Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function

BACKGROUND:

Heart failure (HF) is a major cause of morbidity and mortality, particularly in older
people. Indeed, it is the most common discharge diagnosis in patients older than 65 years.
As the United States population ages, heart failure will continue to grow as a public health
concern. Therapeutic trials of heart failure have dealt almost exclusively with patients who
have systolic dysfunction. However, there is now an emerging awareness that nearly half of
the patients with heart failure have preserved systolic function and that the survival of
these patients is adversely affected. This study is a randomized clinical trial of a novel
therapeutic approach, specifically the use of an aldosterone antagonist, in treating these
patients. While this treatment has been shown to be useful in treating heart failure with
reduced systolic function, it has not been studied in patients with preserved systolic
function.

Patients with heart failure and preserved systolic function have a poor prognosis. The
annual mortality rate is intermediate between the prognosis for those without heart failure
and for those with heart failure and reduced systolic function. For instance, Family Health
Study participants with heart failure and preserved systolic function had a mortality rate
of 9 % compared to 3 % for age- and gender-matched controls. The mortality rate was 19 %
compared to 4 % for matched controls in heart failure patients with reduced systolic
function heart failure.

As heart failure develops, neurohormones are released that initially improve cardiac output
but ultimately contribute to progression of left ventricular dysfunction. The
renin-angiotensin-aldosterone system is an important part of this compensatory response.
Aldosterone levels may rise to 20 times normal levels in heart failure and aldosterone
contributes to the development of myocardial fibrosis. Spironolactone is a potassium-sparing
diuretic that acts on the distal tubule, inhibiting sodium and potassium ion exchange. There
are several potential beneficial actions, including prevention of cardiac fibrosis. A recent
trial evaluated spironolactone in patients with systolic dysfunction heart failure.
Spironolactone treatment caused a 30% reduction in mortality compared to placebo (p< 0.001).
The improvement resulted from a reduction in all cause mortality. More recently, the
Eplerenone Post-Myocardial Infarction (MI) study showed that this aldosterone antagonist
significantly reduces mortality despite background treatment with an angiotensin-converting
enzyme (ACE) inhibitor and beta-blocker. Advantages of using spironolactone in this study
are that it is commercially available, inexpensive, and no longer under patent (therefore
this study will not be done by industry). Also, there is a clear physiologic rationale for
its use, and the side effect profile is well understood. The study is currently enrolling
patients hospitalized with heart failure who have preserved systolic function and who meet
clearly defined eligibility criteria that have been selected to make the results widely
generalizable to clinical practice.

DESIGN NARRATIVE:

This is a randomized, double-blinded, placebo-controlled trial of aldosterone antagonist
therapy (15 mg dose spironolactone or placebo; titrated up to 45 mg/day) in 3,515 adult
patients with heart failure and preserved systolic function. Patients will be recruited over
two and a half years, treated, and followed for approximately two years. Approximately 200
clinical sites will be subcontracted to the clinical trial coordinating center. Patient
visits to a clinical center will occur every four or six months. Data to be collected
include demographic and clinical data, including the results of history and physical exams,
laboratory and imaging data, repository specimens for special physiology studies, and
genetic studies. Additionally, data regarding cost-effectiveness, quality of life, and
compliance with assigned treatment will also be collected and assessed. The protocol has
been developed. Enrollment began August 2006.

INCLUSION CRITERIA:

- Heart failure as defined by at least one of the following symptoms at the time of
screening and at least one of the following signs within 12 months of study entry:

1. SYMPTOMS:

1. Paroxysmal nocturnal dyspnea

2. Orthopnea

3. Dyspnea on mild or moderate exertion

2. SIGNS:

1. Any rales post cough

2. JVP greater than or equal to 10 cm H2O

3. Lower extremity edema

4. Chest x-ray demonstrating pleural effusion, pulmonary congestion, or
cardiomegaly

- LVEF (ideally obtained by echocardiography, although radionuclide ventriculography
and angiography are acceptable) greater than or equal to 45% (per local reading); the
ejection fraction must have been obtained within 6 months prior to randomization and
after any MI or other event that would affect ejection fraction

- Controlled systolic BP, defined as a target systolic BP less than 140 mm Hg;
participants with BP up to and including 160 mm Hg are eligible for enrollment if
they are on three or more medications to control BP

- Serum potassium less than 5.0 mmol/L prior to randomization

- At least one hospital admission for which heart failure was a major component of the
hospitalization some time within the 12 months prior to study entry (transient heart
failure in the context of MI does not qualify) OR brain natriuretic peptide (BNP)
greater than or equal to 100 pg/ml or N-terminal pro-BNP greater than or equal to 360
pg/ml (not explained by another disease entity) within the 30 days prior to study
entry

- Women of child-bearing potential must have a negative serum/urine pregnancy test
within 72 hours prior to randomization, must not be lactating, and must agree to use
an effective method of contraception during the entire course of study participation

- Willing to comply with scheduled visits

EXCLUSION CRITERIA:

- Severe systemic illness with an expected life expectancy of less than 3 years

- Chronic pulmonary disease requiring home O2, oral steroid therapy, or hospitalization
for exacerbation within 12 months of study entry, or significant chronic pulmonary
disease in the opinion of the investigator

- Known infiltrative or hypertrophic obstructive cardiomyopathy or known pericardial
constriction

- Primary hemodynamically significant uncorrected valvular heart disease, obstructive
or regurgitant, or any valvular disease expected to lead to surgery during the trial

- Atrial fibrillation with a resting heart rate greater than 90 bpm

- MI in the past 90 days

- Coronary artery bypass graft surgery in the past 90 days

- Percutaneous coronary intervention in the past 30 days

- Heart transplant recipient

- Currently implanted left ventricular assist device

- Stroke in past 90 days

- Systolic BP less than 160 mm Hg

- Known orthostatic hypotension

- Gastrointestinal disorder that could interfere with study drug absorption

- Use of any aldosterone antagonist or potassium sparing medication in the 7 days prior
to study entry

- Known intolerance to aldosterone antagonists

- Current lithium use

- Current participation (including prior 30 days) in any other therapeutic trial

- Any condition that, in the opinion of the investigator, may prevent the participant
from adhering to the trial protocol

- History of hyperkalemia (serum potassium greater than or equal to 5.5 mmol/L) in the
past 6 months or serum potassium greater than or equal to 5.0 mmol/L within the past
2 weeks

- Severe renal dysfunction, defined as an estimated GFR less than 30 ml/min (per the
Modification of Diet in Renal Disease (MDRD) 4-component study equation);
participants with serum creatinine greater than or equal to 2.5 mg/dl are also
excluded even if their GFR is greater than or equal to 30 ml/min

- Known chronic hepatic disease, defined as AST and ALT levels greater than 3.0 times
the upper limit of normal as read at the local lab