Trial Outcomes & Findings for Irbesartan in Heart Failure With Preserved Systolic Function (I-Preserve) (NCT NCT00095238)

Last Updated: 2015-04-07

Results Overview

Treatment comparisons for time to first occurrence of composite outcome of all-cause death (composite outcome of death) or protocol-specified CV hospitalization. Protocol-specified CV hospitalizations include those ≥24 hrs or involving a calendar date change for a primary cause of worsening heart failure, unstable angina, myocardial infarction, ventricular or atrial dysrhythmia, or stroke, that also require intravenous or intramuscular therapy or a related procedure or significant augmentation of oral therapy. In addition, MI or stroke during any hospitalization are included.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

4128 participants

Primary outcome timeframe

Year 1, Year 2, Year 3, Year 4, Year 5

Results posted on

2015-04-07

Participant Flow

Participant milestones

Participant milestones
Measure	Irbesartan titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo titration from 75 to 300 mg, once daily (QD), up to 6 years
Overall Study STARTED	2067	2061
Overall Study Safety (Treated) Population	2064	2062
Overall Study COMPLETED	1210	1209
Overall Study NOT COMPLETED	857	852

Reasons for withdrawal

Reasons for withdrawal
Measure	Irbesartan titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo titration from 75 to 300 mg, once daily (QD), up to 6 years
Overall Study Lack of Efficacy	9	9
Overall Study Adverse Event	331	287
Overall Study Subject Withdrew Consent	208	223
Overall Study Death	154	170
Overall Study Lost to Follow-up	19	24
Overall Study Noncompliance	44	45
Overall Study No longer met study criteria	4	5
Overall Study Study terminated by sponsor	0	1
Overall Study Missing	1	0
Overall Study Other Reasons	87	88

Baseline Characteristics

Irbesartan in Heart Failure With Preserved Systolic Function (I-Preserve)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Total n=4128 Participants Total of all reporting groups
Age, Customized < 65 years	376 participants n=5 Participants	364 participants n=7 Participants	740 participants n=5 Participants
Age, Customized Between 65 and 74 years	994 participants n=5 Participants	981 participants n=7 Participants	1975 participants n=5 Participants
Age, Customized >=75 years	697 participants n=5 Participants	716 participants n=7 Participants	1413 participants n=5 Participants
Age, Continuous	71.6 years STANDARD_DEVIATION 6.90 • n=5 Participants	71.7 years STANDARD_DEVIATION 7.00 • n=7 Participants	71.6 years STANDARD_DEVIATION 6.95 • n=5 Participants
Sex: Female, Male Female	1227 Participants n=5 Participants	1264 Participants n=7 Participants	2491 Participants n=5 Participants
Sex: Female, Male Male	840 Participants n=5 Participants	797 Participants n=7 Participants	1637 Participants n=5 Participants
Race/Ethnicity, Customized White	1934 participants n=5 Participants	1925 participants n=7 Participants	3859 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	39 participants n=5 Participants	43 participants n=7 Participants	82 participants n=5 Participants
Race/Ethnicity, Customized Asian	19 participants n=5 Participants	15 participants n=7 Participants	34 participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized Other	75 participants n=5 Participants	77 participants n=7 Participants	152 participants n=5 Participants
New York Heart Association (NYHA) Class Class I (Mild)	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
New York Heart Association (NYHA) Class Class II (Mild)	426 participants n=5 Participants	444 participants n=7 Participants	870 participants n=5 Participants
New York Heart Association (NYHA) Class Class III (Moderate)	1582 participants n=5 Participants	1562 participants n=7 Participants	3144 participants n=5 Participants
New York Heart Association (NYHA) Class Class IV (Severe)	59 participants n=5 Participants	53 participants n=7 Participants	112 participants n=5 Participants
B-Type Natriuretic Peptide (Pro-BNP)	363.0 pg/mL n=5 Participants	345.2 pg/mL n=7 Participants	353.9 pg/mL n=5 Participants

PRIMARY outcome

Timeframe: Year 1, Year 2, Year 3, Year 4, Year 5

Population: Randomized Participants

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Percentage of Participants With First Occurrence of the Composite Outcome of Death (All Cause) or Protocol-Specified Cardiovascular (CV) Hospitalization at Given Timepoints Percentage at 1 Year	12.3 percentage of participants	12.1 percentage of participants	—	—	—	—
Percentage of Participants With First Occurrence of the Composite Outcome of Death (All Cause) or Protocol-Specified Cardiovascular (CV) Hospitalization at Given Timepoints Percentage at 2 Years	20.7 percentage of participants	21.3 percentage of participants	—	—	—	—
Percentage of Participants With First Occurrence of the Composite Outcome of Death (All Cause) or Protocol-Specified Cardiovascular (CV) Hospitalization at Given Timepoints Percentage at 3 Years	26.4 percentage of participants	28.4 percentage of participants	—	—	—	—
Percentage of Participants With First Occurrence of the Composite Outcome of Death (All Cause) or Protocol-Specified Cardiovascular (CV) Hospitalization at Given Timepoints Percentage at 4 Years	32.9 percentage of participants	34.2 percentage of participants	—	—	—	—
Percentage of Participants With First Occurrence of the Composite Outcome of Death (All Cause) or Protocol-Specified Cardiovascular (CV) Hospitalization at Given Timepoints Percentage at 5 Years	39.2 percentage of participants	39.5 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Year 1, Year 2, Year 3, Year 4, Year 5

Population: Randomized Participants

Treatment comparisons for time to heart failure mortality or heart failure hospitalization

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Percentage of Participants Experiencing Heart Failure Mortality or Heart Failure Hospitalization at Given Time Points Percentage at 1 Year	7.9 percentage of participants	8.2 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Heart Failure Mortality or Heart Failure Hospitalization at Given Time Points Percentage at 2 Years	12.9 percentage of participants	13.7 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Heart Failure Mortality or Heart Failure Hospitalization at Given Time Points Percentage at 3 Years	15.7 percentage of participants	17.2 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Heart Failure Mortality or Heart Failure Hospitalization at Given Time Points Percentage at 4 Years	19.8 percentage of participants	20.3 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Heart Failure Mortality or Heart Failure Hospitalization at Given Time Points Percentage at 5 Years	23.6 percentage of participants	23.8 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 14

Population: Participants with baseline score and score at timepoint.

Mean score and adjusted mean change from baseline in Minnesota Living with Heart Failure (MLWHF) questionnaire, a 21-item, patient-reported, 6-point (ranging from 0-5; higher score=poorer quality of life; highest possible score=105) measurement of quality of life in persons with heart failure.

Outcome measures

Outcome measures
Measure	Irbesartan n=1552 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=1550 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 n=1434 Participants Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 n=1428 Participants Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Minnesota Living With Heart Failure (MLwHF) Total Score (Sum of Questions 1-21) at Month 6 and Month 14 Baseline Mean Score	42.7 units on a scale Standard Error 0.52	43.0 units on a scale Standard Error 0.53	42.7 units on a scale Standard Error 0.53	42.8 units on a scale Standard Error 0.55	—	—
Minnesota Living With Heart Failure (MLwHF) Total Score (Sum of Questions 1-21) at Month 6 and Month 14 Mean Score at Timepoint	32.9 units on a scale Standard Error 0.48	33.2 units on a scale Standard Error 0.50	31.6 units on a scale Standard Error 0.50	32.1 units on a scale Standard Error 0.50	—	—
Minnesota Living With Heart Failure (MLwHF) Total Score (Sum of Questions 1-21) at Month 6 and Month 14 Adjusted Mean Change from Baseline	-10.0 units on a scale Standard Error 0.41	-9.8 units on a scale Standard Error 0.41	-11.2 units on a scale Standard Error 0.42	-10.6 units on a scale Standard Error 0.42	—	—

SECONDARY outcome

Timeframe: Baseline, Final Visit=last scheduled visit specified in the protocol at conclusion of the entire study by the sponsor. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years.

Population: Participants with baseline score and score at timepoint.

Mean score at baseline and final visit in Minnesota Living with Heart Failure (MLWHF) questionnaire, a 21-item, patient-reported, 6-point (ranging from 0-5; higher score=poorer quality of life; highest possible score=105) measurement of quality of life in persons with heart failure.

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Minnesota Living With Heart Failure (MLwHF) Total Score (Sum of Questions 1-21) at Final Visit Baseline Mean	42.5 units on a scale Standard Error 0.49	38.9 units on a scale Standard Error 0.67	—	—	—	—
Minnesota Living With Heart Failure (MLwHF) Total Score (Sum of Questions 1-21) at Final Visit Final Visit Mean	42.6 units on a scale Standard Error 0.51	38.3 units on a scale Standard Error 0.69	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 14

Population: number of participants with measurement at baseline and at timepoint

Adjusted ratio to baseline in geometric mean in Pro-BNP in the blood. Ratio to Baseline = On-therapy geometric mean divided by baseline geometric mean. A lower score signifies improvement. Change from baseline adjusted for baseline value and angiotensin converting enzyme inhibitor use at baseline. Analysis uses natural logarithms of excretion rate values.

Outcome measures

Outcome measures
Measure	Irbesartan n=1336 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=1337 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 n=1295 Participants Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 n=1281 Participants Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Change From Baseline in B-Type Natriuretic Peptide (Pro-BNP) at Month 6 and Month 14	0.98 pg/mL Standard Error 0.023	0.93 pg/mL Standard Error 0.022	1.00 pg/mL Standard Error 0.026	1.01 pg/mL Standard Error 0.026	—	—

SECONDARY outcome

Timeframe: Year 1, Year 2, Year 3, Year 4, Year 5

Population: Randomized Participants

Treatment comparisons for time to cardiovascular death, non-fatal MI, or non-fatal stroke.

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Percentage of Participants Experiencing CV Death, Non-Fatal Myocardial Infarction (MI), or Non-Fatal Stroke at Given Timepoints Percentage at 1 Year	5.2 percentage of participants	4.2 percentage of participants	—	—	—	—
Percentage of Participants Experiencing CV Death, Non-Fatal Myocardial Infarction (MI), or Non-Fatal Stroke at Given Timepoints Percentage at 2 Years	8.7 percentage of participants	9.3 percentage of participants	—	—	—	—
Percentage of Participants Experiencing CV Death, Non-Fatal Myocardial Infarction (MI), or Non-Fatal Stroke at Given Timepoints Percentage at 3 Years	12.9 percentage of participants	13.6 percentage of participants	—	—	—	—
Percentage of Participants Experiencing CV Death, Non-Fatal Myocardial Infarction (MI), or Non-Fatal Stroke at Given Timepoints Percentage at 4 Years	17.2 percentage of participants	17.6 percentage of participants	—	—	—	—
Percentage of Participants Experiencing CV Death, Non-Fatal Myocardial Infarction (MI), or Non-Fatal Stroke at Given Timepoints Percentage at 5 Years	23.0 percentage of participants	22.4 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Year 1, Year 2, Year 3, Year 4, Year 5

Population: Randomized Subjects

Treatment comparisons for time to cardiovascular death

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Percentage of Participants Experiencing Cardiovascular Death at Given Timepoints Percentage 1 Year	3.3 percentage of participants	3.0 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Cardiovascular Death at Given Timepoints Percentage 2 Years	6.2 percentage of participants	6.5 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Cardiovascular Death at Given Timepoints Percentage 3 Years	9.6 percentage of participants	10.0 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Cardiovascular Death at Given Timepoints Percentage at 4 Years	13.0 percentage of participants	13.1 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Cardiovascular Death at Given Timepoints Percentage at 5 Years	18.0 percentage of participants	17.1 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Year 1, Year 2, Year 3, Year 4, Year 5

Population: Randomized subjects

Treatment comparisons for time to all-cause death

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Percentage of Participants Experiencing All-cause Death at Given Time Points Percentage at 1 Year	4.1 percentage of participants	3.8 percentage of participants	—	—	—	—
Percentage of Participants Experiencing All-cause Death at Given Time Points Percentage at 2 Years	8.1 percentage of participants	8.6 percentage of participants	—	—	—	—
Percentage of Participants Experiencing All-cause Death at Given Time Points Percentage at 3 Years	12.8 percentage of participants	13.8 percentage of participants	—	—	—	—
Percentage of Participants Experiencing All-cause Death at Given Time Points Percentage at 4 Years	17.9 percentage of participants	18.5 percentage of participants	—	—	—	—
Percentage of Participants Experiencing All-cause Death at Given Time Points Percentage at 5 Years	25.0 percentage of participants	23.6 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 10, Month 14, Final Visit. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years.

Population: Randomized participants with measurement at baseline and Month 6, Month 10, Month 14, and Final Visit

NYHA functional classification=4-tiered system relating symptoms to everyday activities \& quality of life. (See Reporting Groups for description of each class.) Change of NYHA functional class from baseline was grouped into 3 categories: improved, unchanged, or worsened (based on case report form \[CRF\] assessment). If a post-randomization CRF assessment was missing or participant died, was hospitalized for worsening heart failure or discontinued study medication for worsening heart failure, the participant was classified as Major Event.

Outcome measures

Outcome measures
Measure	Irbesartan n=426 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=1641 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 n=2067 Participants Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 n=445 Participants Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV n=1615 Participants	Placebo Baseline All Classes Combined n=2060 Participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 6 - Improved	55 participants	881 participants	936 participants	47 participants	834 participants	881 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 6 - Unchanged	310 participants	656 participants	966 participants	338 participants	678 participants	1016 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 6 - Worsened	41 participants	7 participants	48 participants	47 participants	4 participants	51 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 6 - Major Event	2 participants	8 participants	10 participants	2 participants	12 participants	14 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 6 - No Data	18 participants	89 participants	107 participants	11 participants	87 participants	98 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 10 - Improved	44 participants	904 participants	948 participants	42 participants	860 participants	902 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 10 - Unchanged	294 participants	617 participants	911 participants	317 participants	622 participants	939 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 10 - Worsened	53 participants	5 participants	58 participants	63 participants	8 participants	71 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 10 - Major Event	10 participants	31 participants	41 participants	9 participants	33 participants	42 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 10 - No Data	25 participants	84 participants	109 participants	14 participants	92 participants	106 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 14 - Improved	38 participants	895 participants	933 participants	39 participants	863 participants	902 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 14 - Unchanged	287 participants	579 participants	866 participants	312 participants	578 participants	890 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 14 - Worsened	50 participants	11 participants	61 participants	62 participants	7 participants	69 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 14 - Major Event	22 participants	53 participants	75 participants	16 participants	64 participants	80 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Month 14 - No Data	29 participants	103 participants	132 participants	16 participants	103 participants	119 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Final Visit - Improved	42 participants	886 participants	928 participants	42 participants	840 participants	882 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Final Visit - Unchanged	230 participants	428 participants	658 participants	254 participants	440 participants	694 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Final Visit - Worsened	68 participants	29 participants	97 participants	78 participants	29 participants	107 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Final Visit - Major Event	75 participants	249 participants	324 participants	66 participants	254 participants	320 participants
Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit Final Visit - No Data	11 participants	49 participants	60 participants	5 participants	52 participants	57 participants

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 14, Final Visit. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years.

This was an assessment of the change in overall physician opinion of change from baseline status. Assessments are directly based on the Case Report Form (CRF). If the post-randomization CRF assessment was missing and the subject died, was hospitalized for worsening heart failure, or discontinued study medication for worsening heart failure, the subject was considered as having a Major Event. Participants who are summarized under Major Events are categorized as Worsened Markedly.

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - No Data	185 participants	169 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Markedly	180 participants	186 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Moderately	430 participants	367 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Slightly	344 participants	361 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Unchanged	477 participants	504 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Slightly	117 participants	117 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Moderately	41 participants	56 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Markedly	23 participants	28 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Major Event	364 participants	350 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - No Data	91 participants	92 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Markedly	230 participants	198 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Moderately	562 participants	575 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Slightly	533 participants	529 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Unchanged	528 participants	541 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Slightly	60 participants	58 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Moderately	17 participants	16 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Markedly	0 participants	4 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Major Event	8 participants	8 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - No Data	129 participants	132 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Markedly	214 participants	195 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Moderately	546 participants	537 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Slightly	442 participants	435 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Unchanged	507 participants	548 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Slightly	72 participants	73 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Moderately	21 participants	19 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Markedly	5 participants	6 participants	—	—	—	—
Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Major Event	75 participants	79 participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 14, Final Visit. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years.

Population: Randomized Participants

Assessments are directly based on the Case Report Form (CRF). If the post-randomization CRF assessment was missing and the subject died, was hospitalized for worsening heart failure, or discontinued study medication for worsening heart failure, the subject was considered as having a Major Event. Participants who are summarized under Major Events are categorized as Worsened Markedly.

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Moderately	378 Participants	339 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Slightly	332 Participants	352 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Unchanged	480 Participants	495 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Slightly	121 Participants	109 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Moderately	52 Participants	76 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Markedly	25 Participants	28 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Major Event	396 Participants	383 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Event - No Data	76 Participants	78 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Markedly	235 Participants	230 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Moderately	552 Participants	563 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Slightly	529 Participants	519 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Unchanged	537 Participants	529 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Slightly	63 Participants	69 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Moderately	13 Participants	20 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Markedly	8 Participants	8 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Major Event	8 Participants	7 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - No Data	122 Participants	116 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Markedly	234 Participants	206 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Moderately	532 Participants	534 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Slightly	461 Participants	450 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Unchanged	503 Participants	527 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Slightly	78 Participants	82 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Moderately	30 Participants	35 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Markedly	8 Participants	7 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Major Event	68 Participants	74 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - No Data	153 Participants	146 Participants	—	—	—	—
Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Markedly	207 Participants	201 Participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 14, Final Visit. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years.

Population: Randomized Participants

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Markedly	193 Participants	200 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Moderately	523 Participants	519 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Slightly	504 Participants	471 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Unchanged	579 Participants	596 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Slightly	97 Participants	101 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Moderately	28 Participants	38 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Markedly	13 Participants	13 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Major Event	8 Participants	7 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - No Data	122 Participants	116 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Markedly	195 Participants	182 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Moderately	513 Participants	489 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Slightly	439 Participants	443 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Unchanged	525 Participants	559 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Slightly	115 Participants	109 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Moderately	48 Participants	43 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Markedly	11 Participants	16 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Major Event	68 Participants	74 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - No Data	153 Participants	146 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Markedly	157 Participants	178 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Moderately	361 Participants	300 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Slightly	319 Participants	337 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Unchanged	479 Participants	477 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Slightly	166 Participants	176 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Moderately	80 Participants	90 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Markedly	34 Participants	42 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Major Event	395 Participants	383 Participants	—	—	—	—
Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - No Data	76 Participants	78 Participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 14, Final Visit. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years.

Population: Randomized Participants

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Markedly	255 Participants	276 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Moderately	549 Participants	536 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Improved Slightly	512 Participants	501 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Unchanged	508 Participants	510 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Slightly	83 Participants	83 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Moderately	22 Participants	22 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Worsened Markedly	9 Participants	10 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - Major Event	8 Participants	7 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 6 - No Data	121 Participants	116 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Markedly	247 Participants	232 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Moderately	519 Participants	531 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Improved Slightly	460 Participants	430 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Unchanged	476 Participants	509 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Slightly	103 Participants	90 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Moderately	28 Participants	39 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Worsened Markedly	13 Participants	10 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - Major Event	68 Participants	74 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Month 14 - No Data	153 Participants	146 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Markedly	213 Participants	212 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Moderately	382 Participants	339 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Improved Slightly	328 Participants	335 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Unchanged	460 Participants	461 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Slightly	114 Participants	145 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Moderately	64 Participants	75 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Worsened Markedly	35 Participants	32 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - Major Event	395 Participants	384 Participants	—	—	—	—
Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline Final Visit - No Data	76 Participants	78 Participants	—	—	—	—

SECONDARY outcome

Timeframe: Year 1, Year 2, Year 3, Year 4, Year 5

Population: randomized participants

Treatment comparisons for time to CV death or CV hospitalization. Protocol-specified CV hospitalizations include hospitalizations ≥24 hrs or involve a calendar date change for a primary cause of worsening heart failure, unstable angina, myocardial infarction, ventricular dysrhythmia, atrial dysrhythmia or stroke that also requires intravenous or intramuscular therapy or a related procedure or significant augmentation of oral therapy. Protocol specified CV hospitalizations also include myocardial infarction or stroke occurring during any hospitalization.

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Percentage of Participants Experiencing CV Death or CV Hospitalization at Given Timepoints Percentage at 1 Year	11.6 percentage of participants	11.4 percentage of participants	—	—	—	—
Percentage of Participants Experiencing CV Death or CV Hospitalization at Given Timepoints Percentage at 2 Years	19.2 percentage of participants	20.0 percentage of participants	—	—	—	—
Percentage of Participants Experiencing CV Death or CV Hospitalization at Given Timepoints Percentage at 3 Years	24.2 percentage of participants	25.8 percentage of participants	—	—	—	—
Percentage of Participants Experiencing CV Death or CV Hospitalization at Given Timepoints Percentage at 4 Years	30.0 percentage of participants	30.9 percentage of participants	—	—	—	—
Percentage of Participants Experiencing CV Death or CV Hospitalization at Given Timepoints Percentage at 5 Years	35.0 percentage of participants	35.8 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Year 1, Year 2, Year 3, Year 4, Year 5

Treatment comparisons for time to protocol-specified CV hospitalization. Protocol-specified CV hospitalizations include hospitalizations ≥24 hrs or involve a calendar date change for a primary cause of worsening heart failure, unstable angina, myocardial infarction, ventricular dysrhythmia, atrial dysrhythmia or stroke that also requires intravenous or intramuscular therapy or a related procedure or significant augmentation of oral therapy. Protocol specified CV hospitalizations also include myocardial infarction or stroke occurring during any hospitalization.

Outcome measures

Outcome measures
Measure	Irbesartan n=2067 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=2061 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Percentage of Participants Experiencing Protocol-specified Cardiovascular (CV) Hospitalization at Given Timepoints Percentage at 1 Year	9.7 percentage of participants	9.8 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Protocol-specified Cardiovascular (CV) Hospitalization at Given Timepoints Percentage at 2 Years	16.3 percentage of participants	17.1 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Protocol-specified Cardiovascular (CV) Hospitalization at Given Timepoints Percentage at 3 Years	20.5 percentage of participants	21.7 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Protocol-specified Cardiovascular (CV) Hospitalization at Given Timepoints Percentage at 4 Years	24.8 percentage of participants	25.9 percentage of participants	—	—	—	—
Percentage of Participants Experiencing Protocol-specified Cardiovascular (CV) Hospitalization at Given Timepoints Percentage at 5 Years	28.5 percentage of participants	29.0 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Year 1, Year 2, Year 3, Year 4, Year 5

Population: Randomized participants with no prior diabetes history

Treatment comparisons for time to new onset of diabetes (from adverse event reporting) among subjects with no prior history of diabetes.

Outcome measures

Outcome measures
Measure	Irbesartan n=1495 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=1496 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Percentage of Participants With New Onset of Diabetes Among Subjects With No Prior Diabetes History at Given Timepoints Percentage at 1 Year	0.7 percentage of participants	1.2 percentage of participants	—	—	—	—
Percentage of Participants With New Onset of Diabetes Among Subjects With No Prior Diabetes History at Given Timepoints Percentage at 2 Years	2.1 percentage of participants	2.8 percentage of participants	—	—	—	—
Percentage of Participants With New Onset of Diabetes Among Subjects With No Prior Diabetes History at Given Timepoints Percentage at 3 Years	3.1 percentage of participants	3.9 percentage of participants	—	—	—	—
Percentage of Participants With New Onset of Diabetes Among Subjects With No Prior Diabetes History at Given Timepoints Percentage at 4 Years	4.6 percentage of participants	5.4 percentage of participants	—	—	—	—
Percentage of Participants With New Onset of Diabetes Among Subjects With No Prior Diabetes History at Given Timepoints Percentage at 5 Years	5.2 percentage of participants	6.2 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, Month 6, Month 18, Month 30

Population: Participants with baseline score and score at timepoint.

Based on the Cockcroft-Gault formula calculation, a commonly used surrogate marker to estimate creatinine clearance, which in turn is an approximate measure of GFR. It employs serum creatinine measurements and a patient's weight to predict the creatinine clearance. Adjusted for baseline GFR and angiotensin-converting enzyme inhibitor use at baseline (ACE-I). A decrease from baseline signifies worsening. The adjusted mean change from baseline value is from the model (calculated prior to rounding), whereas the other two points are the baseline mean and post mean.

Outcome measures

Outcome measures
Measure	Irbesartan n=1741 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=1734 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 n=1406 Participants Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 n=1379 Participants Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV n=1270 Participants	Placebo Baseline All Classes Combined n=1225 Participants
Mean Change From Baseline in Glomerular Filtration Rate (GFR) at Month 6, Month 18, and Month 30 Baseline Mean	73.02 mL/min/1.73m2 Standard Error 0.536	73.13 mL/min/1.73m2 Standard Error 0.538	73.58 mL/min/1.73m2 Standard Error 0.589	73.49 mL/min/1.73m2 Standard Error 0.591	73.34 mL/min/1.73m2 Standard Error 0.606	74.37 mL/min/1.73m2 Standard Error 0.630
Mean Change From Baseline in Glomerular Filtration Rate (GFR) at Month 6, Month 18, and Month 30 Post-Baseline Mean	71.97 mL/min/1.73m2 Standard Error 0.527	69.21 mL/min/1.73m2 Standard Error 0.562	70.88 mL/min/1.73m2 Standard Error 0.583	68.00 mL/min/1.73m2 Standard Error 0.596	69.51 mL/min/1.73m2 Standard Error 0.589	67.05 mL/min/1.73m2 Standard Error 0.595
Mean Change From Baseline in Glomerular Filtration Rate (GFR) at Month 6, Month 18, and Month 30 Adjusted Mean Change	-1.07 mL/min/1.73m2 Standard Error 0.393	-3.91 mL/min/1.73m2 Standard Error 0.394	-2.69 mL/min/1.73m2 Standard Error 0.436	-5.50 mL/min/1.73m2 Standard Error 0.440	-4.02 mL/min/1.73m2 Standard Error 0.442	-7.12 mL/min/1.73m2 Standard Error 0.450

SECONDARY outcome

Timeframe: Baseline, Month 42, Month 54, Month 66

Population: Participants with baseline score and score at timepoint.

Outcome measures

Outcome measures
Measure	Irbesartan n=928 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=921 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 n=429 Participants Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 n=455 Participants Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV n=22 Participants	Placebo Baseline All Classes Combined n=22 Participants
Mean Change From Baseline in Glomerular Filtration Rate (GFR)at Month 42, Month 54, Month 66 Baseline Mean	74.37 mL/min/1.73m2 Standard Error 0.715	74.95 mL/min/1.73m2 Standard Error 0.711	75.29 mL/min/1.73m2 Standard Error 1.075	75.17 mL/min/1.73m2 Standard Error 1.052	63.47 mL/min/1.73m2 Standard Error 5.596	71.84 mL/min/1.73m2 Standard Error 5.919
Mean Change From Baseline in Glomerular Filtration Rate (GFR)at Month 42, Month 54, Month 66 Post-Baseline Mean	71.34 mL/min/1.73m2 Standard Error 0.700	67.48 mL/min/1.73m2 Standard Error 0.715	72.65 mL/min/1.73m2 Standard Error 1.048	68.24 mL/min/1.73m2 Standard Error 1.055	60.09 mL/min/1.73m2 Standard Error 5.832	64.85 mL/min/1.73m2 Standard Error 6.301
Mean Change From Baseline in Glomerular Filtration Rate (GFR)at Month 42, Month 54, Month 66 Adjusted Mean Change	-3.14 mL/min/1.73m2 Standard Error 0.559	-7.36 mL/min/1.73m2 Standard Error 0.561	-2.63 mL/min/1.73m2 Standard Error 0.863	-6.93 mL/min/1.73m2 Standard Error 0.838	-4.91 mL/min/1.73m2 Standard Error 4.534	-5.46 mL/min/1.73m2 Standard Error 4.534

SECONDARY outcome

Timeframe: Baseline, Final Visit

Population: Randomized subjects (total=4128) with no prior AF history or evidence of AF on baseline ECG, stratified by use of ACE-I

Frequency of new onset AF in participants with no prior AF history or evidence of AF on baseline ECG. Stratified by use of angiotensin-converting enzyme (ACE) inhibitors and measured by adverse events reporting and final ECG recording read by the investigator.

Outcome measures

Outcome measures
Measure	Irbesartan n=538 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo n=510 Participants titration from 75 to 300 mg, once daily (QD), up to 6 years	Placebo - Month 14 n=1529 Participants Cohort of participants in Placebo group with MLwHF scores at Baseline and Month 14	Irbesartan - Month 14 n=1551 Participants Cohort of participants in Irbesartan group with MLwHF scores at Baseline and Month 14	Placebo Class III or IV	Placebo Baseline All Classes Combined
Number of Participants With New Onset Atrial Fibrillation (AF) Among Those With No Prior AF History or Evidence of AF on Baseline Electrocardiograph (ECG) No prior AF history or Evidence on Baseline ECG	366 participants	344 participants	1089 participants	1102 participants	—	—
Number of Participants With New Onset Atrial Fibrillation (AF) Among Those With No Prior AF History or Evidence of AF on Baseline Electrocardiograph (ECG) Participants with New Onset Atrial Fibrillation	35 participants	29 participants	103 participants	99 participants	—	—

Adverse Events

IRBESARTAN

Serious events: 1146 serious events

Other events: 1255 other events

Deaths: 0 deaths

PLACEBO

Serious events: 1155 serious events

Other events: 1191 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

BMS Study Director

Britol-Myers Squibb

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	IRBESARTAN n=2064 participants at risk titration from 75 to 300 mg, once daily (QD), up to 6 years	PLACEBO n=2062 participants at risk titration from 75 to 300 mg, once daily (QD), up to 6 years
Cardiac disorders CARDIAC FAILURE	6.4% 133/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	6.5% 134/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Cardiac disorders ATRIAL FIBRILLATION	5.2% 108/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	5.3% 110/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Vascular disorders HYPOTENSION	9.8% 203/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	4.5% 93/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Vascular disorders HYPERTENSION	9.8% 202/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	12.2% 252/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Nervous system disorders HEADACHE	6.1% 126/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	6.7% 138/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Nervous system disorders DIZZINESS	12.7% 262/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	12.3% 253/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Gastrointestinal disorders DIARRHOEA	6.2% 127/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	4.3% 89/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Infections and infestations INFLUENZA	6.0% 124/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	5.4% 111/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Infections and infestations BRONCHITIS	8.5% 176/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	9.9% 205/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Infections and infestations NASOPHARYNGITIS	8.7% 180/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	8.4% 174/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Musculoskeletal and connective tissue disorders BACK PAIN	6.4% 132/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	5.7% 117/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Musculoskeletal and connective tissue disorders ARTHRALGIA	5.2% 108/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	5.0% 104/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Respiratory, thoracic and mediastinal disorders COUGH	4.8% 99/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	5.7% 117/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
Respiratory, thoracic and mediastinal disorders DYSPNOEA	8.6% 177/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	10.5% 217/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
General disorders FATIGUE	5.2% 108/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	4.7% 96/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
General disorders CHEST PAIN	7.3% 150/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	6.6% 136/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.
General disorders OEDEMA PERIPHERAL	9.9% 204/2064 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.	9.9% 205/2062 • SAEs: from start of study through last treatment +30 days; AEs: through the last dose +1 day.