Table 2.
The Trials Information of MRAs.
| Drug | Trial | Characteristic | n | Groups | Median Follow-up | Inclusion criteria | Outcome | Conclusion |
|---|---|---|---|---|---|---|---|---|
| Spironolactone | ||||||||
| SPI | RALES (Pitt et al.) (33) | a double-blind RCT | 1663 | standard therapy and SPI or placebo | 24 months | severe HF with LVEF≤35% | death from all causes | SPI, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe HF. |
| SPI | Tseng et al. (Taiwan National Health Insurance Research Database) (34) | retrospective cohort study | 27213 | SPI usage +/-before | 3-4 years | CKD stage 5 | all-cause mortality, HHF and MACE (the composite of AMI and ischemic stroke) | SPI may be associated with higher risks for all-cause and infection-related mortality and HHF in pre-dialysis stage 5 CKD patients. |
| SPI | Yang et al. (primary date from Taiwan's National Health Insurance Research Database) (35) | retrospective cohort study | 2079 | SPI usage +/-before | \ | CKD stage 3-4 | ESRD, MACE, HHF, HKAH, all-cause mortality and CV mortality | SPI represented a promising treatment option to retard CKD progression to ESRD amongst stage 3–4 CKD patients, but strategic treatments to prevent hyperkalemia should be enforced. |
| SPI | TOPCAT(NCT00094302) (36) | RCT(phase III) | 3445 | SPI vs. placebo | 6 years | HFpEF (symptomatic, HHF within the past year) | composite outcome of CV mortality, aborted cardiac arrest, or HHF | SPI does not significantly reduce the incidence of the primary composite outcome of death from CV causes, aborted heart arrest or HHF in patients with HFpEF. Greater potassium and creatinine changes and possible clinical benefits with SPI in patients with HFpEF from the Americas. |
| SPI | Enzan et al. (Japanese Cardiac Registry of Heart Failure in Cardiology database) (37) | retrospective registration study | 457 | SPI usage +/-before | 2.2 years | HFmEF (LVEF 40%-49%) |
a composite of all-cause death or HHF | Among patients with HHF for HFmEF, SPI shows better long-term outcomes. |
| SPI | Krieger et al. (NCT01643434) (38) | multicenter RCT study | 1597 | SPI vs. clonidine | 3 months | resistant hypertension | BP control during office (<140/90 mm Hg) and 24h ambulatory (<130/80 mm Hg) BP monitoring | SPI promotes greater decrease in 24h systolic and DBP and diastolic daytime ambulatory BP than clonidine |
| Eplerenone | ||||||||
| EPL | Minakuchi et al.(UMIN000008521) (39) | a single-blinded placebo-controlled prospective observational study | 48 | ACEI/ARB + EPL or placebo | 24-36 months | patients with CKD stage 2-3 whose plasma ALD concentration was above 15 ng/dL | change in eGFR | MRA can be an effective in preventing CKD progression, especially in patients with high plasma ALD. |
| EPL | ElMokadem et al.(NCT04143412) (40) | a single-blind RCT | 75 | ramipril or EPL or both | 24 weeks | T2DM+hypertension and DKD (microalbuminuria) | BP, UACR, serum creatinine, eGFR and serum K level | Addition of EPL to ACEI shows an added anti-albuminuria effect without significant change of the serum potassium level compared with EPL or ACEI. |
| EPL | EPOCH(NCT01832558) (41) | a exploratory RCT study | 15 | ACEI + EPL or placebo | 10 weeks | CKD stages 2-3 and albuminuria due to DKD | quantify plasma angiotensin levels, renin and ALD in PA for 8 weeks MRA treatment. | Combined EPL and ACEI therapy increases Ang-(1–7) levels in patients with CKD indicating a unique nephroprotective RAAS pattern with considerable therapeutic implications. |
| EPL | EPHESU (42) | a multicenter, international, double-blind, phase III RCT | 6442 | different dosage of EPL vs. placebo | 16 months | AMI after 3-14 days with HFrEF (LVEF≤40%) | death from any cause and death from CV causes or HHF, AMI, stroke, or ventricular arrhythmia | The addition of EPL to optimal medical therapy reduces morbidity and mortality among patients with AMI complicated with HFrEF. |
| EPL | EMPHASIS-HF(NCT00232180) (43) | a double-blind phase III RCT study | 2737 | different dosage of EPL vs. placebo | 21 months | HFrEF (NYHA II) with LVEF≤35% | a composite of death from CV causes or HHF | EPL reduces both the risk of death and the risk of hospitalization among patients with systolic HF and mild symptoms. |
| EPL | RAAM-PEF(NCT00108251) (44) | a double-blind, placebo-controlled RCT | 44 | EPL vs. placebo | 6 months | HFpEF and hypertension with/without T2DM | changes in 6-minute walk distance, diastolic function, and biomarkers of collagen turnover | EPL is associated with significant reduction in markers of collagen turnover and improvement in diastolic function. |
| EPL | Schneider et al.(NCT00138944) (45) | a double-blind, placebo-controlled, parallel group RCT | 51 | regular BP medication + low dosage EPL or placebo | 6 months | TRH | LVM assessed by MRI before and after treatment | MRA should be used preferentially in patients with TRH in order to achieve an effective reduction of LVM along with the improvement of BP control. |
| EPL | Kalizki et al.(NCT00138944) (46) | double-blinded, placebo-controlled parallel-group RCT | 51 | regular BP medication + low dosage EPL or placebo | 6 months | TRH | vascular parameters including PWV, AIx, AP, AP@HR75, RRI, IMT and UAER | EPL beneficially affects markers of arterial stiffness and wave reflection in patients with TRH, independently of BP lowering. |
| EPL | OWASE(UMIN000005956) (47) | a multicenter, prospective, open-label RCT | 195 | EPL vs. thiazide diuretic | 48 weeks | ARB-treated hypertension and albuminuria | the change of UACR from baseline to 48 weeks | The antialbuminuric effects and safety of EPL therapy are similar to thiazide diuretics when combined with ARBs in patients with hypertension and albuminuria. |
| EPL | Karashima et al.(UMIN000004581) (48) | an open-label, non-controlled, prospective cohort study | 54 | EPL vs. SPI | 12 months | PA | metabolic factors including BMI, HOMA-IR, serum creatinine, potassium and lipids, UAE and PAC and PRA | EPL and SPI decreases BP and increases serum potassium levels to similar degrees. PAC and PRA are similar between the two groups. |
| EPL | EPATH(NCT02136771) (49) | RCT and observational data prospective cohort study | 4 | different dosage EPL vs. placebo | 8 weeks | PA | ARR | MRA does not significantly alter the ARR in primary hyperparathyroidism patients but significantly reduces the ARR in PA patients. |
| Finerenone (BAY 94-8862) | ||||||||
| FIN | ARTS(NCT01807221; NCT01874431) (7) | multicenter, parallel-group, phase II study, with double-blind placebo and open-label SPI comparator arms phase II RCT | 458 | standard therapy and different dosage (2.5mg/5mg/10mg qd) FIN or placebo | about 30 days | HFrEF (NYHA II-III, LVEF≤40%) and mild or moderate CKD (eGFR 60 to <90 and 30-60 mL/min/1.73 m2, respectively) | serum potassium concentration, eGFR, and albuminuria | In patients with HFrEF and moderate CKD, BAY 94-8862 5–10 mg/day was at least as effective as SPI 25 or 50 mg/day in decreasing biomarkers of hemodynamic stress, but it was associated with lower incidences of hyperkalemia and WRF. |
| FIN | ARTS-HF(NCT01807221) (50) | a double-blind placebo and open-label SPI comparator arms phase IIb RCT study | 1066 | different dosage FIN vs. EPL | 90 days | worsening CHF with exasperated HFrEF and CKD and/or T2DM requiring hospitalization and intravenous diuretic therapy | the percentage of participants with a relative decrease in NT-proBNP of more than 30% from baseline to day 90 | FIN is well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to EPL. |
| FIN | ARTS-DN(NCT01874431) (51) | a multicenter, double-blind, placebo-controlled, parallel-group phase II RCT | 823 | ACEI/ARB + different dosage FIN or placebo | 90 days | T2DM with DKD (albuminuria) | ratio of UACR at day 90 to UACR at baseline | Among patients with DN, most receiving an ACEI/ARB, the addition of FIN compared with placebo resulted in improvement in the UACR. |
| FIN | FIDELIO-DKD(NCT02540993) (52) | a double-blind, placebo-controlled, parallel-group, multicenter, event-driven phase III study | 5734 | ACEI/ARB + FIN (10mg/20mg qd) or placebo | 32 months (2.6 years) |
T2DM with DKD | the first occurrence of the composite endpoint of onset of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death | In patients with CKD and T2DM, FIN lowers the risks of CKD progression and CV events than placebo. |
| FIN | FIGARO-DKD(NCT02545049) (3) | a double-blind, placebo-controlled, parallel-group, multicenter, event-driven phase III study | 7337 | standard therapy + FIN or placebo | 41 months (3.4 years) |
T2DM with DKD | the first occurrence of the composite endpoint of CV death, non-fatal myocardial infarction, nonfatal stroke, or HHF | T2DM and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, FIN therapy improved CV outcomes as compared with placebo. |
| FIN | FIDELITY(NCT02540993; NCT02545049) (31) | meta analysis (FIDELIO-DKD and FIGARO-DKD) |
13026 | standard therapy + FIN or placebo | 2.3-3.8 years | T2DM with DKD | a composite of CV death, non-fatal MI, non-fatal stroke, or HHF, and a composite of kidney failure, a sustained ≥57% decrease in eGFR from baseline over ≥4 weeks, or renal death | FIN reduces the risk of clinically important CV and kidney outcomes vs. placebo across the spectrum of CKD in T2DM |
| FIN | FINEARTS-HF(NCT04435626) | a double-blind, placebo-controlled, parallel-group, multicenter phase III Study | 5500 | different dosage of FIN | – | HFmEF (LVEF≥40%) with clinical symptom | number of CV deaths and HF events | ongoing |
| FIN | FIND-DKD(NCT05047263) | a randomized, double-blind, placebo-controlled, parallel-group, multicenter phase III study | 1500 | FIN vs. placebo | – | CKD without T2DM | change of the slope of eGFR | ongoing |
| FIN | CONFIDENCE(NCT05254002) | a parallel-group treatment, phase II, double-blind, three-arms study | 807 | FIN+empagliflozin vs. FIN+placebo vs. empagliflozin+placebo | 180-210 days | CKD with T2DM | relative changes from baseline in UACR at 180 days in combination therapy group versus empagliflozin/FIN alone | ongoing |
| FIN | Fu et al. (53) | meta-analysis | 7048 | standard therapy + FIN or placebo | – | DM patients with CKD (phase 2) | assessed at least one of the following outcomes: UACR, eGFR, adverse events including CV disorders and hyperkalemia | FIN confers an important antiproteinuric effect on patients with CKD and reduces the risk of CV disorders |
| FIN | Pei et al. (54) | meta-analysis | 1520 | FIN vs. SPI vs. EPL | – | CHF with HFrEF | effective number of cases with a 30% reduction in NT-proBNP | FIN reduces NT-proBNP, UACR, and other biochemical indicators in a dose-dependent manner. |
| Esaxerenone (CS-3150) | ||||||||
| ESA | ESAX-HTN(NCT02890173) (55) | double-blind, three parallel placebo comparator arms phase III trial | 1001 | different dosage of ESA or EPL | 12 weeks | essential hypertension | changes in SBP/DBP at rest relative to baseline after 12 weeks | ESA is an effective and well-tolerated MRA in Japanese patients with essential hypertension, with BP-lowering activity at least equivalent to EPL. |
| ESA | ESAX-DN(JapicCTI-173695) (56) | multicenter, double-blind, placebo control, two- arm, parallel group, comparison study | 449 | CS-3150 vs. placebo | 52 weeks | T2DM with microalbuminuria taking ACEI/ARB | UACR remission rate at the end of the treatment | Adding ESA to existing RAAS inhibitors therapy in patients with T2DM and microalbuminuria increased the likelihood of albuminuria returning to normal levels, and reduced progression of albuminuria to higher levels. |
| Apararenone (MT-3995) | ||||||||
| APA | Izumi et al.(NCT02517320; NCT02676401) (57) | a double-blind, placebo-controlled study | 293/241 | different dosage of APA vs. placebo | 24-52 weeks | stage 2 diabetic nephropathy (DN) | the 24-week percent change from baseline in UACR and 24- and 52-week UACR remission rates | The UACR-lowering effect of APA administered once daily for 24 weeks in patients with stage 2 DN was confirmed, and the 52-week administration was safe and tolerable. |
| Ocedurenone (KBP-5074) | ||||||||
| OCE | BLOCK-CKD(NCT03574363) (58) | a double-blind, placebo-controlled, global, multicenter phase IIb trial | 162 | different dosage of APA vs. placebo | 12 weeks | moderate-to-severe (stage 3b/4; eGFR 15-44 mL/min/1.73m2) CKD and uncontrolled hypertension | changes in trough-cuff seated SBP/DBP and UACR from baseline to day 84 | KBP-5074 demonstrated a clinically meaningful trend in the reduction of UACR. |
| OCE | CLARION-CKD(NCT04968184) | a phase 3 double-Blind placebo-controlled multicenter study | 600 | OCE vs. placebo | 52 weeks | uncontrolled hypertension and moderate or severe CKD (stage 3b/4) | changes in seated trough-cuff SBP from baseline to week 12/48/52 | ongoing |
| Canrenone | ||||||||
| CAN | COFFEE-IT(NCT03263962) (59) | a multicenter, retrospective, observational study | 532 | treated +/- CAN | 10 years | CHF with HFpEF (LVEF ≥ 50%) | the rate of CV mortality in CHF and the rate of death and survival. | CAN preserves systolic fraction, reduces mortality and extends life in CHF patients. |
| CAN | AREA-in-CHF(NCT00403910) (60) | RCT (phase 3) | 500 | CAN vs. placebo | 12 months | compensated HFrEF with LVEF≤45% | changes in echocardiographic left ventricular diastolic volume | CAN, with optimal therapy (ACEI/ARB, β-blockers) in patients with metabolic syndrome, stabilized HF with reduced EF, protects deterioration of myocardial mechano-energetic efficiency, improves diastolic dysfunction and maximizes the decrease in BNP. |
ALD, aldosterone. SPI, spironolactone. EPL, eplerenone. FIN, finerenone. ESA, esaxerenone. APA, apararenone. OCE, ocedurenone. CAN, canrenone. RCT, randomized controlled trials. MACE, major adverse cardiovascular events. ESRD, end-stage renal disease. HHF, hospitalization for heart failure. HKAH, hyperkalemia-associated hospitalization. CV, cardiovascular. CHF, chronic heart failure. HF, heart failure. HFmEF, heart failure with mild ejection fraction. HFrEF, heart failure with reduced ejection fraction. HFpEF, heart failure with preserved ejection fraction. NT-proBNP, amino-terminal pro-B-type natriuretic peptide. AMI, acute myocardial infarction. LVM, left ventricular mass. BP, blood pressure. SBP, systolic blood pressure. DBP, diastolic blood pressure. TRH, treatment-resistant hypertension. CKD, chronic kidney diseases. DKD, diabetic kidney diseases. T2DM, type-2 diabetic mellitus. DN, diabetic nephropathy. eGFR, estimated glomerular filtration rate. UACR, urinary albumin-to-creatinine ratio. MRA, mineralocorticoid receptor antagonists. RAAS, renin-angiotensin-aldosterone system. ACEI, angiotensin-converting enzyme inhibitors. ARB, angiotensin II receptor blockers. PA, primary aldosteronism. ARR, aldosterone to renin ratio. PAC, plasma aldosterone concentration. DRC, direct renin concentration. PWV, pulse wave velocity. AIx, augmentation index. AP, augmentation pressure. AP@HR75, AP normalized to a heart rate of 75/min. RPI, renal resistive index. IMT, intima-media thickness. UAER, and urinary albumin excretion rate. BMI, body mass index. HOMA-IR, homeostasis model assessment-insulin resistance. UAE, urinary albumin excretion. PAC, plasma aldosterone concentration. PRA, plasma renin activity. WRF, worsening renal failure. NCT, the number of trials in ClinicalTrials.gov. UMIN, the number of trials in UMIN Clinical Trials Registry (UMIN-CTR); JapicCTI, the number of trials in JAPIC Clinical Trials Information.