Table 2.

Cardiovascular effects of MRA in humans

Author, study cohorts	Patient population	End point, measurements	Results
Pitt et al. [109], 2003 n = 202 Duration: 9 months	Patients with left ventricular hypertrophy and hypertension (mean age 58 ± 12 years) Eplerenone 200 mg/day; enalapril 40 mg/day; eplerenone 200 mg/day, and enalapril 10 mg/day	Change in left ventricular mass (MRI), changes in systolic and diastolic BP	Eplerenone significantly reduced LV mass from baseline (p = 0.001); eplerenone-enalapril combination was more effective than eplerenone alone (p = 0.007) Eplerenone significantly reduced systolic and diastolic BP from baseline and more effectively than eplerenone alone (p = 0.048)
Kosmala et al. [69], 2013 n = 113 Duration: 6 months	Patients with BMI ≥30 without comorbidities with impaired early diastolic mitral annular velocity (mean age 58 ± 8 years) Spironolactone 25 mg/day; placebo	LV systolic and diastolic function, myocardial reflectivity and serological fibrosis markers (procollagen type III N-terminal propeptide [PIIINP] and procollagen type I C-terminal propeptide [PICP])	Significant reduction in PICP (p = 0.04), E/e’ ratio (p = 0.005), LV systolic function (p = 0.02), and myocardial reflectivity (p = 0.02)
Montalescot et al. [110], 2014 n = 1,012 Duration: 10.5 months	Patients with acute STEMI without a history of HF receiving standard therapy Eplerenone 25–50 mg/day in addition to standard therapy; versus standard therapy control (mean age 58 ± 11 years)	Composite of CV mortality, rehospitalization or extended initial hospital stay due to diagnosis ofHF, sustained ventricular tachycardia or fibrillation, LVEF ≤40% or elevated BNP/NT-proBNP levels (primary end point)	The incidence of primary end point was reduced by 42% in the eplerenone group relative to control (p < 0.0001) Primary end point difference was driven by increased BNP/NT-proBNP in control group Adverse event rates were similar in both groups
Garg et al. [111], 2014 n = 64 Duration: 6 months	Patients with diabetes on chronic ACE inhibition (enalapril 20 mg/day, mean age 55 years) Spironolactone 25 mg/day; HCTZ 12.5 mg/day; placebo	Coronary flow reserve (CFR) was assessed by cardiac PET at baseline, and at the end of treatment	Spironolactone significantly improved CFR compared to control (p = 0.04)
Renal Effects of MRA Epstein et al. [112], 2006 n = 268 Duration: 12 weeks	Patients with diabetes mellitus and UACR ≥ on enalapril (50 mg/day) (mean age of 59 years) Eplerenone 50 mg/day, 100 mg/day or placebo on top of Enalapril therapy	Percentage change from baseline in UACR and incidence of hyperkalemia (primary end points)	By week 12, UACR was reduced 7.4% in placebo group compared to 41.0% in eplerenone (50 mg) group (p = 0.001) and 48.4% in eplerenone 100 mg group (p = 0.001). No significant difference in the incidences of sustained and severe hyperkalemia
Bianchi et al. [113], 2006 n = 165 Duration: 1 year	Patients with CKD receiving ACE inhibitors and/or ARBs (mean age 59 years) Spironolactone 25 mg/day on top background therapy compared with background treatment alone	Proteinuria and eGFR	Spironolactone treatment significantly reduced proteinuria from 2.10 to 0.89 g/g creatinine (p < 0.001), and did not change in patients receiving ACE inhibitors and ARB alone By the end of 1 year, the monthly rate of the decrease in eGFR from baseline was lower in patients treated with spironolactone than in controls
Furumatsu et al. [114], 2008 n = 32 Duration: 1 year Trichlorome thiazide 1 mg/day or furosemide 20 mg/day in addition to enalapril 5 mg/day and losartan 50 mg/day	Patients with nondiabetic nephropathy and proteinuria >0.5 mg/day after receiving an ACE inhibitor and ARB in combination for more than 12 weeks (mean age 52 ± 3 years) Spironolactone 25 mg/day in addition to enalapril 5 mg/day and losartan 50 mg/day (triple blockade)	Proteinuria, urinary type IV collagen level	Urinary protein level decreased by 58% in triple blockade group compared with no change in the control group (p < 0.05) Urinary collagen IV levels decreased by 40% from baseline in triple blockade group compared with no change in the control group (p < 0.05)
Mehdi et al. [115], 2009 n = 81 Duration: 48 weeks	Patients with diabetes mellitus, hypertension and UACR ≥300 mg/g receiving Lisinopril 80 mg/day Spironolactone 25 mg/day; losartan 100 mg/day; placebo	Urine albumin to creatinine ratio, clinic and ambulatory BP, creatinine clearance, and glycemic control	Spironolactone group UACR decreased 34.0% (p = 0.007 vs. placebo) Blood pressure, creatinine clearance, and glycemic control did not change significantly between groups
Boesby et al. [116], 2011 n = 40 Duration: 8 weeks	Patients with nondiabetic CKD and urinary albumin excretion greater than 300 mg/day Eplerenone 25–50 mg/day Mean age 45 years	24-h urinary albumin excretion, BP, plasma potassium, creatinine clearance	Eplerenone treatment lowered mean urinary albumin excretion by 14% (p = 0.008)
Ando et al. [117], 2014 n = 304 Duration: 1 year	Hypertensive patients with albuminuria (UACR = 30–599 mg/g), eGFR >50 mL/min who had received ACE inhibitor or ARB or both for ≥8 weeks Eplerenone 50 mg/day vs. placebo	Mean percent change in UACR	UACR decreased by 27.6% in eplerenone treatment group (p = 0.022 vs. placebo)
Matsumoto et al. [118], 2014 n = 309 Duration: 3 years	Patients with oligo-anuria undergoing hemodialysis (mean age 67 years ± 12 years) Spironolactone, 25 mg/day or placebo	Composite of death from CV causes and hospitalization for CV causes (primary outcome), and death from all causes (secondary outcome)	Spironolactone decreased the rate of incidence of primary outcome by 62% relative to control (p = 0.016), and of the secondary outcome by 67% (p = 0.003)
Bakris et al. [91], 2014 n = 821 Duration: 90 days	Patients with diabetes and high or very high albuminuria receiving ACE inhibition or ARB (mean age 64 years) Finerenone 1.25–20 mg in graded dose increments (7 different doses) or placebo	Ratio of urinary albumin-creatinine ratio (UACR) at day 90 to baseline	UACR was reduced relative to baseline at each dosage: 7.5 mg/day, 0.79 (p = 0.004) 10 mg/day, 0.76 (p = 0.001) 15 mg/day, 0.67 (p < 0.001) 20 mg/day, 0.62 (p < 0.001)

UACR, urine albumin creatinine ratio; ACEI, angiotensin converting enzyme inhibitor; LVEF, left ventricular ejection fraction; BNP, brain natriuretic peptide; PET, positron emission tomography.