Add-on Effects of Valsartan on Morbi- Mortality (KYOTO HEART Study)

Study Overview
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Brief Summary
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The KYOTO HEART Study is to assess the add-on effect of valsartan, an Angiotensin-Receptor Blocker, on top of the conventional treatment in high risk patients in Japan with hypertension in terms of the morbidity and mortality.

Detailed Description
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Although many reports show that ACE inhibitors and angiotensin II receptor blockers (ARB) are superior for prevention of cardiovascular events, previous data are not enough for the patients who have more than one risk factor and for anti-atherosclerotic effects of ARB. In Japan, there were only a few large-scale trials for cardiovascular disease prevention, and it has not been clarified whether the evidence in Western countries could be unqualifiedly applied to Japanese patients as a long-range strategy. The KYOTO HEART Study is to assess the add-on effect of valsartan, an Angiotensin-Receptor Blocker, on top of the conventional treatment in high risk patients with hypertension in terms of the morbidity and mortality.

Official Title
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Add-on Effects of Valsartan on Morbi- Mortality in High Risk Hypertension

Conditions
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Hypertension, Ischemic Heart Disease, Congestive Heart Failure, Stroke

Intervention / Treatment
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* Drug: Valsartan
* Drug: Non-ARB


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of hypertension Clinical diagnosis of one or more risk factors, such as diabetes, smoking habit, lipid metabolism abnormality, history of ischemic heart disease (IHD) or cerebrovascular disease, obesity (BMI>25), chronic heart failure (NYHA II-III), and electrocardiogram (ECG) abnormality (LVH) Exclusion Criteria: Patients who have already been administered ARB Patients with IHD within 6 months after percutaneous coronary intervention(PCI), and who are stable but are going to implement PCI or coronary artery bypass grafting(CABG) Severe/malignant/secondary hypertensive patients Pregnant women and women of childbearing potential History of heart failure, unstable angina, myocardial infarction, PTCA, or CABG within the preceding 6 months Arrhythmia needed to be treated or accompanied with symptoms, second or third degree AV block Severe renal impairment (Serum creatinine >3.0 mg/dl) Severe hepatic impairment (Hepatic failure, Cirrhosis, etc.)

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Non-ARB<br>'Non-ARB' was defined as Conventional anti-hypertensive treatment except for ARB and ACEIs | Drug: Non-ARB<br>* 'Non-ARB' was defined conventional anti-hypertensive treatment except for ACEIs and ARBs<br>* Other names: Conventional anti-hypertensive treatment;|
| Experimental: Valsartan<br>Valsartan add-on treatment | Drug: Valsartan<br>* Valsartan add-on arm: valsartan 40-160 mg per day, and an additional antihypertensive drugs other than ARB and ACEI are administered if necessary.<br>* Other names: Diovan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New Onset or Recurrence of Stroke | Stroke events included brain hemorrhage, infarction, and TIA. They required hospitalization with neurological symptoms and were diagnosed by CT and/or MRI. The first of any of these events to occur in a specific patient was classified as an event to be counted in the primary endpoint by the Endpoint Committee. We estimated the number of enrolled patients to validate the hypothesis under the assumption that the valsartan add-on group achieves a 20% risk reduction compared with the conventional treatment group and gives 80% statistical power for detecting a clinical signiﬁcance with a two-tailed 5% statistical signiﬁcant level. | five years | 
| New Onset or Recurrence of Transient Ischemic Attack | Transient ischemic attack (TIA) was defined as hospitalization with sudden onset of neurological deficit persisting for less than 24 hrs, and without abnormal findings using by CT and/or MRI. The first of any of these events to occur in a specific patient was classified as an event to be counted in the primary endpoint by the Endpoint Committee. We estimated the number of enrolled patients to validate the hypothesis under the assumption that the valsartan add-on group achieves a 20% risk reduction compared with the conventional treatment group and gives 80% statistical power for detecting a clinical signiﬁcance with a two-tailed 5% statistical signiﬁcant level. | five years | 
| New Onset or Recurrence of Acute Myocardial Infarction | Acute myocardial infarction was diagnosed with hospitalization, ECG- change, and biomarkers for myocardial infarction. The first of any of these events to occur in a specific patient was classified as an event to be counted in the primary endpoint by the Endpoint Committee. We estimated the number of enrolled patients to validate the hypothesis under the assumption that the valsartan add-on group achieves a 20% risk reduction compared with the conventional treatment group and gives 80% statistical power for detecting a clinical signiﬁcance with a two-tailed 5% statistical signiﬁcant level. | five years | 
| Hospitalization Due to the New Onset, Recurrence or Worsening of Heart Failure and Additional Concomitant Use of Other Anti-heart Failure Agents or Increase of Dosage | Heart failure event was defined as requiring hospitalization and clinical symptoms together with left ventricular dysfunction by echocardiography according to the guidelines of the AHA/ACC. The first of any of these events to occur in a specific patient was classified as an event to be counted in the primary endpoint by the Endpoint Committee. We estimated the number of enrolled patients to validate the hypothesis under the assumption that the valsartan add-on group achieves a 20% risk reduction compared with the conventional treatment group and gives 80% statistical power for detecting a clinical signiﬁcance with a two-tailed 5% statistical signiﬁcant level. | five years | 
| Hospitalization Due to the New Onset, Occurrence or Worsening of Angina Pectoris and Additional Concomitant Use of Other Anti-anginal Agents or Increase of Dosage | Angina pectoris event required hospitalization and was diagnosed by both ECG changes corresponding with chest symptoms and coronary angiography showing 75% stenosis according to AHA/ACC guidelines. The first of any of these events to occur in a specific patient was classified as an event to be counted in the primary endpoint by the Endpoint Committee. We estimated the number of enrolled patients to validate the hypothesis under the assumption that the valsartan add-on group achieves a 20% risk reduction compared with the conventional treatment group and gives 80% statistical power for detecting a clinical signiﬁcance with a two-tailed 5% statistical signiﬁcant level. | five years | 
| Operation of PCI or Bypass Operation |  | five years | 
| New Onset of Acute Dissecting Aneurysm of the Aorta | Dissecting aneurysm of the aorta required hospitalization and was diagnosed by imaging technique, CT and/or MRI. The first of any of these events to occur in a specific patient was classified as an event to be counted in the primary endpoint by the Endpoint Committee. We estimated the number of enrolled patients to validate the hypothesis under the assumption that the valsartan add-on group achieves a 20% risk reduction compared with the conventional treatment group and gives 80% statistical power for detecting a clinical signiﬁcance with a two-tailed 5% statistical signiﬁcant level. | five years | 
| New Onset, Recurrence or Worsening of Arteriosclerosis Obliterans | Arteriosclerosis obliterans (ASO) event was diagnosed with symptoms and CT / MRI imaging. The first of any of these events to occur in a specific patient was classified as an event to be counted in the primary endpoint by the Endpoint Committee. We estimated the number of enrolled patients to validate the hypothesis under the assumption that the valsartan add-on group achieves a 20% risk reduction compared with the conventional treatment group and gives 80% statistical power for detecting a clinical signiﬁcance with a two-tailed 5% statistical signiﬁcant level. | five years | 
| Transition to Dialysis, Doubling of Plasma Cr Levels | The first of any events, transition to dialysis or doubling of plasma Cr levels compared to the entry, occurring in a specific patient was classified as an event to be counted in the primary endpoint by the Endpoint Committee. We estimated the number of enrolled patients to validate the hypothesis under the assumption that the valsartan add-on group achieves a 20% risk reduction compared with the conventional treatment group and gives 80% statistical power for detecting a clinical signiﬁcance with a two-tailed 5% statistical signiﬁcant level. | five years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Cause Mortality |  | five years | 
| Worsening of Cardiac Function |  | five years | 
| New Onset or Worsening of Arrhythmias |  | five years | 
| New Onset or Worsening of Diabetes Mellitus or IGT | Diabetes mellitus was defined as fasting plasma glucose >=126 mg/dl, causal blood glucose >= 200 mg /dl, HbA1C >= 6.5%, and/or plasma glucose 2hr after 75g glucose load >= 200 mg/dl. The first of these events, new onset diabetes or worsening diabetes following IGT, occurring in a specific patient was classified as an event to be counted in the secondary endpoint by the Endpoint Committee. We estimated the number of enrolled patients to validate the hypothesis under the assumption that the valsartan add-on group achieves a 20% risk reduction compared with the conventional treatment group and gives 80% statistical power for detecting a clinical signiﬁcance with a two-tailed 5% statistical signiﬁcant level. | five years | 
| Uncontrolled Blood Pressure, Etc. |  | five years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High risk hypertension, Ischemic heart disease, Angiotensin receptor blockers, Cardiovascular mortality- morbidity, KYOTO HEART Study