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

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition:	Congestive Heart Failure
Interventions:	Drug: Irbesartan Drug: Placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
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

Participant Flow: Overall Study

	Irbesartan	Placebo
STARTED	2067 ^[1]	2061 ^[1]
Safety (Treated) Population	2064 ^[2]	2062 ^[3]
COMPLETED	1210 ^[4]	1209 ^[4]
NOT COMPLETED	857	852
Lack of Efficacy	9	9
Adverse Event	331	287
Subject Withdrew Consent	208	223
Death	154	170
Lost to Follow-up	19	24
Noncompliance	44	45
No longer met study criteria	4	5
Study terminated by sponsor	0	1
Missing	1	0
Other Reasons	87	88

[1]	number randomized
[2]	Two participants were randomized but not treated; 1 randomized to irbesartan received placebo
[3]	One participant randomized to irbesartan received placebo.
[4]	completed double-blind therapy

Baseline Characteristics

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Reporting Groups

	Description
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

Baseline Measures

	Irbesartan	Placebo	Total
Number of Participants [units: participants]	2067	2061	4128
Age, Customized [units: participants]
< 65 years	376	364	740
Between 65 and 74 years	994	981	1975
>=75 years	697	716	1413
Age [units: years] Mean ± Standard Deviation	71.6 ± 6.90	71.7 ± 7.00	71.6 ± 6.95
Gender [units: participants]
Female	1227	1264	2491
Male	840	797	1637
Race/Ethnicity, Customized [units: participants]
White	1934	1925	3859
Black or African American	39	43	82
Asian	19	15	34
American Indian or Alaska Native	0	0	0
Native Hawaiian or other Pacific Islander	0	1	1
Other	75	77	152
New York Heart Association (NYHA) Class ^[1] [units: participants]
Class I (Mild)	0	1	1
Class II (Mild)	426	444	870
Class III (Moderate)	1582	1562	3144
Class IV (Severe)	59	53	112
B-Type Natriuretic Peptide (Pro-BNP) ^[2] [units: pg/mL] Geometric Mean ( Inter-Quartile Range )	363.0 ( 140.0 to 994.0 )	345.2 ( 131.0 to 948.0 )	353.9 ( 135.0 to 974.0 )

[1]	1 participant in Placebo was not classified. NYHA Classes: I=No limitation of physical activity (does not cause undue fatigue, palpitation, or dyspnea). II=Slight limitation of physical activity (comfortable at rest, ordinary physical activity results in fatigue, palpitation, or dyspnea). III=Marked limitation of physical activity (comfortable at rest, less than ordinary activity causes fatigue, palpitation, or dyspnea). IV=Unable to carry out any physical activity without discomfort (symptoms of cardiac insufficiency at rest; discomfort is increased if any physical activity is undertaken).
[2]	Participant population=those participants with a baseline Pro-BNP measurement. Irbesartan (n=1765), Placebo (n=1798), Total (n=3563)

[1]

1 participant in Placebo was not classified. NYHA Classes: I=No limitation of physical activity (does not cause undue fatigue, palpitation, or dyspnea). II=Slight limitation of physical activity (comfortable at rest, ordinary physical activity results in fatigue, palpitation, or dyspnea). III=Marked limitation of physical activity (comfortable at rest, less than ordinary activity causes fatigue, palpitation, or dyspnea). IV=Unable to carry out any physical activity without discomfort (symptoms of cardiac insufficiency at rest; discomfort is increased if any physical activity is undertaken).

[2]

Participant population=those participants with a baseline Pro-BNP measurement. Irbesartan (n=1765), Placebo (n=1798), Total (n=3563)

Outcome Measures

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1. Primary:

Percentage of Participants With First Occurrence of the Composite Outcome of Death (All Cause) or Protocol-Specified Cardiovascular (CV) Hospitalization at Given Timepoints [ Time Frame: Year 1, Year 2, Year 3, Year 4, Year 5 ]

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2. Secondary:

Percentage of Participants Experiencing Heart Failure Mortality or Heart Failure Hospitalization at Given Time Points [ Time Frame: Year 1, Year 2, Year 3, Year 4, Year 5 ]

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3. Secondary:

Minnesota Living With Heart Failure (MLwHF) Total Score (Sum of Questions 1-21) at Month 6 and Month 14 [ Time Frame: Baseline, Month 6, Month 14 ]

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4. Secondary:

Minnesota Living With Heart Failure (MLwHF) Total Score (Sum of Questions 1-21) at Final Visit [ Time Frame: 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. ]

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5. Secondary:

Change From Baseline in B-Type Natriuretic Peptide (Pro-BNP) at Month 6 and Month 14 [ Time Frame: Baseline, Month 6, Month 14 ]

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6. Secondary:

Percentage of Participants Experiencing CV Death, Non-Fatal Myocardial Infarction (MI), or Non-Fatal Stroke at Given Timepoints [ Time Frame: Year 1, Year 2, Year 3, Year 4, Year 5 ]

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7. Secondary:

Percentage of Participants Experiencing Cardiovascular Death at Given Timepoints [ Time Frame: Year 1, Year 2, Year 3, Year 4, Year 5 ]

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8. Secondary:

Percentage of Participants Experiencing All-cause Death at Given Time Points [ Time Frame: Year 1, Year 2, Year 3, Year 4, Year 5 ]

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9. Secondary:

Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit [ Time Frame: 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. ]

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10. Secondary:

Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline [ Time Frame: 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. ]

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11. Secondary:

Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline [ Time Frame: 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. ]

Show Outcome Measure 11

12. Secondary:

Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline [ Time Frame: 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. ]

Show Outcome Measure 12

13. Secondary:

Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline [ Time Frame: 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. ]

Show Outcome Measure 13

14. Secondary:

Percentage of Participants Experiencing CV Death or CV Hospitalization at Given Timepoints [ Time Frame: Year 1, Year 2, Year 3, Year 4, Year 5 ]

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15. Secondary:

Percentage of Participants Experiencing Protocol-specified Cardiovascular (CV) Hospitalization at Given Timepoints [ Time Frame: Year 1, Year 2, Year 3, Year 4, Year 5 ]

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16. Secondary:

Percentage of Participants With New Onset of Diabetes Among Subjects With No Prior Diabetes History at Given Timepoints [ Time Frame: Year 1, Year 2, Year 3, Year 4, Year 5 ]

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17. Secondary:

Mean Change From Baseline in Glomerular Filtration Rate (GFR) at Month 6, Month 18, and Month 30 [ Time Frame: Baseline, Month 6, Month 18, Month 30 ]

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18. Secondary:

Mean Change From Baseline in Glomerular Filtration Rate (GFR)at Month 42, Month 54, Month 66 [ Time Frame: Baseline, Month 42, Month 54, Month 66 ]

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19. Secondary:

Number of Participants With New Onset Atrial Fibrillation (AF) Among Those With No Prior AF History or Evidence of AF on Baseline Electrocardiograph (ECG) [ Time Frame: Baseline, Final Visit ]

Show Outcome Measure 19

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS 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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: BMS Study Director
Organization: Britol-Myers Squibb
e-mail: Clinical.Trials@bms.com

Publications of Results:

Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A; I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008 Dec 4;359(23):2456-67. Epub 2008 Nov 11.

Zile MR, Gaasch WH, Anand IS, Haass M, Little WC, Miller AB, Lopez-Sendon J, Teerlink JR, White M, McMurray JJ, Komajda M, McKelvie R, Ptaszynska A, Hetzel SJ, Massie BM, Carson PE; I-Preserve Investigators. Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial. Circulation. 2010 Mar 30;121(12):1393-405. Epub 2010 Mar 15.

McMurray JJ, Carson PE, Komajda M, McKelvie R, Zile MR, Ptaszynska A, Staiger C, Donovan JM, Massie BM. Heart failure with preserved ejection fraction: clinical characteristics of 4133 patients enrolled in the I-PRESERVE trial. Eur J Heart Fail. 2008 Feb;10(2):149-56.

Carson P, Massie BM, McKelvie R, McMurray J, Komajda M, Zile M, Ptaszynska A, Frangin G; for the I-PRESERVE Investigators. The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and design. J Card Fail. 2005 Oct;11(8):576-85.

McKelvie RS, Komajda M, McMurray J, Zile M, Ptaszynska A, Donovan M, Carson P, Massie BM; I-Preserve Investigators. Baseline plasma NT-proBNP and clinical characteristics: results from the irbesartan in heart failure with preserved ejection fraction trial. J Card Fail. 2010 Feb;16(2):128-34. Epub 2009 Nov 4.

Publications automatically indexed to this study:

Zile MR, Gottdiener JS, Hetzel SJ, McMurray JJ, Komajda M, McKelvie R, Baicu CF, Massie BM, Carson PE; I-PRESERVE Investigators. Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction. Circulation. 2011 Dec 6;124(23):2491-501. Epub 2011 Nov 7.

Krum H, Elsik M, Schneider HG, Ptaszynska A, Black M, Carson PE, Komajda M, Massie BM, McKelvie RS, McMurray JJ, Zile MR, Anand IS. Relation of peripheral collagen markers to death and hospitalization in patients with heart failure and preserved ejection fraction: results of the I-PRESERVE collagen substudy. Circ Heart Fail. 2011 Sep;4(5):561-8. Epub 2011 Jul 12.

Anand IS, Rector TS, Cleland JG, Kuskowski M, McKelvie RS, Persson H, McMurray JJ, Zile MR, Komajda M, Massie BM, Carson PE. Prognostic value of baseline plasma amino-terminal pro-brain natriuretic peptide and its interactions with irbesartan treatment effects in patients with heart failure and preserved ejection fraction: findings from the I-PRESERVE trial. Circ Heart Fail. 2011 Sep 1;4(5):569-77. Epub 2011 Jun 29.

Komajda M, Carson PE, Hetzel S, McKelvie R, McMurray J, Ptaszynska A, Zile MR, Demets D, Massie BM. Factors associated with outcome in heart failure with preserved ejection fraction: findings from the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE). Circ Heart Fail. 2011 Jan 1;4(1):27-35. Epub 2010 Nov 10.

Responsible Party:	Study Director, Bristol-Myers Squibb
ClinicalTrials.gov Identifier:	NCT00095238 History of Changes
Other Study ID Numbers:	CV131-148
Study First Received:	November 1, 2004
Results First Received:	December 16, 2009
Last Updated:	May 5, 2010
Health Authority:	United States: Food and Drug Administration