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One of the most relevant and differentiating aspects provided by the 2021 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure is the retraction of the historical stepped and vertical pharmacological treatment scheme for heart failure with reduced ejection fraction (HFrEF). Subsequently, it was replaced by an updated algorithm that places four therapeutic families in the same initial horizontal step with an equally high degree of recommendation (class I). In this context, these four pillars, which have demonstrated a significant reduction in mortality and hospitalizations in patients with HFrEF, include (1) angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB)/angiotensin II receptor-neprilysin inhibitors (ARNi), (2) beta blockers, (3) mineralocorticoid receptor antagonists (MRA) and (4) sodium-glucose cotransporter 2 inhibitors (SGLT2is) as the main novelty. This manuscript reviews the current therapeutic algorithm with a special focus on the therapeutic value of adding an MRA (still underused in both clinical trials and real world), changing an ACEi/ARB for an ARNi and incorporating an SGLT2i in patients with HFrEF. This article is part of the Emerging concepts in heart failure management and treatment Special Issue: https://www.drugsincontext.com/special_issues/emerging-concepts-in-heart-failure-management-and-treatment.
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BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) are widely used for chronic central serous chorioretinopathy (cCSCR), but their effectiveness remains unclear. This research was conducted to evaluate the efficacy of this drugs for cCSCR. METHODS: This is a review of randomized clinical trials (RCT) comparing MRAs to placebo in adults with cCSCR, using the effects of MRAs on best-corrected visual acuity (BCVA) and adverse events as primary outcomes and the effects of MRAs on anatomical parameters as secondary outcomes: central subfield thickness (CST), subretinal fluid height (SFH) and central choroidal thickness (CCT). Our all-language online search included Medline (via PubMed), Central, Embase, Lilacs, Ibecs, and RCT registers platforms, as late as May 2021. We used the Cochrane risk-of-bias tool (version 2) to assess the methodological quality of each study and synthesized the results in meta-analyses using a random-effects model. RESULTS: The search identified 302 records, five of which were eligible, totaling 225 cCSCR patients (aged 45-62 years; M/F ratio 3.1:1) treated for 1 to 12 months with spironolactone (50 mg/day) or eplerenone (50 mg/day) vs. placebo. Moderate-certainty evidence suggests MRAs result in little to no improvement in BCVA compared to placebo (SMD 0.22; 95% CI - 0.04 to 0.48; studies = 5; comparisons = 6; participants = 218; I2 = 0%). Very low-certainty evidence suggests that, when compared to placebo, MRAs have a very uncertain impact on adverse effects (no meta-analysis was performed), and CST (MD 18.1; 95% CI - 113.04 to 76.84; participants = 145; studies = 2; I2 = 68%). MRAs also result in little to no difference in SFH (SMD - 0.35; 95% CI - 0.95 to 0.26; studies = 5; comparisons = 6; participants = 221; I2 = 76%; moderate certainty) and CCT (MD - 21.23; 95% CI - 64.69 to 22.24; participants = 206; studies = 4; comparisons = 5; I2 = 85%; low certainty). CONCLUSION: MRAs have little to no effect on BCVA. Evidence for adverse events and CST is very uncertain. MRAs also have little to no effect on SFH and CCT. These findings should be considered when prescribing MRAs for cCSCR. This research was previous registration in the PROSPERO platform (CRD42020182601).
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INTRODUCTION: Mineralocorticoid receptor (MR) antagonists (MRAs) provide cardiorenal protection. However steroidal MRAs might induce hyperkalemia and sex hormone-related adverse effects. Several novel non-steroidal MRAs are being developed that are highly selective for the MR and may have an improved safety profile. AREAS COVERED: This narrative review summarizes data from head-to-head comparisons of emerging non-steroidal MRAs with older steroidal MRAs, including pharmacological characteristics, pharmacokinetic properties, clinical outcomes, and safety, and highlights similarities and differences between emerging agents and established steroidal MRAs. EXPERT OPINION: Head-to-head comparisons in phase 2 trials suggest that the new non-steroidal MRAs exhibit at least equivalent efficacy to steroidal MRAs but may have a better safety profile in patients with heart failure and/or kidney disease. When also taking into account data from recent phase 3 placebo-controlled trials, these novel non-steroidal MRAs have the potential to provide a cardiorenal benefit above that of current optimized standard-of-care treatment in a high-risk population with reduced renal function, and with a lower risk of hyperkalemia. To optimize therapy, further research is needed to clarify the molecular differences in the mode of action of non-steroidal MRAs versus steroidal MRAs, and biomarkers that are predictive of MRA response need to be identified and validated.
Assuntos
Antagonistas de Receptores de Mineralocorticoides/farmacologia , Esteroides/farmacologia , Animais , Desenvolvimento de Medicamentos , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hiperpotassemia/induzido quimicamente , Nefropatias/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Esteroides/efeitos adversosRESUMO
INTRODUCTION: Central serous chorioretinopathy consists of the leakage of fluid from the choroid and its accumulation into the subretinal space. Its chronic form is associated with permanent vision loss. Mineralocorticoid receptor antagonists are an alternative treatment for this condition, although there is no clear evidence about their effectiveness. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified three systematic reviews including 22 studies overall and four of them are randomized trials. We concluded that in chronic central serous chorioretinopathy, mineralocorticoid receptor antagonists probably make little or no difference to best-corrected visual acuity. We are uncertain whether this intervention reduces subretinal fluid height because the certainty of the evidence is very low. Furthermore, this intervention may make little or no difference in terms of adverse effects, but the certainty of the evidence is low.
INTRODUCCIÓN: La coriorretinopatía central serosa consiste en la filtración de fluido desde la coroides y su acumulación en el espacio subretinal. Su forma crónica se asocia a pérdida visual permanente. Los antagonistas de mineralocorticoides son una alternativa de tratamiento para esta patología, aunque no existe evidencia clara sobre su efectividad. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos tres revisiones sistemáticas que en conjunto incluyeron 22 estudios primarios, de los cuales, cuatro corresponden a ensayos aleatorizados. Concluimos que el uso de antagonistas de mineralocorticoides en coriorretinopatía central serosa crónica probablemente resulta en poca o nula diferencia en la agudeza visual corregida. No es posible establecer con claridad si su uso disminuye el grosor del fluido subretinal, debido a que la certeza de la evidencia ha sido evaluada como muy baja. Además, esta intervención podría resultar en poca o nula diferencia en la aparición de efectos adversos, pero la certeza de la evidencia es baja.
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Coriorretinopatia Serosa Central/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Acuidade Visual/efeitos dos fármacos , Coriorretinopatia Serosa Central/fisiopatologia , Doença Crônica , Bases de Dados Factuais , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Líquido Sub-Retiniano/efeitos dos fármacosRESUMO
La Diabetes Mellitus (DM) y la Insuï¬ciencia Cardíaca (IC) son enfermedades crónicas cuyas prevalencias han ido en aumento y que determinan una mayor mortalidad de los pacientes que las padecen. La relación de ambas enfermedades es conocida como "Miocardiopatía Diabética" (MD). Los eventos ï¬siopatológicos principales de la MD son el mal control glicémico, el aumento de captación de ácidos grasos por parte de las células cardiacas, la disfunción endotelial y la remodelación cardíaca. Los nuevos tratamientos, se han enfocado en tratar tanto el control glicémico como la remodelación cardíaca. Los principales exponentes de los fármacos antidiabéticos favorables para la IC en pacientes con DM son los inhibidores del cotransportador de Sodio-Glucosa renal SGLT2 (iSGLT2), y los agonistas del receptor de GLP-1 (aGLP-1). Otros fármacos de relevancia son los antagonistas del receptor de mineralocorticoides (aRMC). Se realiza una revisión de la ï¬siopatología y del manejo actualizado de la IC en pacientes con DM.
Diabetes Mellitus (DM) and Heart Failure (HF) are chronic diseases whose prevalences have risen and which increase patient mortality. The two diseases are inter-related in what is called "Diabetic Cardiomyopathy" (DC). The main pathophysiological characteristics of cardiomyopathy are poor glycemic control, a rise in the capture of fatty acids by cardiac cells, endothelial dysfunction and cardiac remodeling. The principal anti-diabetic medications beneï¬cial for HF in DM patients are renal sodium-glucose cotransporter-2 inhibitors (SGLT2) and GLP-1 receptor agonists (GLP-1RAs). Other relevant medications are mineralocorticoid receptor antagonists (MRA). We review the pathophysiology and current management of HF in diabetic patients.
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INTRODUCCIÓN: La coriorretinopatía central serosa consiste en la filtración de fluido desde la coroides y su acumulación en el espacio subretinal. Su forma crónica se asocia a pérdida visual permanente. Los antagonistas de mineralocorticoides son una alternativa de tratamiento para esta patología, aunque no existe evidencia clara sobre su efectividad. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos tres revisiones sistemáticas que en conjunto incluyeron 22 estudios primarios, de los cuales, cuatro corresponden a ensayos aleatorizados. Concluimos que el uso de antagonistas de mineralocorticoides en coriorretinopatía central serosa crónica probablemente resulta en poca o nula diferencia en la agudeza visual corregida. No es posible establecer con claridad si su uso disminuye el grosor del fluido subretinal, debido a que la certeza de la evidencia ha sido evaluada como muy baja. Además, esta intervención podría resultar en poca o nula diferencia en la aparición de efectos adversos, pero la certeza de la evidencia es baja.
INTRODUCTION: Central serous chorioretinopathy consists of the leakage of fluid from the choroid and its accumulation into the subretinal space. Its chronic form is associated with permanent vision loss. Mineralocorticoid receptor antagonists are an alternative treatment for this condition, although there is no clear evidence about their effectiveness. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified three systematic reviews including 22 studies overall and four of them are randomized trials. We concluded that in chronic central serous chorioretinopathy, mineralocorticoid receptor antagonists probably make little or no difference to best-corrected visual acuity. We are uncertain whether this intervention reduces subretinal fluid height because the certainty of the evidence is very low. Furthermore, this intervention may make little or no difference in terms of adverse effects, but the certainty of the evidence is low.
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Humanos , Acuidade Visual/efeitos dos fármacos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Coriorretinopatia Serosa Central/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Doença Crônica , Bases de Dados Factuais , Coriorretinopatia Serosa Central/fisiopatologia , Líquido Sub-Retiniano/efeitos dos fármacosRESUMO
Mineralocorticoid receptor antagonists (MRAs) constitute a beneficial therapy in chronic heart failure, but their use in the acute heart failure (AHF) setting remains rather unexplored. To assess the effect of MRAs administered during hospitalization on in-hospital outcomes of patients with AHF, we performed a post-hoc analysis of the Acute Heart Failure Global Registry of Standard Treatment (ALARM-HF). Patients of the original study cohort (n = 4953) were categorized according to in-hospital MRA treatment status as MRA-treated (n = 1439) and untreated (n = 3514) subjects. Nearest-neighbor propensity score with 1:1 matching yielded a subsample of pairs of MRA-treated and MRA-untreated patients (n = 1003 in each treatment group) that were balanced in an extensive list of baseline characteristics. In-hospital mortality between MRA-treated and untreated patients were assessed by Cox regression analysis before and after adjustment for known prognostic factors and other concomitantly administered intravenous and oral HF specific therapies. In the matched cohort, in-hospital mortality was 4.2 vs 10.8% in MRA-treated vs untreated patients. Treatment with MRAs was associated with a reduction of in-hospital mortality [HR 0.372 (95% CI, 0.261-0.532), p < 0.001]. This association remained significant after adjustment for known prognostic factors and co-administered intravenous and oral HF therapies [HR: 0.618 (95% CI, 0.383-0.995), p = 0.048]. In conclusion, MRA therapy administered during hospitalization for AHF was associated with reduced in-hospital mortality. The role of MRAs in AHF deserves further examination in adequately powered randomized controlled studies.
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Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Austrália , Distribuição de Qui-Quadrado , Europa (Continente) , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Mortalidade Hospitalar , Humanos , Masculino , México , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Análise Multivariada , Pontuação de Propensão , Modelos de Riscos Proporcionais , Recuperação de Função Fisiológica , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
INTRODUCTION: Aldosterone can induce changes in the expression or activity of Na(+)/H(+) exchanger isoform 1 (NHE-1) in vascular smooth muscle cells. We aimed to clarify whether chronic mineralocorticoid receptor activation exerts an effect on the activity of NHE-1 in the aorta of mineralocorticoid-induced hypertensive rats. METHODS: Uninephrectomized male Sprague-Dawley rats received subcutaneously 10 mg/week of desoxycorticosterone (DOCA) with or without 20 mg/kg of spironolactone, or vehicle alone (n = 20). After four weeks of treatment, the animals were sacrificed; the aorta was excised for subsequent studies, including histological analysis, RT-PCR, Western blot, measurement of NHE-1 activity and vascular contractility in the presence or absence of the selective NHE-1 inhibitor ethyl-isopropyl amiloride (EIPA). RESULTS: Chronic DOCA treatment increased the NHE-1 activity, systolic and diastolic blood pressure, and aortic wall thickness. All these effects were prevented by co-treatment with Spironolactone (p < 0.05). Phenylephrine-induced vascular contractility was significantly reduced in the DOCA group when EIPA was added in the media (p < 0.05). No significant differences in NHE-1 mRNA or protein levels were detected between groups. CONCLUSIONS: Chronic DOCA administration induced functional and morphological alterations in the rat aorta that are partially explained by enhanced NHE-1 activity and prevented by spironolactone. However, we did not observe changes in the NHE-1 transcript or protein levels, suggesting that the effect may be due to post-transcriptional modifications induced by mineralocorticoid receptor activation.
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Aorta/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Espironolactona/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Desoxicorticosterona/farmacologia , Hipertensão/fisiopatologia , Masculino , Mineralocorticoides , Fenilefrina/farmacologia , Ratos Sprague-Dawley , Trocador 1 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismo , Coloração e Rotulagem , Vasoconstrição/efeitos dos fármacosRESUMO
In recent years, much attention has focused on the role of aldosterone and mineralocorticoid receptors (MRs) in the pathophysiology of hypertension and cardiovascular disease. Patients with primary aldosteronism, in whom angiotensin II levels are low, have a higher incidence of cardiovascular complications than patients with essential hypertension. The Randomized Aldactone Evaluation Study (RALES) demonstrated that adding a non-specific MR antagonist, spironolactone, to a standard therapy that included angiotensin-converting enzyme (ACE) inhibitors, loop diuretics, and digoxin, significantly reduced morbidity and mortality in patients with moderate to severe heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) showed that the addition of a selective MR antagonist (ARM), eplerenone, to an optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. These data suggest that aldosterone induces cardiac injury through activation of MRs and support the notion that MR blockade has beneficial effects on aldosterone-dependent cardiac injury, through mechanisms that cannot be simply explained by hemodynamic changes. Although, MRA are highly effective in patients with heart failure, the risk of hyperkalemia should not be overlooked. Serious hyperkalemia events were reported in some MRA clinical trials; however these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up.