RESUMEN
BACKGROUND: Empagliflozin improves cardiovascular outcomes in patients with heart failure, patients with type 2 diabetes who are at high cardiovascular risk, and patients with chronic kidney disease. The safety and efficacy of empagliflozin in patients who have had acute myocardial infarction are unknown. METHODS: In this event-driven, double-blind, randomized, placebo-controlled trial, we assigned, in a 1:1 ratio, patients who had been hospitalized for acute myocardial infarction and were at risk for heart failure to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care within 14 days after admission. The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis. RESULTS: A total of 3260 patients were assigned to receive empagliflozin and 3262 to receive placebo. During a median follow-up of 17.9 months, a first hospitalization for heart failure or death from any cause occurred in 267 patients (8.2%) in the empagliflozin group and in 298 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P = 0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19). Adverse events were consistent with the known safety profile of empagliflozin and were similar in the two trial groups. CONCLUSIONS: Among patients at increased risk for heart failure after acute myocardial infarction, treatment with empagliflozin did not lead to a significantly lower risk of a first hospitalization for heart failure or death from any cause than placebo. (Funded by Boehringer Ingelheim and Eli Lilly; EMPACT-MI ClinicalTrials.gov number, NCT04509674.).
Asunto(s)
Insuficiencia Cardíaca , Infarto del Miocardio , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Método Doble Ciego , Estudios de Seguimiento , Glucósidos/uso terapéutico , Glucósidos/efectos adversos , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/prevención & control , Hospitalización , Estimación de Kaplan-Meier , Infarto del Miocardio/complicaciones , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/mortalidad , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Resultado del Tratamiento , Factores de Riesgo de Enfermedad CardiacaRESUMEN
A serum ferritin level <15 to 20 µg/L historically identified patients who had absent bone marrow iron stores, but serum ferritin levels are distorted by the systemic inflammatory states seen in patients with chronic kidney disease or heart failure. As a result, nearly 25 years ago, the diagnostic ferritin threshold was increased 5- to 20-fold in patients with chronic kidney disease (ie, iron deficiency was identified if the serum ferritin level was <100 µg/L, regardless of transferrin saturation [TSAT], or 100 to 299 µg/L if TSAT was <20%). This guidance was motivated not by the findings of studies of total body or tissue iron depletion, but by a desire to encourage the use of iron supplements to potentiate the response to erythropoiesis-stimulating agents in patients with renal anemia. However, in patients with heart failure, this definition does not reliably identify patients with an absolute or functional iron-deficiency state, and it includes individuals with TSATs (≥20%) and serum ferritin levels in the normal range (20-100 mg/L) who are not iron deficient, have an excellent prognosis, and do not respond favorably to iron therapy. Furthermore, serum ferritin levels may be distorted by the use of both neprilysin and sodium-glucose cotransporter 2 inhibitors, both of which may act to mobilize endogenous iron stores. The most evidence-based and trial-tested definition of iron deficiency is the presence of hypoferremia, as reflected by as a TSAT <20%. These hypoferremic patients are generally iron deficient on bone marrow examination, and after intravenous iron therapy, they exhibit an improvement in exercise tolerance and functional capacity (when meaningfully impaired) and show the most marked reduction (ie, 20%-30%) in the risk of cardiovascular death or total heart failure hospitalizations. Therefore, we propose that the current ferritin-driven definition of iron deficiency in heart failure should be abandoned and that a definition based on hypoferremia (TSAT <20%) should be adopted.
Asunto(s)
Anemia Ferropénica , Ferritinas , Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/sangre , Ferritinas/sangre , Anemia Ferropénica/diagnóstico , Anemia Ferropénica/tratamiento farmacológico , Anemia Ferropénica/sangre , Enfermedad Crónica , Deficiencias de Hierro , Hierro/metabolismo , Hierro/sangreRESUMEN
BACKGROUND: Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown. METHODS: EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes. RESULTS: Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; P=0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; P=0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all P<0.05). CONCLUSIONS: Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Insuficiencia Cardíaca , Hospitalización , Infarto del Miocardio , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Glucósidos/uso terapéutico , Compuestos de Bencidrilo/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Masculino , Femenino , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/mortalidad , Infarto del Miocardio/complicaciones , Anciano , Persona de Mediana Edad , Método Doble Ciego , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Resultado del Tratamiento , Volumen Sistólico/efectos de los fármacosRESUMEN
BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i Meta-analysis Cardio-Renal Trialists Consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across 3 patient populations (patients with diabetes at high risk for atherosclerotic cardiovascular disease, heart failure [HF], or chronic kidney disease). The outcomes of interest were MACE (composite of cardiovascular death, myocardial infarction , or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established atherosclerotic cardiovascular disease, previous myocardial infarction, diabetes, previous HF, albuminuria, chronic kidney disease stages, and risk groups). RESULTS: A total of 78 607 patients across 11 trials were included: 42 568 (54.2%), 20 725 (26.4%), and 15 314 (19.5%) were included from trials of patients with diabetes at high risk for atherosclerotic cardiovascular disease, HF, or chronic kidney disease, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ration [HR], 0.91 [95% CI, 0.87-0.96], P<0.0001) with a consistent effect across all 3 patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in cardiovascular death (HR, 0.86 [95% CI, 0.81-0.92], P<0.0001), with no significant effect for myocardial infarction in the overall population (HR, 0.95 [95% CI, 0.87-1.04], P=0.29), and no effect on stroke (HR, 0.99 [95% CI, 0.91-1.07], P=0.77). The benefit for cardiovascular death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [95% CI, 0.46-1.02] and HR, 0.86 [95% CI, 0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pinteraction=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of atherosclerotic cardiovascular disease, diabetes, kidney function, or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of cardiovascular death, particularly HF death and sudden cardiac death, without a significant effect on myocardial infarction in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.
Asunto(s)
Enfermedades Cardiovasculares , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Humanos , Enfermedades Cardiovasculares/mortalidad , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Masculino , Resultado del Tratamiento , AncianoRESUMEN
Current understanding of iron-deficient heart failure is based on blood tests that are thought to reflect systemic iron stores, but the available evidence suggests greater complexity. The entry and egress of circulating iron is controlled by erythroblasts, which (in severe iron deficiency) will sacrifice erythropoiesis to supply iron to other organs, e.g. the heart. Marked hypoferraemia (typically with anaemia) can drive the depletion of cardiomyocyte iron, impairing contractile performance and explaining why a transferrin saturation < ≈15%-16% predicts the ability of intravenous iron to reduce the risk of major heart failure events in long-term trials (Type 1 iron-deficient heart failure). However, heart failure may be accompanied by intracellular iron depletion within skeletal muscle and cardiomyocytes, which is disproportionate to the findings of systemic iron biomarkers. Inflammation- and deconditioning-mediated skeletal muscle dysfunction-a primary cause of dyspnoea and exercise intolerance in patients with heart failure-is accompanied by intracellular skeletal myocyte iron depletion, which can be exacerbated by even mild hypoferraemia, explaining why symptoms and functional capacity improve following intravenous iron, regardless of baseline haemoglobin or changes in haemoglobin (Type 2 iron-deficient heart failure). Additionally, patients with advanced heart failure show myocardial iron depletion due to both diminished entry into and enhanced egress of iron from the myocardium; the changes in iron proteins in the cardiomyocytes of these patients are opposite to those expected from systemic iron deficiency. Nevertheless, iron supplementation can prevent ventricular remodelling and cardiomyopathy produced by experimental injury in the absence of systemic iron deficiency (Type 3 iron-deficient heart failure). These observations, taken collectively, support the possibility of three different mechanistic pathways for the development of iron-deficient heart failure: one that is driven through systemic iron depletion and impaired erythropoiesis and two that are characterized by disproportionate depletion of intracellular iron in skeletal and cardiac muscle. These mechanisms are not mutually exclusive, and all pathways may be operative at the same time or may occur sequentially in the same patients.
Asunto(s)
Anemia Ferropénica , Insuficiencia Cardíaca , Hierro , Músculo Esquelético , Miocitos Cardíacos , Humanos , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Hierro/metabolismo , Miocitos Cardíacos/metabolismo , Músculo Esquelético/metabolismo , Anemia Ferropénica/metabolismo , Miocardio/metabolismo , Deficiencias de Hierro , Eritropoyesis/fisiología , Eritroblastos/metabolismoRESUMEN
The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism.
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Nefropatías Diabéticas , Insuficiencia Cardíaca , Humanos , Nefropatías Diabéticas/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Mineralocorticoides/uso terapéutico , Naftiridinas/farmacología , Naftiridinas/uso terapéutico , Receptores de Mineralocorticoides/uso terapéuticoRESUMEN
BACKGROUND: It is not known whether the benefits of sodium-glucose cotransporter 2 inhibitors in heart failure persist after years of therapy. METHODS: In the EMPEROR-Reduced (Empagliflozin Outcome Trials in Chronic Heart Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (Empagliflozin Outcome Trials in Chronic Heart Failure With Preserved Ejection Fraction) trials, patients with heart failure were randomly assigned (double-blind) to placebo or empagliflozin 10 mg/day for a median of 16 and 26 months, respectively. At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days off treatment. RESULTS: From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or hospitalization for heart failure was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 [95% CI, 9.0-12.6] versus 13.5 [95% CI, 11.5-15.6] events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI, 0.60-0.96]). When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6-22.1] versus 14.1 [95% CI, 10.1-18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20-2.54), P=0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76-1.66]); time period-by-treatment interaction, P=0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo (P<0.0001). Furthermore, withdrawal of empagliflozin was accompanied by increases in fasting glucose, body weight, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-hormone B-type natriuretic peptide, uric acid, and serum bicarbonate and decreases in hemoglobin and hematocrit (all P<0.01). These physiological and laboratory changes were the inverse of the effects of the drug seen at the start of the trials during the initiation of treatment (≈1-3 years earlier) in the same cohort of patients. CONCLUSIONS: These observations demonstrate a persistent effect of empagliflozin in patients with heart failure even after years of treatment, which dissipated rapidly after withdrawal of the drug. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT03057977 and NCT03057951.
Asunto(s)
Compuestos de Bencidrilo , Insuficiencia Cardíaca , Humanos , Compuestos de Bencidrilo/uso terapéutico , Método Doble Ciego , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Resultado del TratamientoRESUMEN
BACKGROUND: Iron deficiency, with or without anemia, is an adverse prognostic factor in heart failure (HF). In AFFIRM-AHF (a randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure), intravenous ferric carboxymaltose (FCM), although having no significant effect on the primary end point, reduced the risk of HF hospitalization (hHF) and improved quality of life versus placebo in iron-deficient patients stabilized after an acute HF (AHF) episode. These prespecified AFFIRM-AHF subanalyses explored the association between hemoglobin levels and FCM treatment effects. METHODS: AFFIRM-AHF was a multicenter, double-blind, randomized, placebo-controlled trial of FCM in hospitalized AHF patients with iron deficiency. Patients were stratified by baseline hemoglobin level (<12 versus ≥12 g/dL). In each subgroup, the primary composite (total hHF and cardiovascular death) and secondary (total hHF; total cardiovascular hospitalizations and cardiovascular death; time to cardiovascular death, and time to first/days lost due to hHF or cardiovascular death) outcomes were assessed with FCM versus placebo at week 52. Sensitivity analyses using the World Health Organization anemia definition (hemoglobin level <12 g/dL [women] or <13 g/dL [men]) were performed, among others. RESULTS: Of 1108 AFFIRM-AHF patients, 1107 were included in these subanalyses: 464 (FCM group, 228; placebo group, 236) had a hemoglobin level <12 g/dL, and 643 (FCM, 329; placebo, 314) had a hemoglobin level ≥12 g/dL. Patients with a hemoglobin level <12 g/dL were older (mean, 73.7 versus 69.1 years), with more frequent previous HF (75.0% versus 68.7%), serum ferritin <100 µg/L (75.4% versus 68.1%), and transferrin saturation <20% (87.9% versus 81.4%). For the primary outcome, annualized event rates per 100 patient-years with FCM versus placebo were 71.1 and 73.6 (rate ratio, 0.97 [95% CI, 0.66-1.41]), respectively, and 48.5 versus 72.9 (RR, 0.67 [95% CI, 0.48-0.93]) in the hemoglobin levels <12 and ≥12 g/dL subgroups, respectively. No significant interactions between hemoglobin subgroup and treatment effect were observed for primary (Pinteraction=0.15) or secondary outcomes. Changes from baseline in hemoglobin, serum ferritin and transferrin saturation were significantly greater with FCM versus placebo in both subgroups between weeks 6 and 52. Findings were similar using the World Health Organization definition for anemia. CONCLUSIONS: The effects of intravenous FCM on outcomes in iron-deficient patients stabilized after an AHF episode, including improvements in iron parameters over time, did not differ between patients with hemoglobin levels <12 and ≥12 g/dL. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02937454.
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Anemia , Insuficiencia Cardíaca , Deficiencias de Hierro , Masculino , Humanos , Femenino , Calidad de Vida , Compuestos Férricos/efectos adversos , Hierro , Maltosa/efectos adversos , Anemia/complicaciones , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/complicaciones , Hemoglobinas/metabolismo , Ferritinas , Transferrinas , Resultado del TratamientoRESUMEN
BACKGROUND: Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unclear. METHODS: In this double-blind trial, we randomly assigned patients with CKD and type 2 diabetes to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300 and an estimated glomerular filtration rate (eGFR) of 25 to 90 ml per minute per 1.73 m2 of body-surface area (stage 2 to 4 CKD) or a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of at least 60 ml per minute per 1.73 m2 (stage 1 or 2 CKD). Patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary outcome, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The first secondary outcome was a composite of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes. Safety was assessed as investigator-reported adverse events. RESULTS: A total of 7437 patients underwent randomization. Among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3686 patients (12.4%) in the finerenone group and in 519 of 3666 (14.2%) in the placebo group (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; P = 0.03), with the benefit driven primarily by a lower incidence of hospitalization for heart failure (hazard ratio, 0.71; 95% CI, 0.56 to 0.90). The secondary composite outcome occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 1.01). The overall frequency of adverse events did not differ substantially between groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%). CONCLUSIONS: Among patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo. (Funded by Bayer; FIGARO-DKD ClinicalTrials.gov number, NCT02545049.).
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/complicaciones , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Naftiridinas/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Anciano , Albuminuria/etiología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Método Doble Ciego , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Naftiridinas/efectos adversos , Modelos de Riesgos Proporcionales , Insuficiencia Renal Crónica/complicacionesRESUMEN
BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. METHODS: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. RESULTS: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONS: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).
Asunto(s)
Compuestos de Bencidrilo/administración & dosificación , Enfermedades Cardiovasculares/prevención & control , Glucósidos/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Volumen Sistólico , Adulto , Compuestos de Bencidrilo/efectos adversos , Enfermedades Cardiovasculares/mortalidad , Enfermedad Crónica , Método Doble Ciego , Femenino , Glucósidos/efectos adversos , Insuficiencia Cardíaca/fisiopatología , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversosRESUMEN
Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.
Asunto(s)
Cardiopatías , Hipertensión Renal , Nefritis , Humanos , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Aldosterona/farmacología , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Hipertensión Renal/tratamiento farmacológico , Sistema Renina-Angiotensina , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/farmacología , Cardiopatías/tratamiento farmacológicoRESUMEN
AIMS: Aims were to evaluate (1) reclassification of patients from heart failure with mildly reduced (HFmrEF) to reduced (HFrEF) ejection fraction when an EF = 40% was considered as HFrEF, (2) role of EF digit bias, ie, EF reporting favouring 5% increments; (3) outcomes in relation to missing and biased EF reports, in a large multinational HF registry. METHODS AND RESULTS: Of 25,154 patients in the European Society of Cardiology (ESC) HF Long-Term registry, 17% had missing EF and of those with available EF, 24% had HFpEF (EF≥50%), 21% HFmrEF (40%-49%) and 55% HFrEF (<40%) according to the 2016 ESC guidelines´ classification. EF was "exactly" 40% in 7%, leading to reclassifying 34% of the HFmrEF population defined as EF = 40% to 49% to HFrEF when applying the 2021 ESC Guidelines classification (14% had HFmrEF as EF = 41% to 49% and 62% had HFrEF as EF≤40%). EF was reported as a value ending with 0 or 5 in â¼37% of the population. Such potential digit bias was associated with more missing values for other characteristics and higher risk of all-cause death and HF hospitalization. Patients with missing EF had higher risk of all-cause and CV mortality, and HF hospitalization compared to those with recorded EF. CONCLUSIONS: Many patients had reported EF = 40%. This led to substantial reclassification of EF from old HFmrEF (40%-49%) to new HFrEF (≤40%). There was considerable digit bias in EF reporting and missing EF reporting, which appeared to occur not at random and may reflect less rigorous overall care and worse outcomes.
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Insuficiencia Cardíaca , Función Ventricular Izquierda , Humanos , Volumen Sistólico , Pronóstico , Causas de MuerteRESUMEN
The prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) are increasing. Physicians who treat patients with MASLD may acknowledge the strong coincidence with cardiometabolic disease, including atherosclerotic cardiovascular disease (asCVD). This raises questions on co-occurrence, causality, and the need for screening and multidisciplinary care for MASLD in patients with asCVD, and vice versa. Here, we review the interrelations of MASLD and heart disease and formulate answers to these matters. Epidemiological studies scoring proxies for atherosclerosis and actual cardiovascular events indicate increased atherosclerosis in patients with MASLD, yet no increased risk of asCVD mortality. MASLD and asCVD share common drivers: obesity, insulin resistance and type 2 diabetes mellitus (T2DM), smoking, hypertension, and sleep apnea syndrome. In addition, Mendelian randomization studies support that MASLD may cause atherosclerosis through mixed hyperlipidemia, while such evidence is lacking for liver-derived procoagulant factors. In the more advanced fibrotic stages, MASLD may contribute to heart failure with preserved ejection fraction by reduced filling of the right ventricle, which may induce fatigue upon exertion, often mentioned by patients with MASLD. Some evidence points to an association between MASLD and cardiac arrhythmias. Regarding treatment and given the strong co-occurrence of MASLD and asCVD, pharmacotherapy in development for advanced stages of MASLD would ideally also reduce cardiovascular events, as has been demonstrated for T2DM treatments. Given the common drivers, potential causal factors and especially given the increased rate of cardiovascular events, comprehensive cardiometabolic risk management is warranted in patients with MASLD, preferably in a multidisciplinary approach.
RESUMEN
BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and sinus rhythm have a heightened risk of stroke. Whether anticoagulation benefits these patients is uncertain. In this post hoc analysis of the A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure (COMMANDER-HF) trial we evaluated how a previously validated risk model consisting of 3 variables (history of prior stroke, insulin-treated diabetes, and N-terminal pro-B-type natriuretic peptide level) would perform, compared with plasma d-dimer, for stroke prediction and estimation of the benefit of low-dose rivaroxaban. METHODS AND RESULTS: Stroke risk and treatment effect were computed across risk score and plasma d-dimer tertiles. Risk score was available in 58% of the COMMANDER-HF population (nâ¯=â¯2928). Over a median follow-up of 512 days (range 342-747 days), 60 patients experienced a stroke (14.6 per 1000 patient-years). The risk model did not identify patients at higher risk of stroke and showed a low overall prognostic performance (C-indexâ¯=â¯0.53). The effect of rivaroxaban on stroke was homogeneous across risk score tertiles (P-interactionâ¯=â¯.67). Among patients in whom the risk score was estimated, d-dimer was available in 2343 (80%). d-dimer had an acceptable discrimination performance for stroke prediction (C-indexâ¯=â¯0.66) and higher plasma d-dimer concentrations were associated with higher rates of stroke (ie, tertile 3 vs tertile 1, hazard ratio 3.65, 95% confidence interval 1.59-8.39, Pâ¯=â¯.002). Treatment with low-dose rivaroxaban reduced the incidence of stroke in patients at highest risk by d-dimer levels (ie, >515 ng/mL, hazard ratio 0.42, 95% confidence interval 0.18-0.95, P-interactionâ¯=â¯.074), without any safety concerns. CONCLUSIONS: In our analysis, plasma d-dimer concentrations performed better than a previously described 3-variable risk score for stroke prediction in patients with heart failure with reduced ejection fraction, a recent clinical worsening and sinus rhythm as enrolled in the COMMANDER-HF trial. In these patients, a raised plasma d-dimer concentration identified patients who might benefit most from rivaroxaban.
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Enfermedad de la Arteria Coronaria , Insuficiencia Cardíaca Sistólica , Insuficiencia Cardíaca , Accidente Cerebrovascular , Humanos , Enfermedad de la Arteria Coronaria/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca Sistólica/tratamiento farmacológico , Factores de Riesgo , Rivaroxabán/efectos adversos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Volumen SistólicoRESUMEN
BACKGROUND: The effect of empagliflozin, a sodium-glucose-co-transporter-2 inhibitor, on risk for myocardial infarction has not been fully characterized. METHODS: This study comprised prespecified and post-hoc analyses of the EMPA-REG OUTCOME trial in which 7020 people with type 2 diabetes (T2D) and cardiovascular disease [mostly atherosclerotic (ASCVD)] were randomized to empagliflozin or placebo and followed for a median 3.1 years. We assessed the effect of empagliflozin on total (first plus recurrent) events of centrally adjudicated fatal and non-fatal myocardial infarction (MI) using a negative binomial model with robust confidence intervals (CI) that preserves randomization and accounts for the within-patient correlation of multiple events. Post hoc, we analyzed types of MI: type 1 (related to plaque-rupture/thrombus), type 2 (myocardial supply-demand imbalance), type 3 (sudden-death related, i.e. fatal MI), type 4 (percutaneous coronary intervention-related), and type 5 (coronary artery bypass graft-related). MIs could be assigned to > 1 type. RESULTS: There were 421 total MIs (including recurrent); 299, 86, 26, 19, and 1 were classified as type 1, 2, 3, 4, and 5 events, respectively. Overall, empagliflozin reduced the risk of total MI events by 21% [rate ratio for empagliflozin vs. placebo, 0.79 (95% CI, 0.620-0.998), P = 0.0486], largely driven by its effect on type 1 [rate ratio, 0.79 (95% CI, 0.61-1.04)] and type 2 MIs [rate ratio, 0.67 (95% CI, 0.41-1.10)]. CONCLUSIONS: In T2D patients with ASCVD, empagliflozin reduced the risk of MIs, with consistent effects across the two most common etiologies, i.e. type 1 and 2. TRAIL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT01131676.
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Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2 , Glucósidos , Infarto del Miocardio , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Glucósidos/uso terapéutico , Glucósidos/efectos adversos , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Infarto del Miocardio/mortalidad , Infarto del Miocardio/prevención & control , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Masculino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Resultado del Tratamiento , Femenino , Persona de Mediana Edad , Anciano , Factores de Tiempo , Medición de Riesgo , Factores de Riesgo , RecurrenciaRESUMEN
AIM: To assess the effect of empagliflozin on patients with comorbid heart failure (HF) and diabetes with or without baseline insulin, and to study the impact of empagliflozin on insulin requirements over time. MATERIALS AND METHODS: We performed a post-hoc analysis of pooled patient-level data from two cardiovascular outcomes trials of empagliflozin in HF (EMPEROR-Reduced and EMPEROR-Preserved trials). We undertook a subgroup analysis stratified by baseline insulin use, including all patients with diabetes. The studied endpoints included the primary composite endpoint of first hospitalization for HF or cardiovascular death, rate of decline of estimated glomerular filtration rate, composite renal outcome and rates of sustained insulin initiation. RESULTS: Among 4794 patients with diabetes, 1333 (658 in empagliflozin, 675 in placebo) were using insulin at baseline. The treatment effect of empagliflozin on the primary endpoint was consistent irrespective of insulin use [no insulin, hazard ratio 0.74, 95% confidence interval (CI) 0.63-0.86; using insulin, hazard ratio 0.81, 95% CI 0.66-1.00, pinteraction = .49], as was the effect on the rate of decline of the estimated glomerular filtration rate (pinteraction = .75). There was no effect of empagliflozin on the composite renal outcome in patients using or not using insulin (pinteraction = .30). Among patients not using insulin at baseline, those randomized to empagliflozin initiated insulin less frequently throughout the follow-up period compared with those receiving placebo (2.6% vs. 3.8%, odds ratio 0.66, 95% CI 0.50-0.88). CONCLUSIONS: Empagliflozin exerts a consistent benefit on cardiovascular outcomes and renal function decline, irrespective of baseline insulin use, and reduces the need for sustained insulin initiation in patients with HF and diabetes.
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Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2 , Glucósidos , Insuficiencia Cardíaca , Insulina , Humanos , Glucósidos/uso terapéutico , Compuestos de Bencidrilo/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/complicaciones , Masculino , Femenino , Insulina/uso terapéutico , Anciano , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Persona de Mediana Edad , Hipoglucemiantes/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Resultado del TratamientoRESUMEN
AIM: Investigating the effect of finerenone on liver function, cardiovascular and kidney composite outcomes in patients with chronic kidney disease and type 2 diabetes, stratified by their risk of liver steatosis, inflammation and fibrosis. MATERIALS AND METHODS: Post hoc analysis stratified patients (N = 13 026) by liver fibrosis and enzymes: high risk of steatosis (hepatic steatosis index >36); elevated transaminases [alanine transaminase (ALT) >33 (males) and >25 IU/L (females)]; and fibrosis-4 (FIB-4) index scores >3.25, >2.67 and >1.30. Liver enzymes were assessed by changes in ALT, aspartate aminotransferase and gamma-glutamyl transferase. Composite kidney outcome was defined as onset of kidney failure, sustained estimated glomerular filtration rate decline ≥57% from baseline over ≥4 weeks or kidney death. Composite cardiovascular outcome was defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure. RESULTS: ALT, aspartate aminotransferase and gamma-glutamyl transferase levels were consistent between treatment groups and remained stable throughout. Finerenone consistently reduced the risk of composite kidney outcome, irrespective of altered liver tests. Higher FIB-4 score was associated with higher incidence rates of composite cardiovascular outcome. Finerenone reduced the risk of composite cardiovascular outcome versus placebo in FIB-4 subgroups by 52% (>3.25), 39% (>2.67) and 24% (>1.30) (p values for interaction = .01, .13 and .03, respectively). CONCLUSIONS: Finerenone has neutral effects on liver parameters in patients with chronic kidney disease and type 2 diabetes. Finerenone showed robust and consistent kidney benefits in patients with altered liver tests, and profound cardiovascular benefits even in patients with higher FIB-4 scores who were at high risk of developing cardiovascular complications.
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Diabetes Mellitus Tipo 2 , Hígado Graso , Insuficiencia Renal Crónica , Masculino , Femenino , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Hígado Graso/complicaciones , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Aspartato Aminotransferasas/uso terapéutico , Transferasas/uso terapéuticoRESUMEN
Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.
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Insuficiencia Cardíaca , Trasplante de Corazón , Calidad de Vida , Humanos , Consenso , Europa (Continente) , Ejercicio Físico , Insuficiencia Cardíaca/rehabilitación , Insuficiencia Cardíaca/cirugía , Trasplante de Corazón/efectos adversos , Sociedades MédicasRESUMEN
BACKGROUND: In patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces cardiovascular and kidney failure outcomes. Finerenone also lowers the urine albumin-to-creatinine ratio (UACR). Whether finerenone-induced change in UACR mediates cardiovascular and kidney failure outcomes is unknown. OBJECTIVE: To quantify the proportion of kidney and cardiovascular risk reductions seen over a 4-year period mediated by a change in kidney injury, as measured by the change in log UACR between baseline and month 4. DESIGN: Post hoc mediation analysis using pooled data from 2 phase 3, double-blind trials of finerenone. (ClinicalTrials.gov: NCT02540993 and NCT02545049). SETTING: Several clinical sites in 48 countries. PATIENTS: 12 512 patients with CKD and T2D. INTERVENTION: Finerenone and placebo (1:1). MEASUREMENTS: Separate mediation analyses were done for the composite kidney (kidney failure, sustained ≥57% decrease in estimated glomerular filtration rate from baseline [approximately a doubling of serum creatinine], or kidney disease death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) outcomes. RESULTS: At baseline, median UACR was 514 mg/g. A 30% or greater reduction in UACR was seen in 3338 (53.2%) patients in the finerenone group and 1684 (27.0%) patients in the placebo group. Reduction in UACR (analyzed as a continuous variable) mediated 84% and 37% of the treatment effect on the kidney and cardiovascular outcomes, respectively. When change in UACR was analyzed as a binary variable (that is, whether the guideline-recommended 30% reduction threshold was met), the proportions mediated for each outcome were 64% and 26%, respectively. LIMITATION: The current findings are not readily extendable to other drugs. CONCLUSION: In patients with CKD and T2D, early albuminuria reduction accounted for a large proportion of the treatment effect against CKD progression and a modest proportion of the effect against cardiovascular outcomes. PRIMARY FUNDING SOURCE: Bayer AG.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Insuficiencia Renal Crónica , Insuficiencia Renal , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Análisis de Mediación , Albuminuria/orina , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Tasa de Filtración GlomerularRESUMEN
Iron deficiency (ID) is common in patients with cardiovascular disease. Up to 60% of patients with coronary artery disease, and an even higher proportion of those with heart failure (HF) or pulmonary hypertension have ID; the evidence for cerebrovascular disease, aortic stenosis and atrial fibrillation is less robust. The prevalence of ID increases with the severity of cardiac and renal dysfunction and is probably more common amongst women. Insufficient dietary iron, reduced iron absorption due to increases in hepcidin secondary to the low-grade inflammation associated with atherosclerosis and congestion or reduced gastric acidity, and increased blood loss due to anti-thrombotic therapy or gastro-intestinal or renal disease may all cause ID. For older people in the general population and patients with HF with reduced ejection fraction (HFrEF), both anaemia and ID are associated with a poor prognosis; each may confer independent risk. There is growing evidence that ID is an important therapeutic target for patients with HFrEF, even if they do not have anaemia. Whether this is also true for other HF phenotypes or patients with cardiovascular disease in general is currently unknown. Randomized trials showed that intravenous ferric carboxymaltose improved symptoms, health-related quality of life and exercise capacity and reduced hospitalizations for worsening HF in patients with HFrEF and mildly reduced ejection fraction (<50%). Since ID is easy to treat and is effective for patients with HFrEF, such patients should be investigated for possible ID. This recommendation may extend to other populations in the light of evidence from future trials.