Characterization of Mineralocorticoid Receptor Antagonist Therapy Initiation in High-Risk Patients With Heart Failure.
Ontology highlight
ABSTRACT: Heart failure guidelines recommend routine monitoring of serum potassium, and renal function in patients treated with a mineralocorticoid receptor antagonist (MRA). How these recommendations are implemented in high-risk patients or according to setting of drug initiation is poorly characterized.We conducted a retrospective cohort study of Medicare beneficiaries linked to laboratory data in 10 states with prevalent heart failure as of July 1, 2011, and incident MRA use between May 1 and September 30, 2011. Outcomes included laboratory testing before MRA initiation and in the early (days 1-10) and extended (days 11-90) post-initiation periods, based on setting of drug initiation and the presence of renal insufficiency. Additional outcomes included abnormal laboratory results and adverse events proximate to MRA initiation. Of 10?443 Medicare beneficiaries with heart failure started on an MRA, 19.7% were initiated during a hospitalization. Appropriate follow-up laboratory testing across all time periods occurred in 25.2% of patients with inpatient initiation compared with 2.8% of patients begun as an outpatient. Patients with chronic kidney disease had higher rates of both hyperkalemia and acute kidney failure in the early (1.3% and 2.7%, respectively) and extended (5.6% and 9.8%, respectively) post-initiation periods compared with those without chronic kidney disease.Patients initiated on MRA therapy as an outpatient had extremely poor rates of guideline indicated follow-up laboratory monitoring after drug initiation. In particular, patients with chronic kidney disease are at high risk for adverse events after MRA initiation. Quality improvement initiatives focused on systems to improve appropriate laboratory monitoring are needed.
Circulation. Cardiovascular quality and outcomes 20170101 1
<h4>Background</h4>Heart failure guidelines recommend routine monitoring of serum potassium, and renal function in patients treated with a mineralocorticoid receptor antagonist (MRA). How these recommendations are implemented in high-risk patients or according to setting of drug initiation is poorly characterized.<h4>Methods and results</h4>We conducted a retrospective cohort study of Medicare beneficiaries linked to laboratory data in 10 states with prevalent heart failure as of July 1, 2011, a ...[more]
Project description:Finerenone is a novel non-steroidal mineralocorticoid receptor (MR) antagonist (MRA) with high binding affinity, high MR selectivity and a short plasma half-life. In two major endpoint-driven clinical trials in patients with chronic kidney disease and type 2 diabetes mellitus (FIDELIO-DKD and FIGARO-DKD), finerenone induced significant cardiorenal protective actions, and has been recently approved for treatment of these patients. Heart failure with preserved ejection fraction (HFpEF) is a devastating clinical syndrome with increasing prevalence and poor prognosis. Pharmacological therapy of HFpEF is very limited and new therapeutic options are urgently needed. Finerenone has been shown to improve multiple pathophysiological parameters of HFpEF in preclinical models. In consonance, pre-specified subgroup analyses of FIDELIO-DKD and FIGARO-DKD suggested a potential beneficial effect of finerenone in HFpEF. This review will discuss the pharmacodynamic and -kinetic profile of finerenone. We will provide a general overview over the complex pathophysiology of HFpEF and data from pre-clinical studies, focusing on how finerenone improves multiple components of this pathophysiology. Finally, we will discuss current and future clinical trials with finerenone in heart failure patients focusing on HFpEF.
Project description:This prospective cohort study evaluated the association between the renin angiotensin aldosterone system genotypes and response to spironolactone in 155 Egyptian patients with heart failure with reduced ejection fraction (HFrEF). Genotype frequencies for AGT rs699 were: CC = 16%, CT = 48%, and TT = 36%. Frequencies for CYP11B2 rs1799998 were: TT = 33%, TC = 50%, and CC = 17%. After 6 months of spironolactone treatment, change in the left ventricular ejection fraction (LVEF) differed by AGT rs699 (CC, 14.6%; TC, 7.9%; TT, 2.7%; P = 2.1E-26), and CYP11B2 rs1799998 (TT, 9.1%; TC, 8.7%; CC, 1.4%; P = 0.0006) genotypes. Multivariate linear regression showed that the AGT rs699 and CYP11B2 rs1799998 polymorphisms plus baseline serum potassium explained 71% of variability in LVEF improvement (P = 0.001), 63% of variability in serum potassium increase (P = 2.25E-08), and 39% of the variability in improvement in quality of life (P = 2.3E-04) with spironolactone therapy. These data suggest that AGT and CYP11B2 genotypes as well as baseline serum K are predictors of spironolactone response in HFrEF.
Project description:AimsThis study aims to investigate the prognostic impact of mineralocorticoid receptor antagonists (MRAs) on cardiovascular events in patients hospitalized for acute decompensated heart failure with preserved ejection fraction (HFpEF; defined as left ventricular ejection fraction ≥45%).Methods and resultsA prospective multicentre cohort study was conducted in Nagano prefecture, Japan, between July 2014 and December 2018 that contained 518 consecutive HFpEF patients hospitalized for acute decompensated heart failure (HF). The primary outcome was a composite of cardiovascular death and HF readmission. We compared the incidence of cardiovascular events between patients who were prescribed with MRAs and those who were not in a propensity score matched cohort using a Cox proportional hazards regression model with a propensity score derived from 23 baseline variables. For sensitivity analysis, we conducted Cox proportional hazards regression models for the primary outcome adjusting for 16 clinically relevant variables in the crude cohort. The median age was 83 years, and 53% were female. The median left ventricular ejection fraction was 61%. During a median follow-up of 553 days, the primary outcome occurred in 192 (37%) patients. MRAs were used in 255 (49%) patients. After analysis, a matched cohort consisting of 370 patients was created. After propensity score matching, the baseline characteristics were well balanced between the two groups. The incidence of the primary outcome was significantly lower in MRA users than in non-users [32% (59/185) vs. 49% (90/185); hazard ratio (HR) 0.669, 95% confidence interval (CI) 0.482-0.929, P = 0.016]. The incidence of cardiovascular death was also significantly lower in the MRA users [11% (21/185) vs. 22% (41/185); HR, 0.563; 95% CI, 0.333-0.953; P = 0.032]. The risk of HF readmission tended to be lower in the MRA users [29% (54/185) vs. 41% (75/185); HR, 0.738; 95% CI, 0.520-1.048; P = 0.089]. MRA use was also associated with a lower risk of the primary outcome after Cox proportional hazards analysis adjusting for 16 clinically relevant variables in the crude cohort (HR, 0.710; 95% CI 0.507-0.995; P = 0.047).ConclusionsMineralocorticoid receptor antagonist use was significantly associated with a lower risk of the primary composite outcome of cardiovascular death and HF readmission in patients hospitalized for acute decompensated HFpEF. The incidence of cardiovascular mortality was also significantly lower in these patients.
Project description:There are no studies of mineralocorticoid receptor antagonist (MRA) treatment examining outcome in unselected real-life patients with myocardial infarction (MI) and heart failure (HF). There is uncertainty regarding effects of MRA in relation to left ventricular ejection fraction (LVEF) and chronic kidney disease (CKD). The aim was to assess MRA use and compare outcomes in MI patients with HF in relation to LVEF and CKD. Patients with MI and HF registered in the Swedish myocardial infarction registry, SWEDEHEART, 2005-2014, were included. Associations between MRA use and all-cause mortality up to 3 years were assessed with multivariable Cox regression, stratified by EF groups and presence of CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m2). Of 45 071 patients with MI and HF, 4470 (9.9%) received MRA. Those with HF and LVEF <40% more often had MRA (19.6%) compared with those with LVEF 40% to 49% (9.1%) or LVEF ≥50% (4.7%). 8.6% of patients with CKD received MRA. After adjustment, MRA use was associated with lower mortality in those with LVEF <40% (hazard ratio [95% confidence interval] 0.81 [0.75-0.88]) and LVEF 40% to 49% (0.88 [0.75-1.03]) but not in those with LVEF ≥50% (1.29 [1.09-1.53]), with significant interaction between MRA and LVEF (P<0.0001). The association between MRA use and mortality was similar in those without (0.96 [0.88-1.05]) and with (0.92 [0.85-0.99]) CKD. In patients with MI and HF, MRA use was associated with better long-term survival in patients with LVEF <40% but not in those with LVEF ≥50%, while the mortality risk was similar in MRA-treated patients with or without CKD.
Project description:Despite concerns about mineralocorticoid receptor antagonist therapies (MRAs) underuse and misuse in patients with heart failure, temporal and institutional variations of MRA prescription have not been reported.We studied a national sample of veterans hospitalized for heart failure between 2003 and 2009 and left ventricular ejection fraction <40%. We identified ideal and non-ideal candidates for MRA therapy based on American College of Cardiology/American Heart Association guidelines. We measured temporal trends and hospital variation of MRA prescriptions within 90 days after discharge. We determined the median odds ratio (MOR), a measure of the relative odds of an MRA prescription for 2 individuals with similar characteristics discharged at 2 randomly selected hospitals. From 37 126 patients (n=131 hospitals), 9355 were ideal-MRA candidates, and 4056 were non-ideal candidates. Among ideal candidates, 36% received an MRA, but there was a decline in use (41% in 2003 to 31% in 2009, P<0.001). Of non-ideal candidates, 27% received an MRA with a decline in use (34% in 2003 to 22% in 2009, P<0.001). Hospital MRA prescription ranged from 0% to 71% for ideal candidates and 0% to 100% for non-ideal candidates. The median odds ratios of MRA prescription for ideal and non-ideal candidates were 1.44 and 1.36, respectively; a median odds ratio >1.2 indicates significant practice-level variation.There was decreasing MRA use between 2003 and 2009 with wide institutional variation in MRA prescription, which suggests opportunities for improvement to stimulate MRA use in ideal candidates while further reducing use in those with contraindications.
Project description:The mineralocorticoid receptor (MR) plays an important role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option, but their use in patients with CKD is limited due to the associated risk of hyperkalemia. Finerenone is a non-steroidal MRA associated with an improved benefit-risk profile in comparison to steroidal MRAs. In this study, we decided to test whether finerenone improves renal and cardiac function in male hypertensive and diabetic ZSF1 rats as an established preclinical HFpEF model. Finerenone was administered at 10 mg/kg/day for 12 weeks. Cardiac function/hemodynamics were assessed in vivo. ZSF1 rats showed classical signs of CKD with increased BUN, UACR, hypertrophy, and fibrosis of the kidney together with characteristic signs of HFpEF including cardiac fibrosis, diastolic dysfunction, and decreased cardiac perfusion. Finerenone treatment did not impact kidney function but reduced renal hypertrophy and cardiac fibrosis. Interestingly, finerenone ameliorated diastolic dysfunction and cardiac perfusion in ZSF1 rats. In summary, we show for the first time that non-steroidal MR antagonism by finerenone attenuates cardiac diastolic dysfunction and improves cardiac perfusion in a preclinical HFpEF model. These cardiac benefits were found to be largely independent of renal benefits.
Project description:ImportanceScarce data are available on the association of mineralocorticoid receptor antagonist (MRA) use with outcomes in acute decompensated heart failure (ADHF).ObjectiveTo investigate the association of MRA use with all-cause mortality and hospital readmission in patients with ADHF.Design, setting, and participantsThis cohort study examines participants enrolled in the Kyoto Congestive Heart Failure (KCHF) registry, a physician-initiated, prospective, multicenter cohort study of consecutive patients admitted for ADHF, between October 1, 2014, and March 31, 2016, into 1 of 19 secondary and tertiary hospitals throughout Japan. To balance the baseline characteristics associated with the selection of MRA use, a propensity score-matched cohort design was used, yielding 2068 patients. Data analysis was conducted from April to August 2018.ExposuresPrescription of MRA at discharge from the index hospitalization.Main outcomes and measuresComposite of all-cause death or heart failure hospitalization after discharge.ResultsAmong 3717 patients hospitalized for ADHF, 1678 patients (45.1%) had received MRA at discharge and 2039 (54.9%) did not. After propensity score matching, 2068 patients (with a median [interquartile range] age of 80 [72-86] years, and of whom 937 [45.3%] were women) were included. In the matched cohort (n = 1034 in each group), the cumulative 1-year incidence of the primary outcome was statistically significantly lower in the MRA use group than in the no MRA use group (28.4% vs 33.9%; hazard ratio [HR], 0.81; 95% CI, 0.70-0.93; P = .003). Of the components of the primary outcome, the cumulative 1-year incidence of heart failure hospitalization was significantly lower in the MRA use group than in the no MRA use group (18.7% vs 24.8%; HR, 0.70; 95% CI, 0.60-0.86; P < .001), whereas no difference in mortality was found between the 2 groups (15.6% vs 15.8%; HR, 0.98; 95% CI, 0.82-1.18; P = .85). No difference in all-cause hospitalization was observed between the 2 groups (35.3% vs 38.2%; HR, 0.88; 95% CI, 0.77-1.01; P = .07). In additional analyses that stratified by left ventricular ejection fraction, the association of MRA use with the primary outcome was statistically significant in patients with left ventricular ejection fraction of 40% or greater.Conclusions and relevanceUse of MRA at discharge from ADHF hospitalization did not appear to be associated with lower mortality but was associated with a lower risk of heart failure readmission. This finding suggests that MRA treatment at discharge may have minimal, if any, clinical advantages.
Project description:AimsThe effects of adding a sodium-glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor-neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines.Methods and resultsThe efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74-1.01) for MRA non-users versus 0.76 (95% CI 0.64-0.91) for MRA users (pinteraction = 0.30). The corresponding values for ARNI non-users and users were 0.82 (95% CI 0.73-0.92) and 0.74 (95% CI 0.45-1.22), respectively (pinteraction = 0.75). None of the adverse events examined was more common with dapagliflozin compared to placebo overall or in the MRA and ARNI subgroups.ConclusionsThe efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF.
Project description:BackgroundMineralocorticoid receptor (MR) antagonists decrease heart failure (HF) hospitalization and mortality, but the mechanisms are unknown. Preclinical studies reveal that the benefits on cardiac remodeling and dysfunction are not completely explained by inhibition of MR in cardiomyocytes, fibroblasts, or endothelial cells. The role of MR in smooth muscle cells (SMCs) in HF has never been explored.MethodsMale mice with inducible deletion of MR from SMCs (SMC-MR-knockout) and their MR-intact littermates were exposed to HF induced by 27-gauge transverse aortic constriction versus sham surgery. HF phenotypes and mechanisms were measured 4 weeks later using cardiac ultrasound, intracardiac pressure measurements, exercise testing, histology, cardiac gene expression, and leukocyte flow cytometry.ResultsDeletion of MR from SMC attenuated transverse aortic constriction-induced HF with statistically significant improvements in ejection fraction, cardiac stiffness, chamber dimensions, intracardiac pressure, pulmonary edema, and exercise capacity. Mechanistically, SMC-MR-knockout protected from adverse cardiac remodeling as evidenced by decreased cardiomyocyte hypertrophy and fetal gene expression, interstitial and perivascular fibrosis, and inflammatory and fibrotic gene expression. Exposure to pressure overload resulted in a statistically significant decline in cardiac capillary density and coronary flow reserve in MR-intact mice. These vascular parameters were improved in SMC-MR-knockout mice compared with MR-intact littermates exposed to transverse aortic constriction.ConclusionsThese results provide a novel paradigm by which MR inhibition may be beneficial in HF by blocking MR in SMC, thereby improving cardiac blood supply in the setting of pressure overload-induced hypertrophy, which in turn mitigates the adverse cardiac remodeling that contributes to HF progression and symptoms.
