PIE II: Pharmacological Intervention in the Elderly II

Condition(s) targeted: Diastolic Heart Failure; Heart Failure, Congestive

Intervention: Spironolactone (Drug); Placebo (Drug)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: National Institute on Aging (NIA)

Official(s) and/or principal investigator(s):
Dalane W. Kitzman, MD, Principal Investigator, Affiliation: Professor of Internal Medicine, Cardiology, Director of Echocardiography, Wake Forest University Health Sciences

The purpose of this study is to examine whether spironolactone will improve exercise tolerance and quality of life in elderly patients with isolated diastolic heart failure (DHF).

Official title: Exercise Intolerance in Elderly Diastolic Heart Failure

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome:

Exercise intolerance

quality of life

Secondary outcome:

Concentric left ventricular remodeling

left ventricular diastolic stiffness

serum markers of myocardial fibrosis, procollagen type III amino-terminal peptide (PIIINP) and collagen type I carboxy-terminal pro-peptide (CICP)

Detailed description: Exercise intolerance due to diastolic heart failure (DHF) is a major cause of disability among older Americans. Several lines of evidence suggest that aldosterone antagonism may improve exercise tolerance in DHF. Spironolactone is a generic, inexpensive aldosterone antagonist. In an open-label pilot study of spironolactone in 10 elderly patients with isolated DHF there were significant improvements in exercise intolerance, quality of life, and left ventricular (LV) diastolic stiffness. 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 DHF. The secondary aim is to determine whether the improvements in exercise tolerance are related to improvements in abnormal concentric LV remodeling, LV diastolic stiffness, and myocardial fibrosis. These results will be important, not only because diastolic heart failure is highly prevalent among the elderly, but also because exercise intolerance is a pivotal outcome that is modifiable, is independent of mortality, and is a critical determinant of quality of life and disability among the elderly.

A total of 72 participants aged 60 or older will be randomized to receive either spironolactone 25mg daily or a placebo. There will be 9 visits over the 9-month trial period. Three testing visits will last approximately 2 hours each, and 6 follow-up visits will each last approximately 30 minutes.

Minimum age: 60 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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)

Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157, United States

Related publications:

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.

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, Gardin JM, Gottdiener JS, Arnold A, Boineau R, Aurigemma G, Marino EK, Lyles M, Cushman M, Enright PL. 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.

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.

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.

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.

Starting date: April 2005
Ending date: June 2008
Last updated: December 21, 2007