High-Dose Aldactone for Treatment of Diuretic Resistant Heart Failure

Congestive heart failure (CHF) is common and currently affects an estimated 6.6 million
adults in the United States (1). In addition being highly prevalent, CHF is responsible for
~ 1 million hospital discharges per year and approximately 50% of patients with CHF will die
within 5 years making it a highly morbid and lethal disease (1).

Manifestations of CHF include symptoms of volume overload such as dyspnea, abdominal
bloating and/or fatigue. The genesis of these symptoms begins with loss of the integrity of
arterial circulation due to decreased cardiac output (2). Decreased activation of
mechanoreceptors in the carotid sinus, left ventricle, aortic arch and renal afferent
arterioles due to lower systemic arterial pressure stimulates the sympathetic nervous system
(SNS), renal-angiotensin-aldosterone system (RAAS) and non-osmotic release of arginine
vasopressin (3). As a result, sodium reabsorption in the proximal tubule followed by water
absorption increases causing accumulation of intravascular volume to compensating for
arterial underfilling (4). Consequently, activation of neurohumoral reflexes result in
increased cardiac afterload and preload, cardiac remodeling, hyponatremia and pulmonary
edema (5). Renal vasoconstriction, sodium and water retention leads to a continuous positive
feedback loop of further salt and water accumulation accompanied by further renal
vasoconstriction (6).

Diuretic therapy is the most common means to relieve congestion in acute decompensated heart
failure (ADHF) and approximately 90% of patients are treated with loop diuretics (7).
Although loop diuretics are a cornerstone ADHF care and carries the highest level of
recommendation by the American Heart Association (Class I); the guideline is supported by
the lowest level of evidence (Class C) (8). While effective at natriuresis, loop diuretics
are known to stimulate the SNS and RAAS, both of which have adverse consequence in heart
failure (9,10). Not only is the RAAS system stimulated due to changes in arterial filling,
furosemide blocks sodium chloride transport at the macula densa causing renin release
independent of renal sodium loss (11). With increase stimulation of renin release,
vasoconstriction of the renal artery ensues causing or further exacerbating renal
insufficiency (12). Long-term utilization of loop diuretics results in hypertrophy of the
distal nephron and increased expression of a sodium chloride co-transporter (13). These
changes along with increased aldosterone levels further enhances distal sodium reabsorption
and prevents aldosterone escape (14).

In treating heart failure patients as a population, diuretic resistance is encountered
commonly and escalating doses of furosemide may be utilized to achieve fluid loss (15).
Clinically, use of high-doses of loop diuretics is associated with greater rates of clinical
events such as mechanical ventilation and myocardial infarction compared to low-dose loop
diuretics (16). High-dose loop diuretic administration is associated with worsening renal
function (17), increased length of hospital stay and greater in-hospital mortality (17-19).
There is in fact a linear correlation with diuretic dose and mortality (20).

Given the potential hazards of administering loop diuretics in CHF patients, the remaining
options are limited. Changing diuretics strategies from bolus to continuous loop diuretic
infusion does not appear to change overall outcomes (21). Alternative strategies for
relieving congestion include inhibition of the distal nephron using thiazide diuretics.
Thiazide diuretics work synergistically with loop diuretics to induce natriuresis but have
an independent association with worsening renal function and death (20,22). Utilizing
inotropes to increasing renal perfusion pressure may improve natriuresis, however, it comes
with the price of increasing mortality regardless of whether beta-adrenergic agonists
(dobutamine) or phosphodiesterase inhibitors are used (23,24). Ultrafiltration and
mechanical unloading of the heart is another therapeutic option, however it was found to be
ineffective and associated with worsening renal function (25). Even low doses of dopamine or
nesiritide were not effective in improving outcomes in patients with cardiorenal syndrome
(26). Higher doses of spironolactone were recently shown to be safe in a prospective cohort
treated for acute decompensated heart failure (27). Recently a case report was published
showing that patients hospitalized with congestive heart failure, worsening renal function
and diuretic resistance were able to be diuresed without adverse effect on renal function or
hyperkalemia by treating with escalating doses of spironolactone (28)

The study will be a prospective, open-label, randomized cohort study comparing adding
high-dose spironolactone to usual heart failure care versus usual care in patients with
acute decompensated heart failure. Patients will be randomized in a 1:1 fashion to either
usual care or high-dose spironolactone plus usual care. Both arms of the study will continue
with treatment of ADHF until euvolemia as defined as the resolution of pulmonary edema,
peripheral edema, abdominal bloating and/or jugular venous distention. Assessment of
clinical status, urine and serum electrolytes, symptoms and renal function will be performed
in accordance to standard of care.

Inclusion Criteria:

1. 18 years or older patients with congestive heart failure

2. Hypervolemic by at least 2 of the following criteria: 1) Peripheral edema; 2) jugular
venous distention greater than 7 cm; 3) radiographic pulmonary edema or pleural
effusion; 4) enlarged liver or ascites; 5) pulmonary rales, paroxysmal nocturnal
dyspnea or orthopnea

3. Diuretic resistance as defined by loop diuretic requirements of furosemide greater or
equal to 160 mg IV total daily dose or equivalent dose of torsemide or bumetanide. (
1 mg bumetanide = 10 mg torsemide = 20 mg furosemide)

4. Estimated glomerular filtration rate (eGFR) of > 30ml/min. according to the MDRD
Study equation at the time of admission.

5. Female patients of child bearing potential must have a negative urine pregnancy test
to be eligible.

Exclusion Criteria:

1. Acute coronary syndrome

2. Patients with a baseline eGFR < 30 ml/min according to the MDRD equation.

3. Baseline potassium serum concentration 5.3 meq/L

4. Requirement for intravenous pressors

5. Systemic infection

6. Patients with concomitant end-stage liver disease

7. Significant valvular disease

8. Patients with pulmonary embolism

9. Patients with high output heart failure

10. Pregnant patients