Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Vigilancia de la resistencia a antibióticos en enfermedad invasiva por Pseudomonas aeruginosa en Galicia: 2013-2014

Introduction. The aim of this study is to know the antibiotic sensitivity of the Pseudomonas aeruginosa, which produces invasive infections in Galicia in 2013/2014, in the framework of the Surveillance Study of Antimicrobial Resistance. Methods. A total of 357 isolates of P. aeruginosa were analyzed in blood or CSF samples from 9 hospitals in Galicia. The variables were: origin, demographic data, sample type and antibiotic sensitivity. CLSI breakpoints were used. For each antibiotic we analyzed frequencies, cases/100.000 inhabitants, concordance of resistance and differences between hospitals, sex and age. Results. The majority of patients were male gender and the not-sensitives were superior in the 45 to 64 age group with significant differences to ciprofloxacin, imipenem, tobramycin and colistin. The overall not-sensitivity isolates was: piperacillin/tazobactam 18%, ciprofloxacin 28.7%, ceftazidime 17.1%, cefepime 19.7%, imipenem 23.1%, meropenem 22.1%, tobramycin 13.0%, amikacin 7.3% and colistin 4.4%. The cases/100,000 inhabitants were higher in men as age increasing. Without analyzing colistin, the 57.1% of the isolates were sensitives to other antibiotics studied (piperacillin/tazobactam, quinolones, ceftazidime, aminoglycosides, carbapenems), 19.4% were not-susceptible to only one antibiotic, 12. 2% to two, 3.7% to three, 5.1% to four and 2.0% to all antibiotics tested. Conclusions. Of the antibiotics tested, the most susceptible to P. aeruginosa were amikacin and colistin. Our data are consistent with the observed ones nationwide except colistin. Sensitivity patterns of P. aeruginosa should be periodically evaluated in each area and each hospital in order to assess the different therapeutic regimens.Introducción. El objetivo de este estudio es conocer la sensibilidad antibiótica de Pseudomonas aeruginosa productora de enfermedad invasiva en Galicia en 2013/2014, en el marco del Estudio de Vigilancia de las Resistencias Antimicrobianas. Métodos. Se analizaron 357 aislamientos de P. aeruginosa en muestras de sangre o LCR en 9 hospitales de Galicia. Las variables fueron: procedencia, datos demográficos, tipo de muestra y sensibilidad antibiótica. Se usaron puntos de corte de CLSI. Para cada antibiótico se analizaron frecuencias, casos/100.000 habitantes, concordancia de la resistencia y diferencias entre hospitales, sexo y edad. Resultados. El sexo predominante fue el masculino y la no sensibilidad superior en el grupo de 45 a 64 años con diferencias significativas a ciprofloxacino, imipenem, tobramicina y colistina. La no sensibilidad global: piperacilina/tazobactam 18%, ciprofloxacino 28’7%, ceftazidima 17’1%, cefepime 19’7%, imipenem 23’1%, meropenem 22’1%, tobramicina 13’0%; amikacina, 7’3% y colistina 4’4%. Los casos/100.000 habitantes fueron superiores en hombres según aumenta la edad. Sin analizar la colistina, el 57’1% de los aislamientos fueron sensibles a los otros grupos estudiados (piperacilina/tazobactam, quinolonas, ceftazidima, aminoglucósidos, carbapenems), el 19’4% fueron no sensibles a un antibiótico, 12’2% a dos, el 3’7% a tres, el 5’1% a cuatro y el 2’0% a todos los analizados. Conclusiones. De los antibióticos evaluados, los más activos frente a P. aeruginosa fueron amikacina y colistina. Nuestros datos concuerdan con lo observado a nivel nacional, excepto para colistina. Deben evaluarse periódicamente patrones de sensibilidad de P. aeruginosa en cada zona y cada hospital para poder valorar las diferentes pautas terapéuticas

Prevalencia de enfermedades crónicas diagnosticadas en población inmigrante y autóctona Prevalence of diagnosed chronic disorders in the inmigrant and native population

Objetivo: Estimar la prevalencia de problemas de salud crónicos en inmigrantes y compararla con la de la población autóctona, utilizando la historia clínica electrónica (HCE) de atención primaria (AP). Métodos: Estudio descriptivo transversal con pacientes de 16 y más años incluidos en el sistema sanitario público de la Comunidad de Madrid. Se estimaron prevalencias ajustadas por edad para cada sexo y nacionalidad (agrupada en regiones) a partir de los episodios de atención registrados en la HCE de AP con alguna anotación en 2005 o 2006. Resultados: El 36,8% de la población inmigrante presentaba alguna enfermedad crónica (55,3% de autóctonos) tras ajustar por edad, con más frecuencia en mujeres y en población de origen africano y latinoamericano. Las enfermedades más prevalentes en los extranjeros fueron las alergias (tasa cruda: 10,2%), las lumbalgias (9,1%), problemas crónicos de piel (6,8%) y trastornos mentales (6,4%). Conclusiones: La prevalencia de enfermedades crónicas es menor en la población extranjera y varía según el sexo y la procedencia.<br>Objective: To estimate the prevalence rates of chronic disorders in immigrants and to compare them with those in the native population, based on electronic clinical records in primary care (ECRPC). Methods: We performed a descriptive cross-sectional study in patients aged 16 and over included in the Madrid Regional Public Health System. Age-adjusted prevalence rates for each sex and region were estimated on the basis of medically examined cases registered in the ECRPC with any new data entry made in 2005 or 2006. Results: After age-adjustment, a total of 36.8% immigrants had some chronic health problem (vs. 55.3% natives). These disorders were more frequent among women and among the population from Africa and Latin America. The highest overall prevalence rates in the foreign population were allergy (10.2% crude rate), low-back pain (9.1%), chronic skin problems (6.8%) and mental disorders (6.4%). Conclusions: The prevalence rate of chronic disease is lower in the foreign population and differs according to sex and country of origin

Open-Label, Randomized, Multicenter, Phase III Study Comparing Oral Paclitaxel Plus Encequidar Versus Intravenous Paclitaxel in Patients With Metastatic Breast Cancer

PurposeIntravenous paclitaxel (IVpac) is complicated by neuropathy and requires premedication to prevent hypersensitivity-type reactions. Paclitaxel is poorly absorbed orally; encequidar (E), a novel P-glycoprotein pump inhibitor, allows oral absorption.MethodsA phase III open-label study comparing oral paclitaxel plus E (oPac + E) 205 mg/m2 paclitaxel plus 15 mg E methanesulfonate monohydrate 3 consecutive days per week versus IVpac 175 mg/m2 once every 3 weeks was performed. Women with metastatic breast cancer and adequate organ function, at least 1 year from last taxane, were randomly assigned 2:1 to oPac + E versus IVpac. The primary end point was confirmed radiographic response using RECIST 1.1, assessed by blinded independent central review. Secondary end points included progression-free survival (PFS) and overall survival (OS).ResultsFour hundred two patients from Latin America were enrolled (265 oPac + E, 137 IVpac); demographics and prior therapies were balanced. The confirmed response (intent-to-treat) was 36% for oPac + E versus 23% for IVpac (P = .01). The PFS was 8.4 versus 7.4 months, respectively (hazard ratio, 0.768; 95.5% CI, 0.584 to 1.01; P = .046), and the OS was 22.7 versus 16.5 months, respectively (hazard ratio, 0.794; 95.5% CI, 0.607 to 1.037; P = .08). Grade 3-4 adverse reactions were 55% with oPac + E and 53% with IVpac. oPac + E had lower incidence and severity of neuropathy (2% v 15% &gt; grade 2) and alopecia (49% v 62% all grades) than IVpac but more nausea, vomiting, diarrhea, and neutropenic complications, particularly in patients with elevated liver enzymes. On-study deaths (8% oPac + E v 9% IVpac) were treatment-related in 3% and 0%, respectively.ConclusionoPac + E increased the confirmed tumor response versus IVpac, with trends in PFS and OS. Neuropathy was less frequent and severe with oPac + E; neutropenic serious infections were increased. Elevated liver enzymes at baseline predispose oPac + E patients to early neutropenia and serious infections (funded by Athenex, Inc; ClinicalTrials.gov identifier: NCT02594371)

Cyclosporine A in hospitalized COVID-19 pneumonia patients to prevent the development of interstitial lung disease: a pilot randomized clinical trial

Abstract Post-COVID-19 interstitial lung disease (ILD) is a new entity that frequently causes pulmonary fibrosis and can become chronic. We performed a single-center parallel-group open-label pilot randomized clinical trial to investigate the efficacy and safety of cyclosporine A (CsA) in the development of ILD in the medium term among patients hospitalized with COVID-19 pneumonia. Patients were randomized 1:1 to receive CsA plus standard of care or standard of care alone. The primary composite outcome was the percentage of patients without ILD 3 months after diagnosis of pneumonia and not requiring invasive mechanical ventilation (IMV) (response without requiring IMV). The key secondary composite outcomes were the percentage of patients who achieve a response requiring IMV or irrespective of the need for IMV, and adverse events. A total of 33 patients received at least one dose of CsA plus standard of care (n = 17) or standard of care alone (n = 16). No differences were found between the groups in the percentage of patients who achieved a response without requiring IMV or a response requiring IMV. A higher percentage of patients achieved a response irrespective of the need for IMV in the CsA plus standard of care group although the RR was almost significant 2.833 (95% CI, 0.908–8.840; p = 0.057). No differences were found between the groups for adverse events. In hospitalized patients with COVID-19 pneumonia, we were unable to demonstrate that CsA achieved a significant effect in preventing the development of ILD. (EU Clinical Trials Register; EudraCT Number: 2020-002123-11; registration date: 08/05/2020)

Predictors of embolism and death in left-sided infective endocarditis: the European Society of Cardiology EURObservational Research Programme European Infective Endocarditis registry

International audienceBackground and Aims Even though vegetation size in infective endocarditis (IE) has been associated with embolic events (EEs) and mortality risk, it is unclear whether vegetation size associated with these potential outcomes is different in left-sided IE (LSIE). This study aimed to seek assessing the vegetation cut-off size as predictor of EE or 30-day mortality for LSIE and to determine risk predictors of these outcomes. Methods The European Society of Cardiology EURObservational Research Programme European Infective Endocarditis is a prospective, multicentre registry including patients with definite or possible IE throughout 2016–18. Cox multivariable logistic regression analysis was performed to assess variables associated with EE or 30-day mortality. Results There were 2171 patients with LSIE (women 31.5%). Among these affected patients, 459 (21.1%) had a new EE or died in 30 days. The cut-off value of vegetation size for predicting EEs or 30-day mortality was &gt;10 mm [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.13–1.69, P = .0015]. Other adjusted predictors of risk of EE or death were as follows: EE on admission (HR 1.89, 95% CI 1.54–2.33, P &lt; .0001), history of heart failure (HR 1.53, 95% CI 1.21–1.93, P = .0004), creatinine &gt;2 mg/dL (HR 1.59, 95% CI 1.25–2.03, P = .0002), Staphylococcus aureus (HR 1.36, 95% CI 1.08–1.70, P = .008), congestive heart failure (HR 1.40, 95% CI 1.12–1.75, P = .003), presence of haemorrhagic stroke (HR 4.57, 95% CI 3.08–6.79, P &lt; .0001), alcohol abuse (HR 1.45, 95% CI 1.04–2.03, P = .03), presence of cardiogenic shock (HR 2.07, 95% CI 1.29–3.34, P = .003), and not performing left surgery (HR 1.30 95% CI 1.05–1.61, P = .016) (C-statistic = .68). Conclusions Prognosis after LSIE is determined by multiple factors, including vegetation size

Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure

BACKGROUND The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016 -002299-28.)