Pilot Study of Natriuretic Versus Standard Doses of Mineralocorticoid Receptor Antagonists in Heart Failure and Loop Diuretic Resistance in Outpatients
Phase: PHASE2
Conditions: Heart Failure
Sponsor: Columbia University

 
 
 
 
 
 
 
 
 
Pilot Study of Natriuretic Versus Standard Doses of Mineralocorticoid Receptor Antagonists in 
Heart Failure and Loop Diuretic Resistance in Outpatients 
NCT: 02585843 
Date 8/30/2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Design 
We conducted a pilot, prospective, single-center, double-blind, randomized, placebo controlled 
trial assessing the effects of high dose spironolactone in addition to intensified loop diuretic 
therapy vs. standard medical therapy in outpatients with ADHF. Our primary outcome was 
defined as weight change over the seven day study period.  Based on data from a non-
randomized intervention study, we aimed to recruit a total sample size of 40 subjects to detect 
a difference in our primary outcome of weight loss of 1.5kg difference between treatment and 
control. 
 
On Day 1, all potential subjects were evaluated with complete medical history and physical 
examination, review of home medications, measurement of vital signs and body weight with a 
calibrated scale, serum collection for basic metabolic panel, liver function test, biomarkers of 
congestion, and electrocardiogram. “Imminent hospitalization” was determined by two 
independent HF specialists to assess the need for hospitalization for intravenous diuretics. 
Home MRAs were discontinued and potassium supplementation held if baseline serum 
potassium was >4.0mmol/L. Beta-blockers, ACE-I or angiotenin II receptor blockers were 
continued at home dose. Loop diuretic dosage was increased by two-fold. Patients were seen at 
two office visits in total, baseline at day 1 and final visit on day 7. On day 3, participants had 
serum basic metabolic panel to assess potassium levels and renal function for safety 
assessment.  
 
Intervention 
Enrolled patients were randomly assigned in a 1:1 ratio to high-dose (100mg/day) or standard-
dose (25mg/day) spironolactone treatment groups.  
 
Randomization, Allocation and Blinding 
Randomization was stratified by sex and EF<45% in blocks of size 4. 2 by 2 randomization was 
performed via computer model generated by a study investigator. Allocations were concealed 
via the locked research pharmacy and the research team was blinded to treatment arm. All 
treatment medications were labeled in a blinded fashion. Subjects received 2 capsules per day 
(if standard dose: 25mg and placebo, if high dose: two 50mg) dispended in vials of 2 capsules.    
 
Study Endpoints 
The primary endpoint for the study was defined as change in total body weight at day 7 of the 
study period. Multiple secondary endpoints from day 1 to 7 were assessed. These included a) 
changes in dyspnea assessment scores; Visual Analogue Scale and 7-Likert scale, b) signs of 
congestion (i.e. JVP, peripheral edema and respiratory rales), c) 6MWT, d) serum and urinary 
creatinine, sodium, potassium and plasma aldosterone and renin activity and biomarkers of 
congestion and neurohormonal activation, e) furosemide equivalent of treatment loop diuretics 
doses, e) hospitalization at 30-, 60- and 90-days.  
 
Six-minute walk test was performed per American Thoracic Society guidelines, along with Borg 
scores for dyspnea and fatigue at day 1 and 7. Serum and urinary creatinine, potassium, and 
sodium, plasma aldosterone and renin activity, and pro-BNP were assessed at days 1 and 7. 

Other biomarkers of peripheral congestion (CD146), inflammation (interleukin-6, tumor 
necrosis factor-, endothelin-1) oxidative stress (isoprostane) and endothelial activation 
(vascular cell adhesion molecule-1) were assessed at day 1 and 7 and analyzed by ELISA or LC-
MS.  
 
A data monitoring committee of two independent cardiologists was established to evaluate 
safety, with a pre-specified stopping rule for harm but not for efficacy. Safety endpoints 
included changes in serum creatinine levels, eGFR, and the incidence of hyperkalemia during 
the 7 day treatment period. Safety was assessed by tracking adverse events including new or 
worsening renal dysfunction, and hyperkalemia. Serious adverse events were defined as death 
and all-cause hospitalization.