Clinical trial NCT01855334: L-Arginine and Spironolactone Trial in Dialysis-Dependent ESRD
Official title: A Randomized, Controlled Trial of L-arginine and Spironolactone in Dialysis-dependant End Stage Renal Disease
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE4
Conditions: End Stage Renal Disease
Hemodialysis
Keywords: Dialysis
ESRD
Cardiovascular disease
spironolactone
L-arginine
myocardial perfusion
coronary flow reserve
diastolic function
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: Massachusetts General Hospital
name: Beth Israel Deaconess Medical Center
name: Joslin Diabetes Center
First posted: 2013-05-16
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: Cardiovascular disease is the primary cause of death in patients with end stage renal disease (ESRD). New research suggests that the high risk of death may be partly due to high levels of fibrosis and a loss of small blood vessels in the heart of patients with dialysis-dependent ESRD. This study is designed to compare the effects of two different drugs, spironolactone and L-arginine, with placebo on structure and function of the heart in individuals with dialysis-dependent ESRD.

Detailed description: We hypothesize that that abnormalities in aldosterone and nitric oxide (NO) homeostasis contribute to the progression of microvascular disease and myocardial fibrosis in ESRD and that agents designed to restore normal aldosterone and NO homeostasis will improve microvascular and diastolic cardiac function in the heart of individuals with dialysis dependent ESRD. We will test 2 specific agents: The mineralocorticoid receptor blocker spironolactone; and L-arginine, an agent which improves NO bioavailability. Two specific aims will be addressed using a prospective, double-blinded, 2x2 factorial trial in dialysis dependent patients with ESRD. Subjects will be randomized to placebo, spironolactone plus placebo, L-arginine plus placebo, or combination spironolactone and L-arginine therapy. Diastolic cardiac function will be assessed using tissue Doppler index (TDI) determined mitral annular velocities (E') on LV echocardiography, and microvascular supply will be assessed using CFR-the ratio of hyperemic to resting myocardial blood flow-measured by positron emission tomography (PET) scans at baseline, 2 weeks and after 9 months of randomized therapy.

This randomized trial of spironolactone and L-arginine will provide important data about the contributions of aldosterone and NO to the pathogenesis of cardiovascular disease in ESRD, will demonstrate the therapeutic potential of L-arginine and spironolactone as as targeted cardiovascular therapies for use in ESRD, and will provide important insights into the underlying pathophysiology of cardiovascular disease in ESRD. The results generated will provide the data needed to design large-scale trials testing whether spironolactone or L-arginine can improve mortality or cardiovascular outcomes in ESRD.

Eligibility criteria: Inclusion Criteria:

* Chronic dialysis therapy for End Stage Renal Disease
* Age 21-85

Exclusion Criteria:

* Hyperkalemia requiring unscheduled dialysis within 3 months
* Pre-dialysis potassium ≥6.5 meq/L within 3 months
* Hypotension defined as SBP \<100
* Recurrent intra-dialytic hypotension defined as recurrent cramping, light-headedness, or hypotension requiring infusion of saline or other intervention or otherwise limiting ability to achieve dry weight. Or SBP \<80
* History of myocardial infarction
* History of coronary artery bypass surgery
* Non revascularized coronary disease \>90%
* Mitral valve repair or replacement
* Severe mitral valve disease
* Renal transplant expected within 9 months
* Expected survival \< 9 months
* Pregnant
* Prisoners
* Unable to provide consent
* Allergy to spironolactone or L-arginine
* Digitalis use
* 1st or 2nd degree heart block

Primary outcomes:
measure: Change in coronary Flow Reserve (PET)
timeFrame: Between baseline and 9 months
measure: Change in left ventricular diastolic function
timeFrame: Between baseline and 9 months
Secondary outcomes:
measure: Association between coronary flow reserve (CFR) and tissue doppler index (E')
timeFrame: Baseline
measure: Change in resting myocardial blood flow
timeFrame: Between baseline and 9 months
measure: Change in left ventricular mass index
timeFrame: Between baseline and 9 months
measure: Change in coronary vascular resistance
timeFrame: Between 0 and 9 months
measure: Association between change in coronary flow reserve (CFR) and change in diastolic function-tissue doppler index (E')
timeFrame: Between baseline and 9 months
measure: Change in early diastolic function (E')
timeFrame: Between baseline and 2 weeks
measure: Combined cardiovascular safety
timeFrame: Up to 9 months
measure: Cardiovascular death
timeFrame: Up to 9 months
measure: Hyperkalemia
timeFrame: Up to 9 months
measure: Hypotension
timeFrame: Up to 9 months
measure: Change in early coronary flow reserve
timeFrame: Between baseline and 2 weeks
measure: Change in hyperemic myocardial blood flow
timeFrame: Between baseline and 9 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
Study officials:
References:
citation: Hasegawa T, Nishiwaki H, Ota E, Levack WM, Noma H. Aldosterone antagonists for people with chronic kidney disease requiring dialysis. Cochrane Database Syst Rev. 2021 Feb 15;2(2):CD013109. doi: 10.1002/14651858.CD013109.pub2.