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

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ClinicalTrials.gov Identifier: NCT00149227
Recruitment Status : Completed
First Posted : September 8, 2005
Results First Posted : December 12, 2012
Last Update Posted : December 12, 2012
Sponsor:
Information provided by (Responsible Party):
Hiroaki Matsubara, MD., PhD, Kyoto Prefectural University of Medicine

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Diagnostic
Conditions Hypertension
Ischemic Heart Disease
Congestive Heart Failure
Stroke
Interventions Drug: Valsartan
Drug: Non-ARB
Enrollment 3031
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Pre-assignment Details Among 3042 patients eligible, 4 patients were withdrawn due to refusal of informed consent, 7 were withdrawn due to incompatible object.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.
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 1517 1514
Completed 1517 1514
Not Completed 0 0
Arm/Group Title Valsartan Non-ARB Total
Hide Arm/Group Description 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 1517 1514 3031
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1517 participants 1514 participants 3031 participants
65.8  (11.2) 66.1  (10.9) 65.9  (11.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1517 participants 1514 participants 3031 participants
Female
656
  43.2%
647
  42.7%
1303
  43.0%
Male
861
  56.8%
867
  57.3%
1728
  57.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Japan Number Analyzed 1517 participants 1514 participants 3031 participants
1517 1514 3031
1.Primary Outcome
Title New Onset or Recurrence of Stroke
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Analyses were made by the independent Statistical Analysis Organization based on the intention-to-treat principle.
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 1517 1514
Measure Type: Number
Unit of Measure: event number
25 46
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Valsartan, Non-ARB
Comments

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.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Cox's proportional hazard analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.8
Confidence Interval (2-Sided) 95%
-0.975 to 0.975
Parameter Dispersion
Type: Standard Deviation
Value: 2
Estimation Comments [Not Specified]
2.Primary Outcome
Title New Onset or Recurrence of Transient Ischemic Attack
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 1517 1514
Measure Type: Number
Unit of Measure: event number
6 4
3.Primary Outcome
Title New Onset or Recurrence of Acute Myocardial Infarction
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 1517 1514
Measure Type: Number
Unit of Measure: event number
7 11
4.Primary Outcome
Title 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
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 1517 1514
Measure Type: Number
Unit of Measure: event number
12 26
5.Primary Outcome
Title 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
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 1517 1514
Measure Type: Number
Unit of Measure: event number
22 44
6.Primary Outcome
Title Operation of PCI or Bypass Operation
Hide Description [Not Specified]
Time Frame five years
Outcome Measure Data Not Reported
7.Primary Outcome
Title New Onset of Acute Dissecting Aneurysm of the Aorta
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 1517 1514
Measure Type: Number
Unit of Measure: event number
3 5
8.Primary Outcome
Title New Onset, Recurrence or Worsening of Arteriosclerosis Obliterans
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 1517 1514
Measure Type: Number
Unit of Measure: event number
11 12
9.Primary Outcome
Title Transition to Dialysis, Doubling of Plasma Cr Levels
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 1517 1514
Measure Type: Number
Unit of Measure: event number
6 14
10.Secondary Outcome
Title All Cause Mortality
Hide Description [Not Specified]
Time Frame five years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 1517 1514
Measure Type: Number
Unit of Measure: patients
22 32
11.Secondary Outcome
Title Worsening of Cardiac Function
Hide Description [Not Specified]
Time Frame five years
Outcome Measure Data Not Reported
12.Secondary Outcome
Title New Onset or Worsening of Arrhythmias
Hide Description [Not Specified]
Time Frame five years
Outcome Measure Data Not Reported
13.Secondary Outcome
Title New Onset or Worsening of Diabetes Mellitus or IGT
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 1517 1514
Measure Type: Number
Unit of Measure: event number
58 86
14.Secondary Outcome
Title Uncontrolled Blood Pressure, Etc.
Hide Description [Not Specified]
Time Frame five years
Outcome Measure Data Not Reported
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Valsartan Non-ARB
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Valsartan Non-ARB
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Valsartan Non-ARB
Affected / at Risk (%) Affected / at Risk (%)
Total   0/1517 (0.00%)   0/1514 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Valsartan Non-ARB
Affected / at Risk (%) Affected / at Risk (%)
Total   0/1517 (0.00%)   0/1514 (0.00%) 
The study was performed using PROBE design, which does not exclude possible bias for softer endpoints such as angina and TIA. However, all softer endpoints were diagnosed by CAG and CT/MRI. We believe that under reporting would be unlikely.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Prof. Hiroaki Matsubara
Organization: Department of Cardiology, Kyoto Prefectural University of Medicine
Phone: +81-75-251-5511
Responsible Party: Hiroaki Matsubara, MD., PhD, Kyoto Prefectural University of Medicine
ClinicalTrials.gov Identifier: NCT00149227     History of Changes
Other Study ID Numbers: KHS2004
First Submitted: September 6, 2005
First Posted: September 8, 2005
Results First Submitted: July 5, 2011
Results First Posted: December 12, 2012
Last Update Posted: December 12, 2012