Mineralocorticoid Receptor Antagonist Therapy Research Articles

Association between socioeconomic position and discontinuation of pharmacotherapy for heart failure after cardiac resynchronization therapy.

Pharmacological therapy remains a cornerstone in heart failure (HF) treatment despite implantation of a cardiac resynchronization therapy (CRT) device. The aim of this study was to investigate the association between 1) drug discontinuation, and 2) long-term adherence to HF pharmacotherapy after CRT implantation and socioeconomic position and multimorbidity. We conducted a registry-based cohort study including all patients who underwent a first-time CRT implantation at Aarhus University Hospital from 2000-2017. HF pharmacotherapy included beta blockers (BBs), renin angiotensin system inhibitors (ACEI/ARB), and mineralocorticoid receptor antagonists (MRAs). Patients were identified using the Danish Pacemaker and ICD Registry, and information about medication and comorbidities was obtained through linkage to the Danish health registries. We identified 2,007 patients of whom 1,880 (94%) were eligible for inclusion. The cumulative incidence of drug discontinuation at 10 years was 6% (95% confidence interval [CI] 5-8%) for BB, 10% (95% CI 9-12%) for ACEI/ARB, and 24% (95% CI 20-27%) for MRAs. Living alone was associated with higher BB discontinuation rates (hazard ratio [HR] 1.83, 95%CI 1.20-2.79), whereas patients with multimorbidity were more likely to discontinue ACEI/ARB- (HR 1.92, 95%CI 1.33-2.80) and MRA therapy (HR 1.51, 95% CI 1.10-2.09). Income- and educational level did not influence drug discontinuation rates, and similar adherence patterns were observed across all strata of socioeconomic position and multimorbidity. In patients with CRTs, drug discontinuation rates were low, and adherence to HF pharmacotherapy was comparable regardless of socioeconomic position. Living alone and multimorbidity were associated with discontinuation of specific HF drugs.

Mineralocorticoid Receptor Antagonists in Patients With HeartFailure and ImpairedRenalFunction.

Kidney dysfunction often leads to reluctance to start or continue life-saving heart failure (HF) therapy. This study sought to examine the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in patients with HF with reduced ejection fraction experiencing significant kidney dysfunction. We pooled individual patient data from the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in HeartFailure) trials. The association between MRA treatment and outcomes was assessed according to whether the estimated glomerular filtration rate (eGFR) declined to<30mL/min/1.73m2 or not. The primary outcome was cardiovascular death or HF hospitalization. Among 4,355 patients included, 295 (6.8%) experienced a deterioration of eGFR after randomization to<30mL/min/1.73m2. These patients had more impaired baseline cardiac and kidney function (eGFR 47.3 ± 13.4mL/min/1.73m2 vs 70.5 ± 21.8mL/min/1.73m2) and had a higher risk of the primary outcome than patients without eGFR deterioration (HR: 2.49; 95%CI: 2.01-3.08; P< 0.001). However, the risk reduction in the primary outcome with MRA therapy was similar in those who experienced a decrease in eGFR to<30mL/min/1.73m2 (HR: 0.65; 95%CI: 0.43-0.99) compared with those who did not (HR: 0.63; 95%CI: 0.56-0.71) (Pinteraction=0.87). In patients with a decrease in eGFR to<30mL/min/1.73m2, 21 fewer individuals (per 100 person-years) experienced the primary outcome with MRA treatment, vs placebo, compared with an excess of 3 more patients with severe hyperkalemia (>6.0mmol/L). Because patients experiencing a decrease in eGFR to<30mL/min/1.73m2 are at very high risk, the absolute risk reduction with an MRA in these patients is large and this decline in eGFR should not automatically lead to treatment discontinuation.

Cost-Effectiveness of Medical Therapy for HeartFailure With Mildly Reduced and Preserved Ejection Fraction.

Three medications are now guideline-recommended treatments for heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), however, the cost-effectiveness of these agents in combination has yet to be established. The purpose of this study was to determine the cost-effectiveness of mineralocorticoid receptor antagonists (MRA), angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium glucose co-transporter 2 inhibitors (SGLT2is) in individuals with HFmrEF/HFpEF. Using a 3-state Markov model, we performed a cost-effectiveness study using simulated cohorts of 1,000 patients with HFmrEF and HFpEF. Treatment with 1-, 2-, and 3-drug combinations was modeled. Based on a United States health care sector perspective, outcome data was used to calculate incremental cost-effectiveness ratios (ICERs) in 2023 United States dollars based on a 30-year time horizon. Treatment with MRA, MRA+SGLT2i, and MRA+SGLT2i+ARNI therapy resulted in an increase in life years of 1.04, 1.58, and 1.80 in the HFmrEF subgroup, respectively, and 0.99, 1.54, and 1.77 in the HFpEF subgroup, respectively, compared with placebo. At a yearly cost of $18, MRA therapy resulted in ICERs of $10,000 per quality-adjusted life year (QALY) in both subgroups. The ICER for the addition of SGLT2i therapy ($4,962 per year) was $113,000 per QALY in the HFmrEF subgroup and $141,000 in the HFpEF subgroup. The addition of ARNI therapy ($5,504 per year) resulted in ICERs >$250,000 per QALY in both subgroups. If SGLT2i and ARNI were available at generic pricing the ICERs become <$10,000 per QALY in both EF subgroups. Outcomes were highly sensitive to assumed benefit in cardiovascular death. For patients with heart failure, MRA was of high value, SGLT2i was of intermediate value, and ARNI was of low value in both HFmrEF and HFpEF subgroups. For patients with HFmrEF/HFpEF increased use of MRA and SGLT2i therapies should be encouraged and be accompanied with efforts to lower the cost of SGLT2i and ARNI therapies.

Mineralocorticoid receptor antagonists in kidney transplantation.

The fundamental role of the renin-angiotensin-aldosterone system in the pathophysiology of chronic kidney disease, congestive heart failure, hypertension and proteinuria is well established in pre-clinical and clinical studies. Mineralocorticoid receptor antagonists are among the primary options for renin-angiotensin-aldosterone system blockage, along with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. In this narrative review, we aim to evaluate the efficiency and safety of mineralocorticoid receptor antagonists in kidney transplant recipients, including the potential underlying pathophysiology. The efficiency and safety of mineralocorticoid receptor antagonists in managing chronic kidney disease and proteinuria, either non-nephrotic or nephrotic range, have been demonstrated among nontransplanted patients, though studies investigating the role of mineralocorticoid receptor antagonists among kidney transplant recipients are scarce. Nevertheless, promising results have been reported in pre-clinical and clinical studies among kidney transplant recipients regarding the role of mineralocorticoid receptor antagonists in terms of ischaemia-reperfusion injury, proteinuria, or calcineurin inhibitor-mediated nephrotoxicity without considerable adverse events such as hypotension, hyperkalaemia or worsening renal functions. Even though initial results regarding the role of mineralocorticoid receptor antagonist therapy for kidney transplant recipients are promising, there is clear need for large-scale randomized clinical trials with long-term follow-up data.

Moderate salt restriction in primary aldosteronism improves bone metabolism through attenuation of urinary calcium and phosphate losses.

Accumulating evidence links osteoporosis and dietary salt consumption. Primary aldosteronism (PA) is a model disease with increased dietary salt intake and constitutes an independent risk factor for osteoporosis. We, thus, assessed whether a short-term moderate reduction in salt intake in PA results in detectable osteoanabolic effects. Forty-one patients with PA on stable mineralocorticoid receptor antagonist therapy were subjected to a 12-week salt restriction. Serum and urinary electrolytes, markers of bone turnover, and a 15 steroids plasma profile were registered. After 12 weeks, urinary calcium and phosphate decreased, while plasma testosterone, serum phosphate, and bone alkaline phosphatase (BAP) all increased significantly. Longitudinal changes in BAP were independently correlated with changes in serum phosphate, parathyroid hormone, and urinary calcium in multivariate analysis. Salt restriction in PA limits urinary calcium and phosphate losses and may confer favorable osteoanabolic effects. Our findings suggest that salt restriction should be considered in patients with PA to improve bone health.

Solution is not simple; sodium-glucose cotransporter-2 inhibitor use in Conn syndrome.

In patients with bilateral primary hyperaldosteronism (PA) and those with unilateral PA who are unwilling or unable to undergo adrenalectomy an increase in plasma renin activity (PRA) provided by mineralocorticoid receptor antagonists (MRAs) therapy reflects sufficient antagonism for elevated aldosterone. Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) have cardiovascular, renal protective properties and some clinical data have shown an increase in PRA levels with SGLT2-i. Here, we present our experience of using SGLT2-i in PA patients with suppressed PRA despite 100 mg/day spironolactone therapy. We prospectively evaluate the laboratory values of seven patients who were diagnosed with bilateral hyperaldosteronism. All of them were diabetic and had an HbA1c <7% with metformin treatment alone. Spironolactone was started in all of the patients after diagnosis and although the dose was increased to 100 mg/day, PRA levels remained <1 ng/ml/h. Metformin treatment was changed to empagliflozin in all patients and PRA was checked again at the sixth month of treatment. Metformin treatment was changed to empagliflozin in all patients and PRA was checked again at the sixth month of treatment. Mean PRA levels were 0.464 ± 0.189 ng/ml/h before the treatment change and increased to mean 3.257 ± 1.881 ng/ml/h in the sixth month (P = 0.008). The mean PRA was >1 ng/ml/h except for one patient in the sixth month of treatment. Larger molecular and clinical studies are needed to understand whether the increase in PRA after empagliflozin treatment indicates interference, whether spironolactone treatment has become more effective, or whether empagliflozin has aldosterone receptor antagonism apart from its known effects.

Efficacy and safety of mineralocorticoid receptor antagonists for the treatment of low-renin hypertension: a systematic review and 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.

Incidence and progression of atrial fibrillation in patients with and without heart failure using mineralocorticoid receptor antagonists: a meta-analysis.

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. We sought to evaluate the effect of MRAs on AF incidence and progression in patients with and without heart failure. 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). 12 RCTs, comprising 11,419 patients treated with various MRAs were included [5960 (52%) on MRA]. On follow-up (6-39months), 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), I2 = 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 (Pinteraction = 0.013). 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.

The Benefit of Added Ranolazine to the Association of Angiotensin Receptor Blockers and Mineralocorticoid Receptor Antagonists Therapy for Ventricular Extrasystoles Treatment without the Use of Anti-Arrhythmic Drugs

The Benefit of Added Ranolazine to the Association of Angiotensin Receptor Blockers and Mineralocorticoid Receptor Antagonists Therapy for Ventricular Extrasystoles Treatment without the Use of Anti-Arrhythmic Drugs

Effect of eplerenone according to duration of heart failure in EMPHASIS-HF: It is never too late to start an MRA in HFrEF

Abstract Background In the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure trial (EMPHASIS-HF), the mineralocorticoid receptor antagonist (MRA) eplerenone reduced both the risk of death and heart failure (HF) hospitalization in patients with HF and reduced ejection fraction (HFrEF) and mild symptoms. However, many patients are still not prescribed an MRA and physicians may be reluctant to add another treatment in patients with longstanding HF who appear to be "stable" on their current therapy. Purpose As little is known about how the effect of MRA therapy varies by the duration of HF, we examined the efficacy of eplerenone according to time from HF diagnosis among patients in EMPHASIS-HF. The primary trial outcome was the composite of a first hospitalization for HF or cardiovascular death. Methods Three patient groups of similar size were created according to the duration of HF: &amp;lt;1 year, ≥1 to &amp;lt;5 years, and ≥5 years. Outcomes were analysed using Cox regression and the Kaplan-Meier estimate. Treatment effects were examined according to HF duration category and also using the duration of HF as a continuous variable. Results The number of patients in each group was: 975 (&amp;lt;1 year), 769 (1 - &amp;lt;5 years), and 988 (≥5 years), respectively. Patients with longer duration of HF were older and more frequently had an ischaemic aetiology of HF. Additionally, a longer duration of HF was associated with lower eGFR levels, wider QRS duration, and a higher proportion of atrial fibrillation at baseline. The rate of the primary outcome (per 100 person-year) increased with HF duration: 9.8 (95% CI: 8.4-11.4) for &amp;lt;1 year, 13.5 (11.6-15.7) for 1 - &amp;lt;5 years, and 17.6 (15.6-19.8) for ≥5 years. Similar trends were seen in all other outcomes (Figure 1). The hazard ratios for the effect of eplerenone compared to placebo on the primary outcome were 0.57 (95% CI: 0.42-0.79) for &amp;lt;1 year, 0.81 (0.60-1.10) for 1- &amp;lt;5 years, and 0.61 (0.48-0.78) for ≥5 years; P for interaction = 0.24. The benefits of eplerenone were also consistent across the duration of HF examined as a continuous variable (Figure 2). For the primary outcome, The number needed to treat (NNT) over the duration of the trial, for the primary outcome, was 14 for &amp;lt;1 year, 13 for 1 - &amp;lt;5 years and only 10 for ≥5 years duration. Conclusions Patients with a longer duration of HF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent in people with longer-standing HF and HF of shorter duration. These data suggest that it is never too late to start an MRA in patients with HFrEF. Figure 1. Outcomes according to heart failure duration category Abbreviations: CV cardiovascular; HF heart failure Figure 2. Treatment effects according to the duration of heart failure Abbreviations: CV cardiovascular; HF heart failureFigure 1Figure 2

Abstract 16493: An Evaluation of Heart Failure Management in the Non-White Population at a Safety Net Hospital Compared to a National Registry

Introduction: The importance of guideline-directed medical therapy (GDMT) to improve outcomes in patients with heart failure has been proven in multiple studies. However, providers still fall short in prescribing these medications to heart failure patients. This is reflected in the CHAMP-HF registry, one of the largest registries utilized to observe and analyze the use of GDMT for heart failure. The CHAMP-HF registry population includes 3,518 patients from 150 U.S. primary care and cardiology practices. Of this population, approximately 25.1% are non-White. It remains unclear what GDMT treatment patterns are in a majority non-White population. Objective: This study aims to compare GDMT treatment patterns for heart failure at Harbor-UCLA Heart Failure (HUCLA HF) clinic, with a majority-minority population, to the CHAMP-HF registry published data. Methods: This prospective cohort study followed patients who visited the HUCLA HF clinic over four months. Providers used a checklist to prompt them to review each patient’s GDMT at the end of each visit. Patient demographic data and checklist data were entered into the HUCLA HF clinic registry. The registry was used to analyze the utilization of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA). The percentage of patients using GDMT was compared to those in the CHAMP-HF registry. Results: Overall, the HUCLA HF clinic registry revealed a majority-minority patient population with about 91% of patients classified as non-White patients. The HUCLA HF clinic patients had a higher percentage on max ACE/ARB (21% vs 15.7%), max ARNI therapy (42% vs 13.8%), max beta-blocker therapy (47% vs 15.5%), and max MRA therapy (70% vs 14.5%) compared to the non-White population in the CHAMP-HF registry, respectfully. Conclusions: This study demonstrates greater utilization of GDMT at the HUCLA HF clinic compared to the patients in the CHAMP-HF registry. This difference was likely due to the checklist that reminded the provider to review the GDMT at each visit. Strategies that prompt clinicians to review GDMT must be implemented to maximize its use.

Abstract 19087: Cardiac Magnetic Resonance Imaging Increased Utilization of Cardiac Treatment in Young Duchenne Muscular Dystrophy Patients

Introduction: Duchenne muscular dystrophy (DMD), an X-linked recessive disorder affecting up to 1 in 6000. DMD-associated cardiomyopathy (DMD-C) is universal and starts as young as 6 years of age by cardiac magnetic resonance imaging (CMR) with presence of late gadolinium enhancement (LGE). Heart failure signs and symptoms are vague due to skeletal muscle myopathy. Echocardiogram only detects global dysfunction by left ventricular ejection fraction (LVEF) which rarely occur before 10 years of age. The current DMD cardiac care consideration guidelines (CCCG) recommends initiation of cardiac medication around 10 years of age or if there is LGE and/or LVEF abnormalities . Hypothesis: We hypothesized young DMD were more likely to have cardiac therapy initiated after CMR compared to only TTE evaluation. Methods: Electronic medical records for DMD patients (6 to &lt; 10 years) who underwent routine TTE or CMR evaluation between 2014-2023 were included. Demographic data at the time of the study and initiation of cardiac medication including angiotensin-converting-enzyme inhibitor (ACE-I), Angiotensin II receptor blockers (ARB) and/or Mineralocorticoid Receptor Antagonists (MRA) were recorded. Results: 150 patients met inclusion criteria, of these 81 patients underwent TTE only and 69 underwent CMR evaluation in lieu of TTE with no difference in age (8.4±1.1 versus 8.6±0.8 years, P = 0.07). Of those with TTE evaluation 10/81 (12.3%) was initiated with ACE-I or ARB ( 3/10 (33%) had LVEF &lt; 55% (average 53.5%), 4/10 (40%) turned 10 on the follow-up visit and 3/10 (30%)) because family requested. Of the 69 patients with CMR, 51/69 (73.9%) had cardiac therapy initiated (28/51 (54.9%) because of new LGE, 6/51 (11.8%) due to isolated LVEF &lt; 55% (average 53%), 12/51 (23.5%) would turn 10 on follow-up and 5/51 (9.8%)) the family requested. All patients with LGE on CMR also had MRA therapy started. Conclusions: DMC-C is universal and the use of CMR improved disease specific treatment of both ACE-I/ARB and MRA. Duboc et al, in a placebo control study showed that in 9.5 - 13.5 year old DMD patients treated with ACE-I had fewer patients develop dysfunction with reduced mortality at 10 years. Early and aggressive treatment may attenuate DMD-C. Future longitudinal study is needed.

THU568 The Impact of Surgical versus Medical Therapy on Renin Plasma Activity, Renal Function, and Hypertension Control in Patients with Primary Aldosteronism

Abstract Disclosure: S. Rolak: None. N. Venkatesan: None. R. Gregg Garcia: None. W.F. Young: None. I. Bancos: None. Background: Bilateral primary hyperaldosteronism (PA) is treated with mineralocorticoid receptor antagonist (MRA) therapy. However, the best way to monitor the success of MRA therapy is unclear. Aims: To compare the impact of curative adrenalectomy versus MRA therapy in patients with PA on plasma renin activity (PRA), renal function, and hypertension control. Methods: Single center retrospective study of patients with unilateral PA treated with adrenalectomy or bilateral PA treated with MRAs, 2017-2021. Patients underwent adrenal vein sampling to confirm laterality. Hypertension control was defined based on blood pressure measurements and the standardized hypertension daily dose (HDD). Minimum follow-up was defined as first nonsuppressed PRA or &amp;gt;1 month from therapy. Results: Of 73 patients, 53 underwent unilateral adrenalectomy for unilateral PA (median age 57, range 25-71 years, 36% women) and 20 had bilateral PA treated with MRA (median age 49, range 30-70 years, 70% women). At baseline, when compared to the bilateral PA, patients with unilateral PA had higher plasma aldosterone concentrations (median 31 ng/dL vs 19 ng/dL, P= 0.001), similarly suppressed PRA, and similar estimated glomerular filtration rate (eGFR). Uncontrolled hypertension (&amp;gt;130/90 mmHg) was seen in 40 (75%) of patients with unilateral PA and 14 (70%) patients with bilateral PA, despite a more intensive antihypertensive regimen in unilateral PA (median HDD 5, range 1-18 vs median HDD 3.5 in bilateral PA, range 0.5-9; P=0.016). Hypokalemia was present in 50 (94%) patients with unilateral PA and 15 (75%) in bilateral PA, P = 0.02.Following treatment, hyperkalemia developed in 10 (19%) patients post-adrenalectomy and in 2 (10%) patients treated with MRAs, P = 0.36. At a median follow up of 108 days, 24 (45%) patients treated with adrenalectomy and 16 (80%) patients treated with MRAs demonstrated PRA &amp;gt;1.5 ng/mL/hr, P = 0.008. eGFR decreased by at least 10 points in 15 (30%) patients treated with adrenalectomy vs in 11 (59%) patients treated with MRAs (P=0.033). Post-adrenalectomy, antihypertensive management lessened by a median of 2.5 HDD, while HDD increased in patients treated with MRAs by a median of 1.25, P&amp;lt;0.0001. Hypertension control improved, with a mean decrease in systolic blood pressure of -11 mmHg (95%CI -16.5-(-5.5)) without between group differences. Diastolic blood pressure decreased by a mean of -4.7 mmHg (95%CI -8.7-(-0.7)) in the adrenalectomy group but did not change in those treated with MRAs. Conclusions: Following curative adrenalectomy in unilateral PA, more than half of patients continue to have suppressed PRA. Despite less severe PA at baseline, patients treated with MRAs, as compared to those treated with adrenalectomy, demonstrate a higher prevalence of non-suppressed PRA, lower eGFR, similar hypertension control, and a more intense antihypertensive regimen during follow up. Presentation: Thursday, June 15, 2023

Abstract P102: Gender-based Stroke Risk In Patients With Afib And Heart Failure Treated With Mineralocorticoid Receptor Antagonists

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia detected in hospitalized patients. It is independently associated with an increased risk of stroke. Anti-fibrotic properties of mineralocorticoid receptor antagonists (MRA) have been proposed to modulate AF burden. Gender differences in patients with AF exist within the epidemiology and causative mechanisms to outcomes and complications. We compared men and women with known AF while treated with MRA to assess potential differences in stroke rate. Method: After IRB approval, we performed a retrospective chart review of all patients with confirmed HF and AF diagnoses. Patient data were extracted from electronic medical records. Patients with AF and HF treated with MRA were included in this study. Results: 64 patients with HF and AF treated with MRA were reviewed between January 2021 and September 2022. 34 were male, and 30 were female. Females were younger, 66 years (57 -74) compared to males, 73 years (60 - 78), p=.13. The median ejection fraction was similar among women, 42% (31 - 50) compared to men, 41% (33 - 49), p = .43. A significantly higher incidence of atrial fibrillation was found in our male group (59%) compared to the female group (30%), p=.02. There was no significant difference in MRA or anticoagulation use between male and female patients (p = .11, p = .12 respectively). More men had strokes compared to females (16% vs. 26% p = .17). Men were also more likely to be hypertensive compared to females (47% vs. 25%, p&lt;.01). Conclusion: Men were more likely to have AF and stroke compared to females with HF on MRA therapy. Males were more likely to be hypertensive, which may relate to increased stroke rate in this patient population. Increased awareness of the gender-based prevalence of stroke rate in patients with HF and AF may allow for earlier recognition and reduction in stroke events.

The Double Sequential Actions of the Angiotensin II Receptor Blockers and Mineralocorticoid Receptor Antagonists Therapy on the Renin Angiotensin Aldosterone System Produce a Better Reduction of Both Blood Pressure and Central Haemodynamic Parameters and Can Prevent the Appearance of the Atrial Fibrillation

Hypertension is a complex, multifactorial disease that has a significant positive association with adverse cardiovascular outcomes, such as myocardial infarction, stroke, kidney disease, and death. Research studies on hypertension have, so far, generally focused on vascular resistance and small arteries. The development of hypertension is usually accompanied by arterial structural remodelling, such as large artery stiffness, and increased both central systolic blood pressure and pulse pressure. Also, is well-established that hypertension is an important risk factor for atrial fibrillation. The goal of antihypertensive therapy is to prevent cardiovascular complications. Therefore, treatment with combination of antihypertensive agents acting on multiple targets is necessary for successful in the majority of patients. New therapeutics models are necessary to reduce both arterial stiffness and volume cardiovascular to ameliorate the stress of the arterial-ventricular-atrial dynamic coupling and the abnormal pulsatile system. The objective of the study was to assess the levels reached on both the systolic and diastolic blood pressure, and the central haemodynamic parameters into each one of the three groups of patients during the angiotensin II receptor blockers therapy alone, associated with hydrochlorothiazide or mineralocorticoid receptor antagonists, and observing the presence of episodes of atrial fibrillation during 24-hour Holter monitoring. The results suggest that the latter association of sequential double blockade on the renin angiotensin aldosterone system achieves the best haemodynamic conditions to avoid or reduce the presence of brief phases of atrial fibrillation on hypertensive patients with normal kidney function.

Trends in Medical and Device Therapies Following Incident Heart Failure in Denmark during 1996-2019: A Nationwide Register-Based Follow-Up Study.

Introduction: Data on temporal trends in guideline-based medical and device therapies in real-world chronic heart failure (HF) patients are lacking. Methods: Register-based nationwide follow-ups of temporal trends in characteristics, guideline-recommended therapies, one-year all-cause mortality, and HF rehospitalizations in incident HF patients in Denmark during 1996-2019. Results: Among 291,720 incident HF patients, the age at the onset of HF was stable over time. While initially fairly equal, the sex distribution markedly changed over time with more incidents occurring in men overall. Hypertension and diabetes increased significantly over time, while other comorbidities remained stable. Between 1996 and 2019, significant increases in angiotensin-converting enzyme inhibitor and angiotensin II-receptor blocker (ACEi/ARB) therapy (38.2% to 69.9%), beta-blocker therapy (15.5% to 70.6%), and mineralocorticoid receptor antagonist (MRA) therapy (11.8% to 34.5%) were seen. Angiotensin receptor-neprilysin inhibitor (ARNI) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) were introduced in the middle of the past decade, with minor increases but overall low uses: ARNI (2015: 0.1% vs. 2019: 3.9%) and SGLT2i (2012: <0.1% vs. 2019: 3.9%). Between 1999 and 2019, implantable cardioverter-defibrillator (ICD) use increased significantly: 0.1% to 3-4%. Cardiac resynchronization therapy (CRT) use similarly increased between 2000 and 2019: 0.2% to 2.3%. Between 1996 and 2019, one-year all-cause mortality decreased significantly: 34.6% to 20.9%, as did HF rehospitalizations (6% to 1.3%). Conclusions: Among 291,720 incident HF patients in Denmark during 1996-2019, significant increases in the use of ACEi/ARB, beta-blockers, MRAs, and devices were seen, with concurrent significant decreases in the one-year all-cause mortality and HF rehospitalization rates. The use of CRT, ARNI, and SGLT2i remained low, and MRAs were relatively underutilized, thereby representing future targets to potentially further improve HF prognoses.

Mineralocorticoid receptor antagonist use and the effects of empagliflozin on clinical outcomes in patients admitted for acute heart failure: findings from EMPULSE.

In patients hospitalized for acute heart failure (AHF) empagliflozin produced greater clinical benefit than placebo. Many patients with AHF are treated with mineralocorticoid receptor antagonists (MRAs). The interplay between empagliflozin and MRAs in AHF is yet to be explored. To study the efficacy and safety of empagliflozin versus placebo according to MRA use at baseline in the EMPULSE trial (NCT04157751). In this analysis all comparisons were performed between empagliflozin and placebo, stratified by baseline MRA use. The primary outcome included all-cause death, HF events, and a ≥5 point difference in KCCQ-TSS at 90 days, assessed using the win ratio (WR). First HF hospitalization or cardiovascular death was a secondary outcome. From the 530 patients randomized, 276 (52%) were receiving MRA at baseline. MRA users were younger, had lower ejection fraction, better renal function, and higher KCCQ scores. The primary outcome showed benefit of empagliflozin irrespective of baseline MRA use (WR=1.46, 95%CI=1.08-1.97 and WR=1.27, 95%CI=0.93-1.73 in MRA users and non-users, respectively; interactionP=0.52). The effect of empagliflozin on first HF hospitalization or cardiovascular death was not modified by MRA use (HR=0.58, 95%CI=0.30-1.11 and HR=0.85, 95%CI=0.47-1.52 in MRA users and non-users, respectively; interactionP=0.39). Investigator-reported and severe hyperkalemia events were infrequent (<6%) irrespective of MRA use. In patients admitted for AHF, initiation of empagliflozin produced clinical benefit and was well tolerated irrespective of background MRA use. These findings support the early use of empagliflozin on top of MRA therapy in patients admitted for AHF. This article is protected by copyright. All rights reserved.

Mineralocorticoid receptor antagonist initiation during admission is associated with improved outcomes irrespective of ejection fraction in patients with acute heart failure.

Heart failure (HF) guidelines recommend initiation and optimization of guideline-directed medical therapy, including mineralocorticoid receptor antagonists (MRAs), before hospital discharge. However, scientific evidence for this recommendation is lacking. Our objective was to determine whether initiation of MRA prior to hospital discharge is associated with improved outcomes. We performed a secondary analysis of 6197 patients enrolled in the RELAX-AHF-2 study. Patients were divided into four groups according to MRA therapy at baseline and discharge. At baseline 30% of patients received MRA therapy, which increased to 50% of patients at discharge. In-hospital initiation of an MRA was observed in 1690 (27%) patients, 1438 (23%) patients remained on MRA therapy, 418 (7%) patients discontinued MRA treatment, and 2651 (43%) patients did not receive an MRA during hospital stay. Compared with patients who did not receive MRA therapy, in-hospital initiation of an MRA was independently associated with lower risks of mortality (multivariable hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.60-0.96; p = 0.02), cardiovascular death (HR 0.77, 95% CI 0.59-1.01; p = 0.06), hospitalization for HF or renal failure (HR 0.72, 95% CI 0.60-0.86; p = 0.0003) and the composite endpoint of cardiovascular death and/or rehospitalization for HF or renal failure (HR 0.71, 95% CI 0.61-0.83; p < 0.0001) at 180 days. These results were independent of baseline left ventricular ejection fraction. In patients hospitalized for acute HF, in-hospital initiation of an MRA was associated with improved post-discharge outcomes, independent of left ventricular ejection fraction and other potential confounders.

Association of Reversal of Renin Suppression With Long-Term Renal Outcome in Medically Treated Primary Aldosteronism.

Renin suppression in primary aldosteronism indicates mineralocorticoid receptor activation via excessive aldosterone secretion, inducing renal damage. We investigated whether the reversal of renin suppression after the initiation of mineralocorticoid receptor antagonist therapy was associated with long-term renal outcomes in medically treated patients with primary aldosteronism. This retrospective cohort study included 318 patients with primary aldosteronism treated with mineralocorticoid receptor antagonist between 2008 and 2020 at the Yokohama Rosai Hospital in Japan. The posttreatment renin status was defined as unsuppressed (ie, reversal of renin suppression) when individual plasma renin activity after the initiation of mineralocorticoid receptor antagonist (post-plasma renin activity) was ≥1.0 ng/mL per hour; otherwise, it was defined as suppressed. We analyzed the association of posttreatment renin status with subsequent longitudinal estimated glomerular filtration rate changes using linear mixed-effects models for repeated measurements, adjusting for potential confounders. The posttreatment renin status of 119 patients was unsuppressed (median post-plasma renin activity, 1.7 ng/mL per hour) and that of 199 patients was suppressed (median post-PRA, 0.5 ng/mL per hour). Through the median follow-up period of 3.1 years, the decline in estimated glomerular filtration rate was milder among patients with the unsuppressed posttreatment renin (-0.46 [95% CI, -0.63 to -0.28] mL/min per 1.73 m2 per year) than those with suppressed posttreatment renin (-1.41 [95% CI, -1.56 to -1.27] mL/min per 1.73 m2 per year; difference, 0.96 [95% CI, 0.72-1.20] mL/min per 1.73 m2 per year). Our findings may highlight the importance of reversing renin suppression with optimal mineralocorticoid receptor antagonist titration in medically treated primary aldosteronism, which could mitigate adverse renal outcomes.

Cardiorenal interactions in heart failure - insights from recent therapeutic advances.

Heart failure is a syndrome that may develop when cardiovascular disease progresses or is insufficiently treated and associated with a poor quality of life, high mortality rates and increased health care expenditures. Prevention and treatment of heart failure is therefore of utmost importance. New therapies in patients with cardiovascular disease have recently been shown to be effective in the prevention and sometimes treatment of heart failure, and additional research is underway. Specifically, in high risk patients with either (a combination of) diabetes, chronic kidney disease and/or heart failure, three specific drug classes (sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon like peptide 1 receptor agonists (GLP-1-RA) and non steroidal mineralocorticoid receptor antagonists (MRA)) have taken center stage in therapeutic approach for these high cardiovascular risk patients. The commonality of these drugs is the finding that they improve cardiovascular and renal endpoints across the cardiorenal continuum, SGTL2i have already proven effective in all subtypes of heart failure, while we await data on non steroidal MRA therapy in heart failure. The story may be different for GLP-1-RA in patients with established heart failure, but these drugs are effective in reducing cardiovascular events in patients with diabetes. Taken together, these new therapies advance the treatment and improve the associated outcomes of patients with cardiorenal disease and diabetes, with similar characteristics and effectiveness in different conditions.