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Chinese Medical Journal May 2024Angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers (BBs), and...
BACKGROUND
Angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) are the cornerstones in treating heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) are included in HFrEF treatment guidelines. However, the effect of SGLT-2i and the five drugs on HFrEF have not yet been systematically evaluated.
METHODS
PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) from inception dates to September 23, 2022. Additional trials from previous relevant reviews and references were also included. The primary outcomes were changes in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter/dimension (LVEDD), left ventricular end-systolic diameter/dimension (LVESD), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), and left ventricular end-diastolic volume index (LVEDVI). Secondary outcomes were New York Heart Association (NYHA) class, 6-min walking distance (6MWD), B-type natriuretic peptide (BNP) level, and N-terminal pro-BNP (NT-proBNP) level. The effect sizes were presented as the mean difference (MD) with 95% confidence interval (CI).
RESULTS
We included 68 RCTs involving 16,425 patients. Compared with placebo, ARNI + BB + MRA + SGLT-2i was the most effective combination to improve LVEF (15.63%, 95% CI: 9.91% to 21.68%). ARNI + BB + MRA + SGLT-2i (5.83%, 95% CI: 0.53% to 11.14%) and ARNI + BB + MRA (3.83%, 95% CI: 0.72% to 6.90%) were superior to the traditional golden triangle "ACEI + BB + MRA" in improving LVEF. ACEI + BB + MRA + SGLT-2i was better than ACEI + BB + MRA (-8.05 mL/m2, 95% CI: -14.88 to -1.23 mL/m2) and ACEI + BB + SGLT-2i (-18.94 mL/m2, 95% CI: -36.97 to -0.61 mL/m2) in improving LVEDVI. ACEI + BB + MRA + SGLT-2i (-3254.21 pg/mL, 95% CI: -6242.19 to -560.47 pg/mL) was superior to ARB + BB + MRA in reducing NT-proBNP.
CONCLUSIONS
Adding SGLT-2i to ARNI/ACEI + BB + MRA is beneficial for reversing cardiac remodeling. The new quadruple drug "ARNI + BB + MRA + SGLT-2i" is superior to the golden triangle "ACEI + BB + MRA" in improving LVEF.
REGISTRATION
PROSPERO; No. CRD42022354792.
PubMed: 38811344
DOI: 10.1097/CM9.0000000000003118 -
Current Problems in Cardiology Jul 2024Several randomized controlled trials (RCTs) have examined mineralocorticoid receptor antagonists (MRAs) in heart failure (HF) with reduced ejection fraction (HFrEF).... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Several randomized controlled trials (RCTs) have examined mineralocorticoid receptor antagonists (MRAs) in heart failure (HF) with reduced ejection fraction (HFrEF). This systematic review and network meta-analysis (NMA) evaluated the comparative efficacy and safety of MRAs in HFrEF.
MATERIALS AND METHODS
MEDLINE(Pubmed), Scopus, Cochrane and ClinicalTrials.gov were searched until April 8, 2024 for RCTs examining the efficacy and/or safety of MRAs in HFrEF. Double-independent study selection, extraction and quality assessment were performed. Random-effects frequentist NMA models were used. Evidence certainty was assessed via Grading of Recommendations Assessment, Development and Evaluation (GRADE).
RESULTS
Totally, 32 RCTs (15685 patients) were analyzed. Eplerenone ranked above spironolactone in all-cause mortality (hazard ratio {HR}=0.78, 95% confidence interval {CI} [0.66,0.91], GRADE:"Moderate"), cardiovascular death (HR=0.74, 95%CI [0.53, 1.04], GRADE:"Low") and in all safety outcomes. Spironolactone was superior to eplerenone in the composite of cardiovascular death or hospitalization (HR=0.67, 95%CI [0.50,0.89], GRADE:"Moderate"), HF hospitalization (HR=0.61, 95%CI [0.43,0.86], GRADE:"Moderate"), all-cause hospitalization (HR=0.51, 95%CI [0.26,0.98], GRADE:"Moderate") and cardiovascular hospitalization (HR=0.56, 95%CI [0.37,0.84], GRADE:"Moderate"). Canrenone ranked first in all-cause mortality, the composite outcome and HF hospitalization. Finerenone ranked first in hyperkalemia (risk ratio [RR]=1.56, 95%CI [0.89,2.74], GRADE:"Moderate"), renal injury (RR=0.56, 95%CI [0.24,1.29]), any adverse event (RR=0.84, 95%CI [0.75,0.94], GRADE:"Moderate"), treatment discontinuation (RR=0.89, 95%CI [0.64,1.23]) and hypotension (RR=1.06, 95%CI [0.12,9.41]).
CONCLUSIONS
MRAs are effective in HFrEF with certain safety disparities. Spironolactone and eplerenone exhibited similar efficacy, however, eplerenone demonstrated superior safety. Finerenone was the safest MRA, while canrenone exhibited considerable efficacy, nonetheless, evidence for these MRAs were scarce.
Topics: Mineralocorticoid Receptor Antagonists; Humans; Heart Failure; Stroke Volume; Randomized Controlled Trials as Topic; Network Meta-Analysis; Spironolactone; Eplerenone; Treatment Outcome
PubMed: 38692445
DOI: 10.1016/j.cpcardiol.2024.102615 -
High Blood Pressure & Cardiovascular... Mar 2024Resistant hypertension (RHT) is characterized by persistently high blood pressure (BP) levels above the widely recommended therapeutic targets of less than 140/90 mmHg...
Resistant hypertension (RHT) is characterized by persistently high blood pressure (BP) levels above the widely recommended therapeutic targets of less than 140/90 mmHg office BP, despite life-style measures and optimal medical therapies, including at least three antihypertensive drug classes at maximum tolerated dose (one should be a diuretic). This condition is strongly related to hypertension-mediated organ damage and, mostly, high risk of hospitalization due to hypertension emergencies or acute cardiovascular events. Hypertension guidelines proposed a triple combination therapy based on renin angiotensin system blocking agent, a thiazide or thiazide-like diuretic, and a dihydropyridinic calcium-channel blocker, to almost all patients with RHT, who should also receive either a beta-blocker or a mineralocorticoid receptor antagonist, or both, depending on concomitant conditions and contraindications. Several other drugs may be attempted, when elevated BP levels persist in these RHT patients, although their added efficacy in lowering BP levels on top of optimal medical therapy is uncertain. Also, renal denervation has demonstrated to be a valid therapeutic alternative in RHT patients. More recently, novel drug classes and molecules have been tested in phase 2 randomised controlled clinical trials in patients with RHT on top of optimal medical therapy with at least 2-3 antihypertensive drugs. These novel drugs, which are orally administered and are able to antagonize different pathophysiological pathways, are represented by non-steroid mineralocorticorticoid receptor antagonists, selective aldosterone synthase inhibitors, and dual endothelin receptor antagonists, all of which have proven to reduce seated office and 24-h ambulatory systolic/diastolic BP levels. The main findings of randomized clinical trials performed with these drugs as well as their potential indications for the clinical management of RHT patients are summarised in this systematic review article.
Topics: Humans; Antihypertensive Agents; Blood Pressure; Drug Resistance; Drug Therapy, Combination; Hypertension; Precision Medicine; Treatment Outcome
PubMed: 38616212
DOI: 10.1007/s40292-024-00634-4 -
Therapeutic Advances in Chronic Disease 2024The effectiveness and side effects between different medical treatments in patients with primary hyperaldosteronism have not been systematically studied.
BACKGROUND
The effectiveness and side effects between different medical treatments in patients with primary hyperaldosteronism have not been systematically studied.
OBJECTIVE
To analyze the efficacy between different mineralocorticoid receptor antagonists (MRAs) and epithelial sodium channel (ENaC) inhibitors in a network meta-analysis (NMA) framework, while also evaluating adverse events.
DESIGN
Systematic review and NMA.
DATA SOURCES AND METHODS
The systematic review and NMA was reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, MEDLINE, the Cochrane library, and Excerpta Medica database (EMBASE) were searched for randomized controlled trials (RCTs) involving adult patients with primary hyperaldosteronism until 23 June 2023. Studies that compared the efficacy and side effects of different medical treatments of primary hyperaldosteronism were included. The primary outcomes included the effect on blood pressure, serum potassium, and major adverse cardiovascular events. The secondary outcomes were adverse events related to MRAs (hyperkalemia and gynecomastia). Frequentist NMA and pairwise meta-analysis were conducted.
RESULTS
A total of 5 RCTs comprising 392 participants were included. Eplerenone, esaxerenone, and amiloride were compared to spironolactone and demonstrated comparable effect on the reduction of systolic blood pressure. In comparison to spironolactone, eplerenone exhibited a less pronounced effect on reducing diastolic blood pressure [-4.63 mmHg; 95% confidence interval (CI): -8.87 to -0.40 mmHg] and correcting serum potassium (-0.2 mg/dL; 95% CI: -0.37 to -0.03 mg/dL). Spironolactone presented a higher risk of gynecomastia compared with eplerenone (relative risk: 4.69; 95% CI: 3.58-6.14).
CONCLUSION
The present NMA indicated that the blood pressure reduction and potassium-correcting effects of the three MRAs may demonstrate marginal differences, with confidence levels in the evidence being very low. Therefore, further research is needed to explore the efficacy of these MRAs, especially regarding their impact on mortality and cardiovascular outcomes.
TRIAL REGISTRATION
PROSPERO (CRD: 42023446811).
PubMed: 38511069
DOI: 10.1177/20406223241239775 -
Frontiers in Pharmacology 2024To systematically review the efficacy and safety of nonsteroidal mineralocorticoid receptor antagonists (MRAs) in chronic kidney disease (CKD). We systematically...
Efficacy and safety of nonsteroidal mineralocorticoid receptor antagonists for renal and cardiovascular outcomes in patients with chronic kidney disease: a meta-analysis of randomized clinical trials.
To systematically review the efficacy and safety of nonsteroidal mineralocorticoid receptor antagonists (MRAs) in chronic kidney disease (CKD). We systematically searched six databases to identify randomized controlled trials (RCTs) about nonsteroidal MRAs for CKD, from inception to 22 August 2023. Two reviewers independently screened the retrieved articles, extracted data, and assessed the risk of bias of included RCTs using the Cochrane risk of bias tool. We then conducted meta-analysis of the data using Stata 17.0 software. 11 RCTs (n = 15,817) were included in this meta-analysis. Compared with placebo, nonsteroidal MRAs significantly reduced the proportion of patients with ≥40% decline in estimated glomerular filtration rate (eGFR) from baseline [RR = 0.85, 95% CI (0.78, 0.92), ], although the magnitude of eGFR reduction was greater [WMD = -2.83, 95% CI (-3.95, -1.72), ]. The experimental group also had lower incidence of composite renal outcome [RR = 0.86, 95% CI (0.79, 0.93), ] and greater reduction in urine albumin-to-creatinine ratio (UACR) from baseline [WMD = -0.41, 95% CI (-0.49, -0.32), ], as well as reduced cardiovascular events [RR = 0.88, 95% CI (0.80, 0.95), = 0.003]. MRAs did not increase any adverse events compared to placebo [RR = 1.00, 95% CI (0.99, 1.01), = 0.909], but had higher incidence of hyperkalemia [RR = 2.05, 95% CI (1.85, 2.280), < 0.001]. Compared with eplerenone, there was no significant difference in the proportion of patients with ≥40% decline in eGFR [RR = 0.57, 95% CI (0.18, 1.79), ] or hyperkalemia [RR = 0.95, 95%CI (0.48, 1.88), = 0.875]. Nonsteroidal MRAs can reduce the incidence of end-stage renal disease and cardiovascular adverse events in patients. Although there was still a risk of hyperkalemia compared to placebo, there was no significant difference in any adverse events compared to either placebo or eplerenone. It has become a new option for drug treatment of CKD patients, but more clinical trials are still needed to verify its efficacy and safety. Especially further direct comparison of the nonsteroidal MRAs to eplerenone in view of the relatively small number of patients reviewed are needed.
PubMed: 38476327
DOI: 10.3389/fphar.2024.1338044 -
Clinical Endocrinology May 2024Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. A systematic review of phenotype-genotype correlation and data on testicular histology in...
OBJECTIVE
Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. A systematic review of phenotype-genotype correlation and data on testicular histology in LCAH patients is unavailable. We aim to describe our experience and provide phenotype-genotype correlation. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective review of three genetically proven LCAH patients from our centre and per-patient data analysis from a systematic review of 292 probands. The phenotypic subgroups of 46,XY were Group A (typical female genitalia), Group B (atypical genitalia) and Group C (typical male genitalia).
RESULTS
We report three new LCAH probands from India, all diagnosed post-infancy with preserved gonadal function and one novel variant. The systematic review reports 46,XY to 46,XX LCAH ratio of 1.1 (155:140). Patients with 46,XY LCAH in Group A were diagnosed in infancy (116/117) and had higher mineralocorticoid involvement than Group C (96.4% vs. 75%, p = 0.035), whereas Group C had preserved gonadal function. Hyperplastic adrenals are noted in ~60% of LCAH diagnosed with primary adrenal insufficiency in infancy. There was no report of gonadal germ cell cancer and rare reports of germ cell neoplasia in situ in adolescents, especially with intraabdominal gonads. Two-thirds of LCAH probands were East-Asian and 11/16 regional recurrent variants were from East Asia. There was minimal overlap between variants in Groups A (n = 55), B (n = 9) and C (n = 8). All nonsense and frameshift and most of the splice-site variants and deletion/insertions were present in Group A.
CONCLUSIONS
We report three new cases of LCAH from India. We propose a phenotype-derived genotypic classification of reported STAR variants in 46,XY LCAH.
Topics: Adolescent; Humans; Male; Female; Adrenal Hyperplasia, Congenital; Mutation; Phosphoproteins; Phenotype; Genotype; Disorder of Sex Development, 46,XY
PubMed: 38368602
DOI: 10.1111/cen.15032 -
Heart, Lung & Circulation Mar 2024Chronic kidney disease (CKD) coexists in up to 50% of heart failure (HF) patients, affecting both those with reduced ejection fraction (HFrEF) and those with preserved... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronic kidney disease (CKD) coexists in up to 50% of heart failure (HF) patients, affecting both those with reduced ejection fraction (HFrEF) and those with preserved ejection fraction (HFpEF). Although the efficacy of several guideline-directed medical therapies (GDMT) has been well established, the treatment recommendations are similar for those patients with HF with and without CKD. We aimed to investigate the efficacy of GDMT in patients with HF with versus those without CKD.
METHOD
This systematic review and meta-analysis included randomised controlled trials that compared the efficacy of GDMT (angiotensin-converting enzyme inhibitor [ACE-I], beta blocker, sodium-glucose cotransporter-2 inhibitor, mineralocorticoid receptor antagonist, angiotensin receptor-neprilysin inhibitor) in patients with HF with and without CKD. The primary outcome was the composite of cardiovascular death and HF hospitalisation. Risk ratios (RR) were pooled using random-effects meta-analysis.
RESULTS
A total of 19 trials (15 trials in HFrEF and four trials in HFpEF) enrolling 63,677 (38% had CKD) participants were included. Among HFrEF patients, GDMT reduced the primary endpoint in those with CKD (RR 0.77, 95% confidence interval [CI] 0.72-0.82) and without CKD (RR 0.79, 95% CI 0.74-0.84). Among HFpEF patients, the pooled summary RR for GDMT reducing the primary endpoint was 0.82 (95% CI 0.74-0.91) among those with CKD and 0.88 (95% CI 0.77-0.99) among those without CKD. There was no significant difference in the efficacy of GDMT in head-to-head comparisons between those with and without CKD in HFrEF (ratio of RR 0.97, 95% CI 0.88-1.06) and HFpEF (ratio of RR 0.94, 95% CI 0.80-1.11).
CONCLUSIONS
Among patients with HF, GDMT had a consistent effect in reducing adverse cardiovascular events in those with and without CKD. Future studies should investigate the best strategy to ensure patients with HF with CKD receive and tolerate GDMT when indicated.
Topics: Humans; Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Heart Failure; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume
PubMed: 38365495
DOI: 10.1016/j.hlc.2023.12.013 -
Journal of Human Hypertension May 2024Hypertension is the leading risk factor for premature death. The optimal treatment of low-renin hypertension (LRH), present in 30% of hypertensive individuals, is not... (Meta-Analysis)
Meta-Analysis
Hypertension is the leading risk factor for premature death. The optimal treatment of low-renin hypertension (LRH), present in 30% of hypertensive individuals, is not known. LRH likely reflects a state of excess salt, expanded volume and/or mineralocorticoid receptor (MR) activation. Therefore, targeted treatment with MR antagonists (MRA) may be beneficial. The objective of this systematic review was to assess the efficacy of MRA therapy in LRH. MEDLINE, Embase and Cochrane databases were searched for randomised controlled trials of adults with LRH that compared the efficacy of MRA to placebo or other antihypertensive treatments. Risk of bias was assessed using the Cochrane risk of bias tool. A meta-analysis was performed using a random-effects model to estimate the difference in blood pressure and the certainty of evidence was assessed using the GRADE approach. The protocol is registered on PROSPERO (CRD42022318763). From the 1612 records identified, 17 studies met the inclusion criteria with a total sample size of 1043 participants. Seven studies (n = 345) were assessed as having a high risk of bias. Meta-analysis indicated that MRA reduced systolic blood pressure by -6.8 mmHg (95% confidence interval -9.6 to -4.1) and -4.8 mmHg (95% confidence interval -11.9 to 2.4) compared to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) and diuretics. The certainty of the evidence was assessed as moderate and very low, respectively. The findings of this systematic review suggest that MRA is effective in lowering blood pressure in LRH and may be better than ACEi/ARB. Translation to clinical practice is limited by the uncertainty of evidence.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Hypertension; Treatment Outcome; Renin; Blood Pressure; Antihypertensive Agents
PubMed: 38200100
DOI: 10.1038/s41371-023-00891-1 -
Journal of Pharmacy & Pharmaceutical... 2023Hyperkalemia is a common electrolyte disorder in patients with chronic kidney disease (CKD) that increases in prevalence with the decline of glomerular fltration rate... (Review)
Review
Hyperkalemia is a common electrolyte disorder in patients with chronic kidney disease (CKD) that increases in prevalence with the decline of glomerular fltration rate (GFR). Another risk of hyperkalemia is the use of renin-angiotensin-aldosterone system inhibitors (RAASi) and/or mineralocorticoid receptor antagonists (MRAs) in managing CKD and proteinuria. The treatment of chronic hyperkalemia is challenging especially for outpatients. Treatment options for hyperkalemia include the potassium exchange resins of which two new potassium binders, Patiromer Sorbitex Calcium, and Sodium Zirconium Cyclosilicate (SZC) have demonstrated their clinical efficacy in reducing serum potassium with a positive safety profile. The old potassium exchange resin sodium polystyrene sulfonate (Kayexalate™) has some negative side effects including colonic necrosis, hypomagnesemia, and hypernatremia. In this review and literature search, we compare the available oral potassium exchange resins, highlight their advantages and disadvantages and comment on efficacy and safety parameters specifically in CKD patients.
Topics: Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Potassium; Renal Insufficiency, Chronic; Renin-Angiotensin System
PubMed: 38173862
DOI: 10.3389/jpps.2023.11892 -
Clinical Research in Cardiology :... Jun 2024Mineralocorticoid receptor antagonists (MRAs) have emerged as potential therapy to target the underlying arrhythmogenic substrate in atrial fibrillation (AF).... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Mineralocorticoid receptor antagonists (MRAs) have emerged as potential therapy to target the underlying arrhythmogenic substrate in atrial fibrillation (AF). Nevertheless, there have been inconsistent results on the impact of MRAs on AF.
OBJECTIVE
We sought to evaluate the effect of MRAs on AF incidence and progression in patients with and without heart failure.
METHODS
Electronic databases were searched up to September, 2022 for randomized controlled trials (RCTs) that evaluated MRA use and reported AF outcomes. Primary outcome was a composite of new-onset or recurrent AF. Safety outcomes included hyperkalemia and gynecomastia risks. A random-effects meta-analysis estimated pooled odds ratios (OR) and 95% confidence intervals (CI).
RESULTS
12 RCTs, comprising 11,419 patients treated with various MRAs were included [5960 (52%) on MRA]. On follow-up (6-39 months), 714 (5.5%) patients developed AF. MRA therapy was associated with a 32% reduction in the risk of new-onset or recurrent AF [OR 0.68 (95% CI 0.51-0.92), I = 40%]. On subgroup analysis, the greatest benefit magnitude was demonstrated in reducing AF recurrence [OR 0.50 (95% CI 0.30-0.83)] and among patients with left ventricular dysfunction [OR 0.59 (95% CI 0.40-0.85)]. Gynecomastia, but not hyperkalemia, was associated with MRA use. Meta-regression analysis demonstrated that therapy duration was a significant interaction factor driving the effect size (P = 0.013).
CONCLUSION
MRA use is associated with a reduction in AF risk, especially AF progression. A prominent effect is seen in patients with heart failure, further augmented by therapy duration. Prospective trials are warranted to evaluate MRA use as upstream therapy for preventing this common arrhythmia.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Atrial Fibrillation; Heart Failure; Incidence; Disease Progression; Randomized Controlled Trials as Topic; Global Health
PubMed: 38170251
DOI: 10.1007/s00392-023-02349-3