or IHD in this post-hoc study. During 3.2 years of follow-up, the authors proved that cardiac complications as a whole are associated with the CV events rate, and further, both LVH and IHD are independent predictors for CV events. Moreover, the authors found that there are different effects on each event category of CV events between LVH and IHD. After adjustment for baseline characteristics, LVH is linked to cerebrovascular events, but not to CV death or other cardiac events, whereas IHD is associated with cardiac death, especially sudden death, and other cardiac events, but not with cerebrovascular events. Neither LVH nor IHD related to the onset of renal and vascular events. An extensive body of population studies has provided consistent evidence that LVH confers increased risk for CV events, including heart failure, myocardial infarction, sudden

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.

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 Committee's 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.

Effects of Candesartan Compared With Amlodipine in Hypertensive Patients With High Cardiovascular Risks

The Candesartan Antihypertensive Survival Evaluation in Japan Trial was designed to compare the long-term effects of the angiotensin II receptor blocker candesartan and the calcium channel blocker amlodipine on the incidence of cardiovascular events, represented as a composite of sudden death and cerebrovascular, cardiac, renal, and vascular events in high-risk Japanese hypertensive patients. We conducted a prospective, randomized, open-label study with blinded assessment of the end point in 4728 Japanese hypertensive patients (mean age: 63.8 years; mean body mass index: 24.6 kg/m(2)). Patients were followed for an average of 3.2 years. Blood pressure was well controlled with both treatment-based regimens (systolic blood pressure/diastolic blood pressure: 136.1/77.3 mm Hg for candesartan-based regimens and 134.4/76.7 mm Hg for amlodipine-based regimens after 3 years). Primary cardiovascular events occurred in 134 patients with both the candesartan- and amlodipine-based regimens. The 2 treatment-based regimens produced no significant differences in cardiovascular morbidity or mortality in the high-risk Japanese hypertensive patients (hazard ratio: 1.01; 95% CI: 0.79 to 1.28; P=0.969). In each primary end point category, there was no significant difference between the 2 treatment-based regimens. New-onset diabetes occurred in fewer patients taking candesartan (8.7/1000 person-years) than in those taking amlodipine (13.6/1000 person-years), which resulted in a 36% relative risk reduction (hazard ratio: 0.64; 95% CI: 0.43 to 0.97; P=0.033). We disclosed that candesartan-based and amlodipine-based regimens produced no statistical differences in terms of the primary cardiovascular end point, whereas candesartan prevented new-onset diabetes more effectively than amlodipine.

The Optimal Target Blood Pressure for Antihypertensive Treatment in Japanese Elderly Patients with High-Risk Hypertension: A Subanalysis of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) Trial

For hypertensive patients, it has been recommended that antihypertensive treatment strategies be chosen on the basis of the patients' conditions and age. In this sub-analysis of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, we aimed to compare the effects of candesartan and amlodipine on cardiovascular mortality and morbidity in Japanese elderly patients with high-risk hypertension and to determine their optimal target blood pressures (BPs). The effect of the two drugs on cardiovascular events was compared across different age subgroups (<65, 65-74, and 75-84 years) by use of Cox regression analysis. We also evaluated the associations between the achieved BP and the incidence of cardiovascular events, irrespective of the allocated drugs in multiple Cox regression analyses. The incidence of cardiovascular events was independent of the assigned treatment for each of the age subgroups. For systolic BP (SBP), cardiovascular risk increased steeply when control of SBP was inadequate (higher than 140 mmHg) for patients younger than 65 years old and those between 65 and 74 years old. Patients aged 75 to 84 years old showed a significantly increased risk when their SBP was >or=150 mmHg. For diastolic BP (DBP), the risk significantly increased for the subgroup aged 75 to 84 years when the DBP was >or=85 mmHg. The present results show that candesartan and amlodipine are equally effective in Japanese elderly patients with high-risk hypertension. Moreover, it is important to control BP levels to less than 150/85 mmHg for patients 75-84 years old.

Informed Consent in the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) Trial: A Survey of Collaborating Physicians

An anonymous postal survey was conducted among the physicians collaborating in a randomized controlled trial to examine their method of convincing patients, their consent process, the factors related to higher accrual, and the predictors of 100% success in the process of obtaining informed consent (IC). A total of 512 questionnaires were sent out and 448 responses were received, for a response rate of 87.5%. The 448 physicians solicited a total of 5371 eligible patients (12.0 per physician), among which 3763 patients (8.4 per physician) agreed to participate. One-fifth (22.3%) of the physicians were able to obtain IC from 100% of the patients they solicited. Physicians who thought that the information on the IC sheet was sufficient to obtain consent (odds ratio [OR] = 2.0, 95% confidence interval [CI] = 1.1-3.9; p = 0.03) and those who did not consider that the patient's decision was influenced by relatives and friends (OR = 0.2, CI = 0.1-0.4; p = 0.001), were significantly more likely to obtain IC from 100% of the eligible patients. Three-fourths (73.2%) of the physicians targeted only patients who they perceived would easily provide IC, and 81.2% favored some form of incentives for patients. The results of this study should be useful for efficiently implementing randomized controlled trials in Japan.

Physicians' Attitudes towards and Reasons for Participation in the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) Trial

BACKGROUND: Physicians’ perception and attitudes towards a research topic and trial management could influence their participation in a randomized controlled trial. The objectives of this study were to determine the reasons for physicians’ participation in and attitudes towards the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial.METHODS: CASE-J’s main objective is to compare the effectiveness of an angiotensin II receptor antagonist (candesartan cilexetil) with that of a calcium channel blocker (amlodipine besilate) in terms of the incidence of cardiovascular events among high-risk hypertensive patients. We conducted a questionnaire survey among the physicians (n=512) participating in that trial to determine the reasons behind their participation and to elicit their reactions to the trial management.RESULTS: Eighty-eight percent of the 512 participating physicians responded to our survey. The main reasons for participation were clear objectives of the trial (85.1%), a simple protocol (61.1%), interest in finding out the inhibiting effects of the drugs on cardiac events (80.2%), and a well-organized support system (59.8%). As for negative factors, case registration and follow-up were considered cumbersome by 28.6% and 10.8%, respectively while 44.2% stated that support by the clinical research coordinators provided by the trial management authority was necessary for case screening, recruitment process, patient registration, and follow-up. Multivariate logistic regression analysis showed that participants who did not use a computer very regularly (odds ratio = 1.9, 95% confidence interval = 1.1-3.6) were more likely to consider the case registration and follow-up procedures as a cumbersome.CONCLUSION: The information generated by this study could be useful in designing future randomized controlled trials in Japan and abroad.

Physicians’ Choice in Using Internet and Fax for Patient Recruitment and Follow-up in a Randomized Controlled Trial

To examine the physicians' preference between Web and fax-based remote data entry (RDE) system for an ongoing randomized controlled trial (RCT) in Japan. We conducted a survey among all the collaborating physicians (n = 512) of the CASE-J (Candesartan Antihypertensive Survival Evaluation in Japan) trial, who have been recruiting patients and sending follow-up data using the Web or a fax-based RDE system. The survey instrument assessed physicians' choice between Web and fax-based RDE systems, their practice pattern, and attitudes towards these two modalities. A total of 448 (87.5%) responses were received. The proportions of physicians who used Web, fax, and the combination of these two were 45.9%, 33.3% and 20.8%, respectively. Multivariate logistic regression analyses revealed that physicians 55 years or younger [odds ratio (OR) = 1.9, 95% confidence interval (CI) = 1.1-3.3] and regular users of computers (OR = 4.2, 95% CI = 2.1-8.2) were more likely to use the Web-based RDE system. This information would be useful in designing an RCT with a Web-based RDE system in Japan and abroad.