PIE II: Pharmacological Intervention in the Elderly II

• Sponsor: Wake Forest University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00123955
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 80
• Location: 1
• Arms: 2
• Duration (Months): 92
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to examine whether spironolactone will improve exercise tolerance and quality of life in elderly patients with heart failure preserved ejection fraction (HFPEF).

Condition or Disease	Intervention/Treatment	Phase
Diastolic Heart Failure; Heart Failure, Congestive	Drug: Spironolactone; Drug: Placebo	Phase 3

Detailed Description

Exercise intolerance due to HFPEF is a major cause of disability among older Americans. Several lines of evidence suggest that aldosterone antagonism may improve exercise tolerance in HFPEF. Therefore, the primary aim of this study is to test the hypothesis that spironolactone will improve exercise tolerance and quality of life in elderly patients with isolated HFPEF. A total of 72 participants aged 60 or older will be randomized to receive either spironolactone 25mg daily or a placebo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Exercise Intolerance in Elderly Diastolic Heart Failure
• Study Start Date: Apr 1, 2005
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Spironolactone	Drug: Spironolactone; 25mg tablet daily for 9 months; Other Names: Aldactone
Placebo Comparator: 2 Placebo	Drug: Placebo; Placebo tablet daily for 9 months

Outcome Measures

Primary Outcome Measures

1. Exercise Intolerance [Baseline, 4 and 9 months]

   Peak exercise VO2

2. Quality of Life Measured by the Minnesota Living With Heart Failure Questionnaire-total Score [Baseline, 4 and 9 months]

   The Minnesota Living with Heart Failure Questionnaire (MLHF) is a self-administered disease-specific questionnaire for patients with Heart Failure, comprising 21 items rated on six-point Likert scales, representing different degrees of impact of HF on HRQoL, from 0 (none) to 5 (very much). It provides a total score (range 0-105, from best to worst HRQoL), as well as scores for two dimensions, physical (8 items, range 0-40) and emotional (5 items, range 0-25). The other eight items (of the total of 21) are only considered for the calculation of the total score. Scale of 0-105:The higher the score the worse the heart failure related Quality of Life.

Secondary Outcome Measures

1. Concentric Left Ventricular Remodeling [Baseline, 9 month]

   Left ventricle measurements by MRI: Mass/end diastolic volume ratio: g/ml

2. Left Ventricular Diastolic Stiffness [Baseline, 4 month and 9 month]

   Echocardiography Doppler measurement of left ventricular diastolic function: Early mitral annulus velocity (lateral) (Ea; cm/s)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ambulatory

• Medically stable

• Ages 60 or older

• Diagnosis of diastolic heart failure

Exclusion Criteria:

• Valvular heart disease

• Significant change in cardiac medication within the past 4 weeks

• Uncontrolled hypertension

• Recent or debilitating stroke

• Cancer or other noncardiovascular conditions with life expectancy less than 2 years

• Anemia

• Elevated serum potassium

• Renal insufficiency

• Psychiatric disease (uncontrolled major psychoses, depression, dementia, or personality disorder)

• Allergy to spironolactone; currently taking spironolactone or any aldosterone antagonist

• Plans to leave area within 1 year

• Refuses informed consent

• Failure to pass screening tests: pulmonary function, echocardiogram, or exercise

• Contra-indications to magnetic resonance imaging [MRI] (indwelling metal-containing prosthesis; pacemaker or defibrillator; history of welding occupation; uncontrollable claustrophobia)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina	United States	27157

Sponsors and Collaborators

• Wake Forest University
• National Institute on Aging (NIA)

Investigators

• Principal Investigator: Dalane W. Kitzman, MD, Professor of Internal Medicine, Cardiology, Director of Echocardiography, Wake Forest University Health Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

• Cicoira M, Zanolla L, Franceschini L, Rossi A, Golia G, Zeni P, Caruso B, Zardini P. Relation of aldosterone "escape" despite angiotensin-converting enzyme inhibitor administration to impaired exercise capacity in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 2002 Feb 15;89(4):403-7.
• Daniel KR, Wells G, Stewart K, Moore B, Kitzman DW. Effect of aldosterone antagonism on exercise tolerance, Doppler diastolic function, and quality of life in older women with diastolic heart failure. Congest Heart Fail. 2009 Mar-Apr;15(2):68-74. doi: 10.1111/j.1751-7133.2009.00056.x.
• Kitzman DW, Gardin JM, Gottdiener JS, Arnold A, Boineau R, Aurigemma G, Marino EK, Lyles M, Cushman M, Enright PL; Cardiovascular Health Study Research Group. Importance of heart failure with preserved systolic function in patients > or = 65 years of age. CHS Research Group. Cardiovascular Health Study. Am J Cardiol. 2001 Feb 15;87(4):413-9.
• Kitzman DW, Herrington DM, Brubaker PH, Moore JB, Eggebeen J, Haykowsky MJ. Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction. Hypertension. 2013 Jan;61(1):112-9. doi: 10.1161/HYPERTENSIONAHA.111.00163. Epub 2012 Nov 12.
• Kitzman DW, Higginbotham MB, Cobb FR, Sheikh KH, Sullivan MJ. Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol. 1991 Apr;17(5):1065-72.
• Kitzman DW, Little WC, Brubaker PH, Anderson RT, Hundley WG, Marburger CT, Brosnihan B, Morgan TM, Stewart KP. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002 Nov 6;288(17):2144-50.
• Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep 2;341(10):709-17.
• Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000 Nov 28;102(22):2700-6. Erratum in: Circulation 2001 Jan 23;103(3):476.

• Responsible Party: Wake Forest University
• ClinicalTrials.gov Identifier: NCT00123955
• Other Study ID Numbers: AG0030; R01AG018915; 2R01AG018915-05
• First Posted: Jul 26, 2005
• Last Update Posted: Feb 27, 2019
• Last Verified: Feb 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Heart Failure; Heart Failure, Diastolic; Spironolactone

Study Results

Participant Flow

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone Spironolactone: 25mg tablet daily for 9 months	Placebo Placebo: Placebo tablet daily for 9 months
Period Title: Overall Study
STARTED	42	38
COMPLETED	37	34
NOT COMPLETED	5	4

Baseline Characteristics

Arm/Group Title	Spironolactone	Placebo	Total
Arm/Group Description	Spironolactone Spironolactone: 25mg tablet daily for 9 months	Placebo Placebo: Placebo tablet daily for 9 months	Total of all reporting groups
Overall Participants	42	38	80
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.0 (7.3)	71.7 (7.3)	70.8 (7.3)
Sex: Female, Male (Count of Participants)
Female	34 81%	30 78.9%	64 80%
Male	8 19%	8 21.1%	16 20%
Peak VO2 (ml/kg/min) (ml/kg/min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/kg/min]	13.5 (2.9)	13.3 (2.9)	13.4 (2.9)
Workload (Watts) (Watts) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Watts]	63 (26)	60 (26)	62 (26)

Outcome Measures

1. Primary Outcome

Title	Exercise Intolerance
Description	Peak exercise VO2
Time Frame	Baseline, 4 and 9 months

Outcome Measure Data

Analysis Population Description

The outcome measure data uses data from all participants with 4 and/or 9 month follow-up. Thirty-seven participants randomized to spironolactone and 35 participants randomized to placebo completed 4 months of follow-up, and 37 participants randomized to spironolactone and 34 participants randomized to placebo completed 9 months of follow-up.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone Spironolactone: 25mg tablet daily for 9 months	Placebo Placebo: Placebo tablet daily for 9 months
Measure Participants	37	35
Baseline	13.5 (2.9)	13.3 (2.9)
4 months	13.6 (3.5)	13.5 (3.4)
9 months	13.8 (3.2)	13.9 (3.7)

2. Primary Outcome

Title	Quality of Life Measured by the Minnesota Living With Heart Failure Questionnaire-total Score
Description	The Minnesota Living with Heart Failure Questionnaire (MLHF) is a self-administered disease-specific questionnaire for patients with Heart Failure, comprising 21 items rated on six-point Likert scales, representing different degrees of impact of HF on HRQoL, from 0 (none) to 5 (very much). It provides a total score (range 0-105, from best to worst HRQoL), as well as scores for two dimensions, physical (8 items, range 0-40) and emotional (5 items, range 0-25). The other eight items (of the total of 21) are only considered for the calculation of the total score. Scale of 0-105:The higher the score the worse the heart failure related Quality of Life.
Time Frame	Baseline, 4 and 9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone Spironolactone: 25mg tablet daily for 9 months	Placebo Placebo: Placebo tablet daily for 9 months
Measure Participants	37	35
Baseline	32 (21)	28 (19)
4 months	29 (20)	29 (23)
Final- 9 months	29 (18)	25 (18)

3. Secondary Outcome

Title	Concentric Left Ventricular Remodeling
Description	Left ventricle measurements by MRI: Mass/end diastolic volume ratio: g/ml
Time Frame	Baseline, 9 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone Spironolactone: 25mg tablet daily for 9 months	Placebo Placebo: Placebo tablet daily for 9 months
Measure Participants	37	35
baseline	1.8 (.4)	1.7 (.5)
9 month	1.7 (.4)	1.6 (.4)

4. Secondary Outcome

Title	Left Ventricular Diastolic Stiffness
Description	Echocardiography Doppler measurement of left ventricular diastolic function: Early mitral annulus velocity (lateral) (Ea; cm/s)
Time Frame	Baseline, 4 month and 9 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone Spironolactone: 25mg tablet daily for 9 months	Placebo Placebo: Placebo tablet daily for 9 months
Measure Participants	37	35
baseline	7.0 (2.1)	6.8 (1.4)
4 month	7.0 (2.1)	6.8 (1.4)
9 month	7.4 (2.2)	6.6 (1.6)

Adverse Events

Arm/Group Title	Spironolactone		Placebo
Arm/Group Description	Spironolactone Spironolactone: 25mg tablet daily for 9 months		Placebo Placebo: Placebo tablet daily for 9 months
All Cause Mortality
	Spironolactone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Spironolactone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/42 (14.3%)		6/38 (15.8%)
Cardiac disorders
Hospitalization for chest pain	2/42 (4.8%)	2	1/38 (2.6%)	1
Hospitalization for shortness of breath	0/42 (0%)	0	3/38 (7.9%)	5
Hospitalization for syncope	2/42 (4.8%)	2	0/38 (0%)	0
Hospitalization for hypotension	1/42 (2.4%)	1	0/38 (0%)	0
General disorders
Elective surgery	1/42 (2.4%)	1	3/38 (7.9%)	3
Death	0/42 (0%)	0	1/38 (2.6%)	1
Vascular disorders
Hospitalization for angioedema	1/42 (2.4%)	1	0/38 (0%)	0
Other (Not Including Serious) Adverse Events
	Spironolactone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/38 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.