RESUMEN
INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have previously demonstrated cardioprotective properties in patients with type 2 diabetes, suggesting a preventive effect on heart failure (HF). The Empire Prevent trial program investigates the therapeutic potential for HF prevention by evaluating the cardiac, metabolic, and renal effects of the SGLT2 inhibitor empagliflozin in patients with increased risk of developing HF, but without diabetes or established HF. METHODS: The Empire Prevent trial program is an investigator-initiated, double-blind, randomized clinical trial program including elderly and obese patients (60-84 years, body mass index >28 kg/m2) with at least one manifestation of hypertension, cardiovascular or chronic kidney disease, but no history of diabetes or HF. The aims are to investigate the effects of empagliflozin on 1) physical capacity and left ventricular and atrial structural changes with peak oxygen consumption and left ventricular mass as primary endpoints (Empire Prevent Cardiac), and 2) cardiac-adipose tissue interaction and volume homeostasis with primary endpoints of changes in epicardial adipose tissue and estimated extracellular volume (Empire Prevent Metabolic). At present, 138 of 204 patients have been randomized in the Empire Prevent trial program. Patients are randomized 1:1 to 180 days treatment with empagliflozin 10 mg daily or placebo, while undergoing a comprehensive examination program at baseline and follow-up. DISCUSSION: The Empire Prevent trial program will mark the first step towards elucidating the potential of SGLT2 inhibition for HF prevention in an outpatient setting in elderly and obese patients with increased risk of developing HF, but with no history of diabetes or established HF. Furthermore, the Empire Prevent trial program will supplement the larger event-driven trials by providing mechanistic insights to the beneficial effects of SGLT2 inhibition. TRIAL REGISTRATION: Both parts of the trial program have been registered on September 13th 2021 (Clinical Trial Registration numbers: NCT05084235 and NCT05042973) before enrollment of the first patient. All patients will provide oral and written informed consent. The trial is approved by The Regional Committee on Health Research Ethics and the Danish Medicines Agency. Data will be disseminated through scientific meetings and peer-reviewed journals irrespective of outcome.
Asunto(s)
Compuestos de Bencidrilo , Glucósidos , Insuficiencia Cardíaca , Obesidad , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos de Bencidrilo/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Glucósidos/uso terapéutico , Insuficiencia Cardíaca/prevención & control , Insuficiencia Cardíaca/etiología , Obesidad/complicaciones , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Sodium-glucose co-transporter-2 inhibitors improve cardiac structure but most studies suggest no change in left ventricular (LV) systolic function at rest. Whether sodium-glucose co-transporter-2 inhibitors improve LV contractile reserve is unknown. We investigated the effect of empagliflozin on LV contractile reserve in patients with heart failure (HF) and reduced ejection fraction. METHODS: Prespecified sub-study of the Empire HF trial, a double-blind, placebo-controlled, and randomized trial. Patients with LV ejection fraction (LVEF) ≤ 40% on guideline-directed HF therapy were randomized (1:1) to empagliflozin 10 mg or placebo for 12 weeks. The treatment effect on contractile reserve was assessed by low dose dobutamine stress echocardiography. RESULTS: In total, 120 patients were included. The mean age was 68 (SD 10) years, 83% were male, and the mean LVEF was 38 (SD 10) %. Respectively 60 (100%) and 59 (98%) patients in the empagliflozin and placebo groups completed stress echocardiography. No statistically significant effect of empagliflozin was observed for the contractile reserve assessed by LV-GLS (adjusted mean absolute change, empagliflozin vs placebo, 0.7% [95% confidence interval {CI} -0.5 to 2.0, P = .25]) or LVEF (adjusted mean absolute change, empagliflozin vs placebo, 2.2% [95% CI -1.4 to 5.8, P = .22]) from baseline to 12 weeks. LV-GLS contractile reserve was associated with accelerometer-measured daily activity level (coefficient -24 accelerometer counts [95% CI -46 to -1.8, P = .03]). CONCLUSIONS: Empagliflozin for 12 weeks added to guideline-directed HF therapy did not improve LV contractile reserve in patients with HF and reduced ejection fraction.
Asunto(s)
Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Simportadores , Disfunción Ventricular Izquierda , Anciano , Compuestos de Bencidrilo , Método Doble Ciego , Femenino , Glucosa/uso terapéutico , Glucósidos , Humanos , Masculino , Persona de Mediana Edad , Sodio , Volumen Sistólico , Simportadores/farmacología , Simportadores/uso terapéutico , Disfunción Ventricular Izquierda/inducido químicamenteRESUMEN
BACKGROUND: Plasma growth differentiation factor-15 (GDF-15) biomarker levels increase in response to inflammation and tissue injury, and increased levels of GDF-15 are associated with increased risk of mortality in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which improve outcome in HFrEF, have been shown to increase plasma GDF-15 in diabetic patients. We aimed to investigate the effect of empagliflozin on GDF-15 in HFrEF patients. METHODS: This Empire HF Biomarker substudy was from the multicentre, randomized, double-blind, placebo-controlled Empire HF trial that included 190 patients from June 29, 2017, to September 10, 2019. Stable ambulatory HFrEF patients with ejection fraction of ≤ 40% were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo for 12 weeks. Changes from baseline to 12 weeks in plasma levels of GDF-15, high-sensitive C-reactive protein (hsCRP), and high-sensitive troponin T (hsTNT) were assessed. RESULTS: A total of 187 patients who were included in this study, mean age was 64 ± 11 years; 85% male, 12% with type 2 diabetes, mean ejection fraction 29 ± 8, with no differences between the groups. Baseline median plasma GDF-15 was 1189 (918-1720) pg/mL with empagliflozin, and 1299 (952-1823) pg/mL for placebo. Empagliflozin increased plasma GDF-15 compared to placebo (adjusted between-groups treatment effect; ratio of change (1·09 [95% confidence interval (CI), 1.03-1.15]: p = 0.0040). The increase in plasma GDF15 was inversely associated with a decrease in left ventricular end-systolic (R = - 0.23, p = 0.031), and end-diastolic volume (R = - 0.29, p = 0.0066). There was no change in plasma hsCRP (1.09 [95%CI, 0.86-1.38]: p = 0.48) or plasma hsTNT (1.07 [95%CI, 0.97-1.19]: p = 0.18) compared to placebo. Patients with diabetes and treated with metformin demonstrated no increase in plasma GDF-15 with empagliflozin, p for interaction = 0·01. CONCLUSION: Empagliflozin increased plasma levels of GDF-15 in patients with HFrEF, with no concomitant increase in hsTNT nor hsCRP. TRIAL REGISTRATION: The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585.
Asunto(s)
Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Anciano , Compuestos de Bencidrilo/efectos adversos , Biomarcadores , Diabetes Mellitus Tipo 2/inducido químicamente , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Femenino , Glucósidos , Factor 15 de Diferenciación de Crecimiento , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Volumen SistólicoRESUMEN
BACKGROUND: The optimal antibiotic treatment length for infective endocarditis (IE) is uncertain. International guidelines recommend treatment duration of up to 6 weeks for patients with left-sided IE but are primarily based on historical data and expert opinion. Efficacies of modern therapies, fast recovery seen in many patients with IE, and complications to long hospital stays challenge the rationale for fixed treatment durations in all patients. OBJECTIVE: The objective was to conduct a noninferiority randomized controlled trial (acronym POET II) investigating the safety of accelerated (shortened) antibiotic therapy as compared to standard duration in patients with left-sided IE. METHODS: The POET II trial is a multicenter, multinational, open-label, noninferiority randomized controlled trial. Patients with definite left-sided IE due to Streptococcus spp, Staphylococcus aureus, or Enterococcus faecalis will be eligible for enrolment. Each patient will be randomized to accelerated antibiotic treatment or standard-length treatment (1:1) following clinical stabilization as defined by clinical parameters, laboratory values, and transesophageal echocardiography findings. Accelerated treatment will be between 2 and 4â¯weeks, whereas standard-length treatment will be between 4 and 6â¯weeks, depending on microbiologic etiology, complications, need for valve surgery, and prosthetic versus native valve endocarditis. The primary outcome is a composite of all-cause mortality, unplanned cardiac surgery, relapse of bacteremia, or embolization within 6â¯months of randomization. CONCLUSIONS: The POET II trial will investigate the safety of accelerated antibiotic therapy for patients with left-sided IE caused by Streptococcus spp, Staphylococcus aureus, or Enterococcus faecalis. The results of the POET II trial will improve the evidence base of treatment recommendations, and clinical practice may be altered.
Asunto(s)
Antibacterianos/administración & dosificación , Endocarditis Bacteriana/tratamiento farmacológico , Enterococcus faecalis , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus , Infecciones Estreptocócicas/tratamiento farmacológico , Estudios de Equivalencia como Asunto , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Humanos , Estudios Multicéntricos como Asunto , Factores de TiempoRESUMEN
AIMS: To investigate the effect of the sodium-glucose co-transporter-2 inhibitor empagliflozin on N-terminal pro-b-type natriuretic peptide (NT-proBNP) in patients with heart failure (HF) and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Empire HF was an investigator-initiated, multi-center, double-blinded, placebo-controlled, randomized trial. Patients with mildly symptomatic HFrEF, mean (standard deviation (SD)) age 64 (11) years, 85% male, and mean left ventricular ejection fraction 29% (8), on recommended HF therapy were assigned to receive either empagliflozin 10 mg once daily or placebo for 12 weeks. The primary endpoint was the between-group difference in the change of NT-proBNP from baseline to 12 weeks. In total, 95 patients were assigned to empagliflozin and 95 to placebo. No significant difference in the change of NT-proBNP with empagliflozin versus placebo was observed [Empagliflozin: baseline, median (interquartile range (IQR)) 582 (304-1020) pg/mL, 12 weeks, 478 (281-961) pg/mL; Placebo: baseline, 605 (322-1070) pg/mL, 12 weeks, 520 (267-1075) pg/mL, adjusted ratio of change empagliflozin/placebo 0.98; 95% confidence interval (CI) 0.82-1.11, P = 0.7]. Further, no significant difference was observed in accelerometer-measured daily activity level [adjusted mean difference of change, empagliflozin versus placebo, -26.0 accelerometer counts; 95% CI -88.0 to 36.0, P = 0.4] or Kansas City Cardiomyopathy Questionnaire Overall Summary Score [adjusted mean difference of change, empagliflozin versus placebo 0.8; 95% CI -2.3 to 3.9, P = 0.6]. CONCLUSION: In low-risk patients with HFrEF with mild symptoms and on recommended HF therapy, empagliflozin did not change NT-proBNP after 12 weeks. Further, no change in daily activity level or health status was observed.
Asunto(s)
Acelerometría/métodos , Actividades Cotidianas , Compuestos de Bencidrilo , Glucósidos , Insuficiencia Cardíaca , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Disfunción Ventricular Izquierda/diagnóstico , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/efectos adversos , Método Doble Ciego , Femenino , Glucósidos/administración & dosificación , Glucósidos/efectos adversos , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Volumen SistólicoAsunto(s)
Compuestos de Bencidrilo/uso terapéutico , Glucósidos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Compuestos de Bencidrilo/farmacología , Método Doble Ciego , Glucósidos/farmacología , Humanos , Masculino , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Resultado del TratamientoRESUMEN
BACKGROUND: Heart failure (HF) patients with diabetes (DM) have an adverse prognosis and reduced functional capacity, which could be associated with cardiac fibrosis, increased chamber stiffness and reduced left ventricular (LV) contractile reserve. Galectin-3 (Gal-3) and fibulin-1 are circulating biomarkers potentially reflecting cardiac fibrosis. We hypothesize that plasma levels of Gal-3 and fibulin-1 are elevated in HF patients with DM and are associated with reduced LV contractile reserve in these patients. METHODS: A total of 155 patients with HF with reduced ejection fraction underwent a low-dose dobutamine echocardiography and blood sampling for biomarker measurements. Patients were classified according to history of DM and an oral glucose tolerance test (OGTT) as: normal glucose tolerance (NGT) (n = 70), impaired glucose tolerance (IGT) (n = 25) and DM (n = 60). RESULTS: Galectin-3 levels were elevated in DM patients as compared to non-diabetic patients (P = 0.02), while higher fibulin-1 levels were observed in HF patients with IGF and DM (P = 0.07). Reduced LV contractile reserve was associated with increasing Gal-3 levels (ß = -0.19, P = 0.03) although, this association was attenuated after adjustment for estimated glomerular filtration rate (P = 0.66). Fibulin-1 was not associated with LV contractile reserve (P = 0.71). CONCLUSIONS: Galectin-3 and fibulin-1 levels were elevated in HF patients with impaired glucose metabolism. However, reduced LV contractile reserve among HF patients with DM does not to have an independent impact on plasma Gal-3 and fibulin-1 levels.
Asunto(s)
Glucemia/metabolismo , Proteínas de Unión al Calcio/sangre , Diabetes Mellitus/sangre , Galectina 3/sangre , Insuficiencia Cardíaca Sistólica/sangre , Contracción Miocárdica , Miocardio/metabolismo , Función Ventricular Izquierda , Agonistas de Receptores Adrenérgicos beta 1/administración & dosificación , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Proteínas Sanguíneas , Estudios Transversales , Diabetes Mellitus/diagnóstico , Dobutamina/administración & dosificación , Ecocardiografía de Estrés/métodos , Femenino , Fibrosis , Galectinas , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/metabolismo , Insuficiencia Cardíaca Sistólica/diagnóstico por imagen , Insuficiencia Cardíaca Sistólica/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Miocardio/patología , Valor Predictivo de las Pruebas , Regulación hacia ArribaRESUMEN
INTRODUCTION: Pleural effusion is present in half of the patients hospitalised with acute heart failure. The condition is treated with diuretics and/or therapeutic thoracentesis for larger effusions. No evidence from randomised trials or guidelines supports thoracentesis to alleviate pleural effusion due to acute heart failure. The Thoracentesis to Alleviate cardiac Pleural effusion Interventional Trial (TAP-IT) will investigate if a strategy of referring patients with acute heart failure and pleural effusion to up-front thoracentesis by pleural pigtail catheter insertion in addition to pharmacological therapy compared with pharmacological therapy alone can increase the number of days the participants are alive and not hospitalised during the 90 days following randomisation. METHODS AND ANALYSIS: TAP-IT is a pragmatic, multicentre, open-label, randomised controlled trial aiming to include 126 adult patients with left ventricular ejection fraction ≤45% and a non-negligible pleural effusion due to heart failure. Participants will be randomised 1:1, stratified according to site and anticoagulant treatment, and assigned to referral to up-front ultrasound-guided pleural pigtail catheter thoracentesis in addition to standard pharmacological therapy or to standard pharmacological therapy only. Thoracentesis is performed according to local guidelines and can be performed in participants in the pharmacological treatment arm if their condition deteriorates or if no significant improvement is observed within 5 days. The primary endpoint is how many days participants are alive and not hospitalised within 90 days from randomisation and will be analysed in the intention-to-treat population. Key secondary outcomes include 90-day mortality, complications, readmissions, and quality of life. ETHICS AND DISSEMINATION: The study has been approved by the Capital Region of Denmark Scientific Ethical Committee (H-20060817) and Knowledge Center for Data Reviews (P-2021-149). All participants will sign an informed consent form. Enrolment began in August 2021. Regardless of the nature, results will be published in a peer-reviewed medical journal. TRIAL REGISTRATION NUMBER: NCT05017753.
Asunto(s)
Insuficiencia Cardíaca , Derrame Pleural , Adulto , Humanos , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/terapia , Estudios Multicéntricos como Asunto , Derrame Pleural/terapia , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Volumen Sistólico , Toracocentesis , Función Ventricular Izquierda , Ensayos Clínicos Pragmáticos como AsuntoRESUMEN
BACKGROUND: Whether continued follow-up in specialized heart failure (HF) clinics after optimization of guideline-directed therapy improves long-term outcomes in patients with HF with reduced ejection fraction (HFrEF) is unknown. METHODS AND RESULTS: 921 medically optimized HFrEF patients enrolled in the NorthStar study were randomly assigned to follow up in a specialized HF clinic or primary care and followed for 10 years using Danish nationwide registries. The primary outcome was a composite of HF hospitalization or cardiovascular death. We further assessed the 5-year adherence to prescribed neurohormonal blockade in 5-year survivors. At enrollment, the median age was 69 years, 24,7% were females, and the median NT-proBNP was 1139 pg/ml. During a median follow-up time of 4.1 (Q1-Q3 1.5-10.0) years, the primary outcome occurred in 321 patients (69.8%) randomized to follow-up in specialized HF clinics and 325 patients (70.5%) randomized to follow-up in primary care. The rate of the primary outcome, its individual components, and all-cause death did not differ between groups (primary outcome, hazard ratio 0.96 [95% CI, 0.82-1.12]; cardiovascular death, 1.00 [0.81-1.24]; HF hospitalization, 0.97 [0.82-1.14]; all-cause death, 1.00 [0.83-1.20]). In 5-year survivors (N = 660), the 5-year adherence did not differ between groups for angiotensin-converting enzyme inhibitors (p = 0.78), beta-blockers (p = 0.74), or mineralocorticoid receptor antagonists (p = 0.47). CONCLUSIONS: HFrEF patients on optimal medical therapy did not benefit from continued follow-up in a specialized HF clinic after initial optimization. Development and implementation of new monitoring strategies are needed.
Asunto(s)
Insuficiencia Cardíaca , Femenino , Humanos , Anciano , Masculino , Insuficiencia Cardíaca/tratamiento farmacológico , Estudios de Seguimiento , Volumen Sistólico , Antagonistas Adrenérgicos beta/uso terapéutico , Sistema de Registros , Atención Primaria de Salud , Antagonistas de Receptores de AngiotensinaRESUMEN
AIMS: It remains unknown whether the consistently observed increase in haematocrit with sodium-glucose cotransporter 2 inhibitors is caused by diuresis-associated haemoconcentration or increased erythropoiesis. We aimed to investigate the early effect of empagliflozin on erythropoiesis and iron metabolism in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: The Empire HF was a double-blind, randomized, placebo-controlled trial. Patients with a left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association (NYHA) class I-III symptoms, and on stable guideline-directed HFrEF therapy were randomly assigned (1:1) to empagliflozin or matching placebo once daily for 12 weeks. Exploratory outcomes reflecting changes in erythropoiesis and iron metabolism were analysed. In total, 190 patients were randomized. Baseline characteristics were well-balanced between the groups (age: mean 64 [± 11] years; male: 85%; LVEF: mean 29 [± 8)%; NYHA class II: 78%; type 2 diabetes: 13%; anaemia: 28%; chronic kidney disease: 13%). In this post hoc analysis, erythropoietin was increased with empagliflozin compared to placebo from baseline to 12 weeks (adjusted mean difference 2.6 IU/L, 95% confidence interval [CI] 0.8-4.4; p = 0.0046). Moreover, hepcidin was reduced (adjusted ratio of change 0.76, 95% CI 0.59-0.97; p = 0.031), with no change observed for erythroferrone (adjusted ratio of change 1.17, 95% CI 0.86-1.60; p = 0.31) compared to placebo. No significant treatment-by-subgroup interactions were observed regarding baseline type 2 diabetes, anaemia, or chronic kidney disease (pinteraction >0.05). CONCLUSION: These findings suggest that empagliflozin increases erythropoiesis and augments early iron utilization in patients with HFrEF. These mechanisms may contribute to the cardioprotective properties of empagliflozin.
Asunto(s)
Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Disfunción Ventricular Izquierda , Humanos , Masculino , Volumen Sistólico , Función Ventricular Izquierda , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Eritropoyesis , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Disfunción Ventricular Izquierda/tratamiento farmacológicoRESUMEN
Infective endocarditis (IE) is one of the most severe infectious diseases with an in-hospital mortality of 20-25%. Several studies have shown, that the incidence of IE is increasing, and that patients now are older with a higher burden of comorbidities than previously. The diagnostic work-up is mainly based upon the presence of bacteraemia and echocardiography. The treatment is antibiotics and, in some cases, also cardiac surgery. In most cases, after clinical stabilization, it is safe to switch antibiotic treatment from intravenous to oral administration, as argued in this review.
Asunto(s)
Bacteriemia , Endocarditis Bacteriana , Endocarditis , Administración Oral , Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Endocarditis/diagnóstico por imagen , Endocarditis/tratamiento farmacológico , Endocarditis Bacteriana/diagnóstico por imagen , Endocarditis Bacteriana/tratamiento farmacológico , HumanosRESUMEN
Importance: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve outcomes in patients with heart failure and a reduced ejection fraction (HFrEF). The association with cardiac remodeling has not been investigated. Objective: To investigate the outcome of the SGLT2i empagliflozin, compared with placebo, on cardiac remodeling in patients with HFrEF. Design, Setting, and Participants: This exploratory post hoc analysis included participants with stable HFrEF and ejection fractions of 40% or less, who were randomly enrolled in an investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trial in Denmark. Enrollment commenced on June 29, 2017, and continued through September 10, 2019, with the last participant follow-up on December 20, 2019. Interventions: Randomization (1:1) to empagliflozin (10 mg once daily) or matching placebo in addition to recommended heart failure therapy for 12 weeks. Main Outcomes and Measures: Efficacy measures were changes from baseline to week 12 in left ventricular end-systolic and end-diastolic volume indexes, left atrial volume index, and left ventricular ejection fraction adjusted for age, sex, type 2 diabetes, and atrial fibrillation. Secondary efficacy measures included changes in left ventricular mass index, global longitudinal strain, and relative wall thickness. Results: A total of 190 patients were randomized (95 each receiving empagliflozin and placebo), with a mean (SD) age of 64 (11) years; 162 were men (85.3%), 97 (51.1%) had ischemic HFrEF, 24 (12.6%) had type 2 diabetes, and the mean (SD) latest recorded left ventricular ejection fraction was 29% (8%). Of the 190, 186 completed the study. Empagliflozin significantly reduced left ventricular end-systolic volume index (-4.3 [95% CI, -8.5 to -0.1] mL/m2; P = .04), left ventricular end-diastolic volume index (-5.5 [95% CI, -10.6 to -0.4] mL/m2; P = .03), and left atrial volume index (-2.5 [95% CI, -4.8 to -0.1] mL/m2; P = .04) compared with placebo at 12 weeks' follow-up, with no change in left ventricular ejection fraction (1.2% [95% CI, -1.2% to 3.6%]; P = .32). These findings were consistent across subgroups. Of secondary efficacy measures, left ventricular mass index was significantly reduced by empagliflozin (-9.0 [95% CI, -17.2 to -0.8] g/m2; P = .03). Conclusions and Relevance: In this small, randomized, short-term study, empagliflozin was associated with modest reductions in left ventricular and left atrial volumes with no association with ejection fraction. Effects beyond 12 weeks of SGLT2i use require further study. Trial Registration: ClinicalTrials.gov Identifier: NCT03198585.
Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Glucósidos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Ventrículos Cardíacos/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Volumen Sistólico/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Anciano , Ecocardiografía , Femenino , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/efectos de los fármacosRESUMEN
BACKGROUND: SGLT2 inhibitors are a promising treatment option in patients with heart failure and reduced ejection fraction. We aimed to investigate the effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate (GFR) in patients with heart failure and reduced ejection fraction. METHODS: Empire HF Renal was a prespecified substudy of the investigator-initiated, double-blind, randomised, placebo-controlled Empire HF trial. The study was done at Herlev and Gentofte University Hospital (Herlev, Denmark), with patients recruited from four Danish heart failure outpatient clinics. Patients with New York Heart Association class I-III symptoms, with a left ventricular ejection fraction of 40% or lower, and on guideline-directed heart failure therapy were randomly assigned (1:1) to receive either oral empagliflozin 10 mg or matched placebo once daily for 12 weeks. The allocation sequence was computer-generated. Patients and study investigators were masked to treatment allocation. The coprimary prespecified renal outcomes were the between-group difference in the changes in estimated extracellular volume, estimated plasma volume, and measured GFR from baseline to 12 weeks. All analyses were done in the intention-to-treat population (apart from safety analyses, which were done in patients who received at least one dose of study drug), with no interim analyses done during the trial. The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585, and EudraCT, 2017-001341-27. FINDINGS: Between June 29, 2017, and July 15, 2019, we assessed 391 patients for eligibility, of whom 120 (31%) were randomly assigned to empagliflozin or placebo, including 105 (88%) without diabetes. In intention-to-treat analyses, 60 (100%) patients in the empagliflozin group and 59 (98%) patients in the placebo group were included for estimated extracellular volume and estimated plasma volume, and 59 (98%) patients in the empagliflozin group and 58 (97%) patients in the placebo group were included for measured GFR. Empagliflozin treatment resulted in reductions in estimated extracellular volume (adjusted mean difference -0·12 L, 95% CI -0·18 to -0·05; p=0·00056), estimated plasma volume (-7·3%, -10·3 to -4·3; p<0·0001), and measured GFR (-7·5 mL/min, -11·2 to -3·8; p=0·00010) compared with placebo. Five (8%) of 60 patients in the empagliflozin group and three (5%) of 60 patients in the placebo group had one or more serious adverse events. INTERPRETATION: In patients with heart failure and reduced ejection fraction, empagliflozin reduced estimated extracellular volume, estimated plasma volume, and measured GFR after 12 weeks. Fluid volume changes might be an important mechanism underlying the beneficial clinical effects of SGLT2 inhibitors. FUNDING: Research Council at Herlev and Gentofte University Hospital, Research and Innovation Foundation of the Department of Cardiology at Herlev and Gentofte University Hospital, Capital Region of Denmark, Danish Heart Foundation, and AP Møller Foundation for the Advancement of Medical Science.
Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Glucósidos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Anciano , Compuestos de Bencidrilo/administración & dosificación , Método Doble Ciego , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Glucósidos/administración & dosificación , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Volumen Plasmático/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Volumen Sistólico/efectos de los fármacos , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
BACKGROUND: Data from recent cardiovascular outcome trials in patients with type 2 diabetes (T2D) suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors can prevent development of heart failure (HF) and prolong life in patients without HF. Ongoing event-driven trials are investigating whether the same effect is present in patients with well-defined HF. The mechanism behind the effect of SGLT2 inhibitors in patients with T2D and the potential effect in patients with overt HF is presently unknown. METHODS: This is a randomized, double-blinded, placebo-controlled, parallel group, clinical trial including HF patients with reduced left ventricular ejection fraction (HFrEF) with an ejection fraction ≤ 40% on optimal therapy recruited from specialized HF clinics in Denmark. The primary aim is to investigate the effect of the SGLT2 inhibitor empagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP). Secondary endpoints include cardiac biomarkers, function and hemodynamics, metabolic and renal parameters, daily activity level, and quality of life. Patients are assigned 1:1 to 90 days treatment with empagliflozin 10 mg daily or placebo. Patients with T2D are required to be on recommended doses of anti-glycemic therapy with a hemoglobin A1c (HbA1c) of 6.5-10.0% (48-86 mmol/mol). To show a between-group difference in the change of NT-proBNP of 30%, a total of 189 patients will be included. DISCUSSION: The Empire HF trial will elucidate the effects and modes of action of empagliflozin in HFrEF patients with and without T2D and provide important mechanistic data which will complement ongoing event-driven trials. TRIAL REGISTRATION: Clinicaltrialsregister.eu, EudraCT Number 2017-001341-27 . Registered on 29 May 2017. ClinicalTrials.gov, NCT03198585 . Registered on 26 June 2017.
Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Glucósidos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Volumen Sistólico/efectos de los fármacos , Compuestos de Bencidrilo/efectos adversos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Glucósidos/efectos adversos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/psicología , Humanos , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Calidad de VidaRESUMEN
BACKGROUND: Randomized clinical trials have shown that newly discharged and symptomatic patients with chronic heart failure (CHF) benefit from follow-up in a specialized heart failure clinic (HFC). Clinical stable and educated patients are usually discharged from the HFC when on optimal therapy. It is unknown if risk stratification using natriuretic peptides could identify patients who would benefit from longer-term follow-up. Furthermore, data on the use of natriuretic peptides for monitoring of stable patients with CHF are sparse. AIMS: The aims of this study are to test the hypothesis that clinical stable, educated, and medical optimized patients with CHF with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels > or = 1,000 pg/mL benefit from long-term follow-up in an HFC and to assess the efficacy of NT-proBNP monitoring. METHODS: A total of 1,250 clinically stable, medically optimized, and educated patients with CHF will be enrolled from 18 HFCs in Denmark. The patients will be randomized to treatment in general practice, to a standard follow-up program in the HFC, or to NT-proBNP monitoring in the HFC. The patients will be followed for 30 months (median). RESULTS: Data will be collected from 2006 to 2009. At present (March 2008), 720 patients are randomized. Results expect to be presented in the second half of 2010. CONCLUSIONS: This article outlines the design of the NorthStar study. If our hypotheses are confirmed, the results will help cardiologists and nurses in HFCs to identify patients who may benefit from long-term follow-up. Our results may also indicate whether patients with CHF will benefit from adding serial NT-proBNP measurements to usual clinical monitoring.
Asunto(s)
Atención Ambulatoria/métodos , Continuidad de la Atención al Paciente , Insuficiencia Cardíaca/terapia , Monitoreo Fisiológico/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Instituciones de Atención Ambulatoria , Dinamarca , Insuficiencia Cardíaca/sangre , Humanos , Estudios Multicéntricos como Asunto , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangreAsunto(s)
Endocarditis Bacteriana , Endocarditis , Prótesis Valvulares Cardíacas , Reemplazo de la Válvula Aórtica Transcatéter , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Electrónica , Endocarditis/diagnóstico por imagen , Endocarditis/etiología , Endocarditis Bacteriana/diagnóstico por imagen , Endocarditis Bacteriana/etiología , Humanos , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Secretion of natriuretic peptides is related to cardiac wall stress and influenced by the renin-angiotensin system. Therefore, we investigated the influence of blood pressure (BP) reduction with losartan versus atenolol on N-terminal pro-atrial natriuretic peptide (Nt-proANP) and N-terminal pro-brain natriuretic peptide (Nt-proBNP). METHODS: In 183 patients with hypertension and electrocardiographic left ventricular (LV) hypertrophy, enrolled in the LIFE Study, we measured BP and serum Nt-proANP and Nt-proBNP by immunoassay after 2 weeks of placebo treatment and after 1, 2, 4, 6, 12, 24, 36 and 48 months of randomized treatment with losartan- or atenolol-based antihypertensive regimens. RESULTS: There was no significant difference in BP at any time point between the two treatment groups. In patients treated with losartan, median Nt-proANP decreased gradually throughout the study, reaching significance after 6 months of treatment (1125-1060 pmol/l, P < 0.001), and Nt-proBNP decreased within the first month (24.7-18.7 pmol/l, P < 0.01) and stayed reduced throughout the study. During losartan-based antihypertensive treatment, Nt-proANP and Nt-proBNP as a percentage of baseline values were correlated to reductions in systolic BP (r = 0.11, P < 0.01 and r = 0.10, P = 0.01) and diastolic BP (r = 0.17, P < 0.001 and r = 0.07, P = 0.09). In atenolol-treated patients, Nt-proANP (1100-1640 pmol/l, P < 0.001) and Nt-proBNP (20.0-37.7 pmol/l, P < 0.001) increased during the first month, and remained elevated throughout the study. During atenolol-based antihypertensive treatment, changes in Nt-proANP (r = -0.16, P < 0.001) and Nt-proBNP (r = -0.07, P = 0.08) were negatively related to change in heart rate. CONCLUSION: Nt-proANP and Nt-proBNP were reduced in parallel with BP in losartan-treated patients whereas they increased in parallel with decreased heart rate in atenolol-treated patients.
Asunto(s)
Atenolol/farmacología , Factor Natriurético Atrial/sangre , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Losartán/farmacología , Proteínas del Tejido Nervioso/sangre , Fragmentos de Péptidos/sangre , Anciano , Atenolol/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Femenino , Humanos , Hipertensión/sangre , Hipertensión/fisiopatología , Losartán/uso terapéutico , Masculino , Persona de Mediana Edad , Péptido Natriurético EncefálicoRESUMEN
Twenty-six patients were examined during attacks of common migraine as well as during headache-free interval. Pericranial tenderness was scored blindly by a systematic manual palpation on both occasions by the same observer. Pressure-pain threshold (PPT) in a fixed location over the temporal muscle was determined by the use of a pressure algometer. A 28% increase in total tenderness score was observed during attacks (P less than 0.01). During unilateral attacks, tenderness scores were significantly higher on the ipsilateral side as compared to the contralateral (P less than 0.01). A positive correlation was observed between tenderness on the two sides (P less than 0.05) and the two occasions (P less than 0.01). PPT showed no changes during migraine attacks and there was no difference in PPT between the ipsilateral and contralateral side. A positive correlation was observed between PPT on the two sides and the two occasions (P less than 0.01). PPT was not correlated to the tenderness scores obtained by manual palpation. The absence of a decrease in PPT and the presence of several tender areas in multiple regions, particularly where pain was spontaneously reported to be located, suggest the presence of either a multi-focal peripheral pathological process or referred pain from other structures in the head and neck region.
Asunto(s)
Presión Intracraneal , Trastornos Migrañosos/complicaciones , Músculos/fisiopatología , Dolor/etiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Lóbulo TemporalRESUMEN
BACKGROUND: N-terminal pro-brain natriuretic peptide (Nt-proBNP) and N-terminal pro-atrial natriuretic peptide (Nt-proANP) are strong cardiovascular risk markers in patients with chronic heart failure, as well as in the general population. We investigated whether high Nt-proBNP or Nt-proANP could also predict the composite endpoint (CEP) of cardiovascular death, non-fatal stroke or non-fatal myocardial infarction in patients with hypertension and left ventricular (LV) hypertrophy. METHODS: After 2 weeks of placebo treatment, clinical, laboratory and echocardiographic variables were assessed in 183 hypertensive participants in the LIFE echo substudy with electrocardiographic LV hypertrophy. Nt-proBNP and Nt-proANP were measured by immunoassay at baseline. The patients were followed for 60 +/- 5 months. RESULTS: Using Cox regression analysis, the 25 CEP were predicted by ln(Nt-proBNP) (hazard ratio 1.61 per 2.73-fold increase, P < 0.01) as well as ln(Nt-proANP) (hazard ratio 2.93, P < 0.05). Nt-proBNP above the median value of 21.8 pmol/ml was associated with higher incidence of CEP (19.6 versus 7.7%, P < 0.05). Nt-proBNP above the median value was associated with higher incidence of CEP in the 123 patients without history of diabetes or cardiovascular disease (14.8 versus 4.3%, P < 0.05), but the association was insignificant in the 60 patients with a history of diabetes or cardiovascular disease (26.3 versus 18.2%, NS). Nt-proANP showed the same tendency. CONCLUSION: Nt-proBNP, more than Nt-proANP, strongly predicts cardiovascular events in patients with hypertension and LV hypertrophy, especially in patients without diabetes or clinically overt cardiovascular disease.