Congestive Heart Failure, Hypertension, Ischemic Heart Disease, Stroke
Conditions
Keywords
High risk hypertension, Ischemic heart disease, Angiotensin receptor blockers, Cardiovascular mortality- morbidity, KYOTO HEART Study
Brief summary
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
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.
Interventions
DRUGValsartan
Valsartan add-on arm: valsartan 40-160 mg per day, and an additional antihypertensive drugs other than ARB and ACEI are administered if necessary.
DRUGNon-ARB
'Non-ARB' was defined conventional anti-hypertensive treatment except for ACEIs and ARBs
Sponsors
Kyoto Prefectural University of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 79 Years
Healthy volunteers
No
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.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Transition to Dialysis, Doubling of Plasma Cr Levels | five years | 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. |
| 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 | five years | 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. |
| 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 | five years | 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. |
| Operation of PCI or Bypass Operation | five years | — |
| New Onset of Acute Dissecting Aneurysm of the Aorta | five years | 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. |
| New Onset, Recurrence or Worsening of Arteriosclerosis Obliterans | five years | 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. |
| New Onset or Recurrence of Stroke | five years | 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. |
| New Onset or Recurrence of Transient Ischemic Attack | five years | 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. |
| New Onset or Recurrence of Acute Myocardial Infarction | five years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Worsening of Cardiac Function | five years | — |
| New Onset or Worsening of Arrhythmias | five years | — |
| New Onset or Worsening of Diabetes Mellitus or IGT | five years | 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. |
| Uncontrolled Blood Pressure, Etc. | five years | — |
| All Cause Mortality | five years | — |
Countries
Japan
Participant flow
Recruitment details
We recruited patients between January 2004 and June 2007. Participating centres included 31 associated hospitals led by physicians (cardiology specialists) from Kyoto Prefectural University School of Medicine.
Pre-assignment details
Among 3042 patients eligible, 4 patients were withdrawn due to refusal of informed consent, 7 were withdrawn due to incompatible object. Finally, 3031 patients were assigned to the treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Valsartan For the valsartan add-on group, valsartan 80 mg once daily in the morning was administered to the patient as an initial dose, the dose was doubled after 4 weeks if the initial dose could not achieve the target blood pressure of less than 140/90 mmHg (in patients with diabetes or renal disease, target blood pressure was set to less than 130/80 mmHg). After 8 weeks, an additional administration of other antihypertensive drugs with flexible dosing regimen other than ARBs and ACE inhibitors was allowed if necessary. | 1,517 |
| Non-ARB For the conventional treatment group, the anti-hypertensive drugs other than ARB and ACE inhibitors were provided for the patients to reach the target blood pressure. | 1,514 |
| Total | 3,031 |
Baseline characteristics
| Characteristic | Valsartan | Non-ARB | Total |
|---|---|---|---|
| Age Continuous | 65.8 years STANDARD_DEVIATION 11.2 | 66.1 years STANDARD_DEVIATION 10.9 | 65.9 years STANDARD_DEVIATION 11.1 |
| Region of Enrollment Japan | 1517 participants | 1514 participants | 3031 participants |
| Sex: Female, Male Female | 656 Participants | 647 Participants | 1303 Participants |
| Sex: Female, Male Male | 861 Participants | 867 Participants | 1728 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 1,517 | 0 / 1,514 |
| serious Total, serious adverse events | 0 / 1,517 | 0 / 1,514 |
Outcome results
Primary
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.
Time frame: five years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan | 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 | 22 event number |
| Non-ARB | 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 | 44 event number |
Primary
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.
Time frame: five years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan | 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 | 12 event number |
| Non-ARB | 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 | 26 event number |
Primary
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.
Time frame: five years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan | New Onset of Acute Dissecting Aneurysm of the Aorta | 3 event number |
| Non-ARB | New Onset of Acute Dissecting Aneurysm of the Aorta | 5 event number |
Primary
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.
Time frame: five years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan | New Onset or Recurrence of Acute Myocardial Infarction | 7 event number |
| Non-ARB | New Onset or Recurrence of Acute Myocardial Infarction | 11 event number |
Primary
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.
Time frame: five years
Population: Analyses were made by the independent Statistical Analysis Organization based on the intention-to-treat principle.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan | New Onset or Recurrence of Stroke | 25 event number |
| Non-ARB | New Onset or Recurrence of Stroke | 46 event number |
Comparison: 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.~with a two-tailed 5% statistical significant level.p-value: <0.0595% CI: [-0.975, 0.975]Cox's proportional hazard analysis
Primary
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.
Time frame: five years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan | New Onset or Recurrence of Transient Ischemic Attack | 6 event number |
| Non-ARB | New Onset or Recurrence of Transient Ischemic Attack | 4 event number |
Primary
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.
Time frame: five years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan | New Onset, Recurrence or Worsening of Arteriosclerosis Obliterans | 11 event number |
| Non-ARB | New Onset, Recurrence or Worsening of Arteriosclerosis Obliterans | 12 event number |
Primary
Operation of PCI or Bypass Operation
Time frame: five years
Primary
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.
Time frame: five years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan | Transition to Dialysis, Doubling of Plasma Cr Levels | 6 event number |
| Non-ARB | Transition to Dialysis, Doubling of Plasma Cr Levels | 14 event number |
Secondary
All Cause Mortality
Time frame: five years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan | All Cause Mortality | 22 patients |
| Non-ARB | All Cause Mortality | 32 patients |
Secondary
New Onset or Worsening of Arrhythmias
Time frame: five years
Secondary
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.
Time frame: five years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valsartan | New Onset or Worsening of Diabetes Mellitus or IGT | 58 event number |
| Non-ARB | New Onset or Worsening of Diabetes Mellitus or IGT | 86 event number |
Secondary
Uncontrolled Blood Pressure, Etc.
Time frame: five years
Secondary
Worsening of Cardiac Function
Time frame: five years