Trial Outcomes & Findings for Add-on Effects of Valsartan on Morbi- Mortality (KYOTO HEART Study) (NCT NCT00149227)

NCT ID: NCT00149227

Last Updated: 2012-12-12

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 3031 participants
• Primary outcome timeframe: five years
• Results posted on: 2012-12-12

Participant Flow

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.

Among 3042 patients eligible, 4 patients were withdrawn due to refusal of informed consent, 7 were withdrawn due to incompatible object.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.

Participant milestones

Measure	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.	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.
Overall Study STARTED	1517	1514
Overall Study COMPLETED	1517	1514
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Valsartan n=1517 Participants 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.	Non-ARB n=1514 Participants 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 n=3031 Participants Total of all reporting groups
Age Continuous	65.8 years STANDARD_DEVIATION 11.2 • n=5 Participants	66.1 years STANDARD_DEVIATION 10.9 • n=7 Participants	65.9 years STANDARD_DEVIATION 11.1 • n=5 Participants
Sex: Female, Male Female	656 Participants n=5 Participants	647 Participants n=7 Participants	1303 Participants n=5 Participants
Sex: Female, Male Male	861 Participants n=5 Participants	867 Participants n=7 Participants	1728 Participants n=5 Participants
Region of Enrollment Japan	1517 participants n=5 Participants	1514 participants n=7 Participants	3031 participants n=5 Participants

PRIMARY outcome

Timeframe: five years

Population: Analyses were made by the independent Statistical Analysis Organization based on the intention-to-treat principle.

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.

Outcome measures

Measure	Valsartan n=1517 Participants 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.	Non-ARB n=1514 Participants 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.
New Onset or Recurrence of Stroke	25 event number	46 event number

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Valsartan n=1517 Participants 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.	Non-ARB n=1514 Participants 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.
New Onset or Recurrence of Transient Ischemic Attack	6 event number	4 event number

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Valsartan n=1517 Participants 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.	Non-ARB n=1514 Participants 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.
New Onset or Recurrence of Acute Myocardial Infarction	7 event number	11 event number

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Valsartan n=1517 Participants 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.	Non-ARB n=1514 Participants 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.
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	26 event number

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Valsartan n=1517 Participants 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.	Non-ARB n=1514 Participants 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.
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	44 event number

PRIMARY outcome

Timeframe: five years

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Valsartan n=1517 Participants 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.	Non-ARB n=1514 Participants 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.
New Onset of Acute Dissecting Aneurysm of the Aorta	3 event number	5 event number

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Valsartan n=1517 Participants 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.	Non-ARB n=1514 Participants 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.
New Onset, Recurrence or Worsening of Arteriosclerosis Obliterans	11 event number	12 event number

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Valsartan n=1517 Participants 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.	Non-ARB n=1514 Participants 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.
Transition to Dialysis, Doubling of Plasma Cr Levels	6 event number	14 event number

SECONDARY outcome

Timeframe: five years

Outcome measures

Measure	Valsartan n=1517 Participants 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.	Non-ARB n=1514 Participants 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	22 patients	32 patients

SECONDARY outcome

Timeframe: five years

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: five years

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Valsartan n=1517 Participants 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.	Non-ARB n=1514 Participants 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.
New Onset or Worsening of Diabetes Mellitus or IGT	58 event number	86 event number

SECONDARY outcome

Timeframe: five years

Outcome measures

Outcome data not reported

Adverse Events

Non-ARB

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Valsartan

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Prof. Hiroaki Matsubara

Department of Cardiology, Kyoto Prefectural University of Medicine

Phone: +81-75-251-5511

Email: matsubah@koto.kpu-m.ac.jp

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place