Clinical considerations on the posology of direct oral anticoagulants

Los anticoagulantes dicumarínicos han demostrado su eficacia en pacientes con fibrilación auricular no valvular. Sin embargo, presentan desventajas como la necesidad de ajustar la dosis y la interacción con fármacos y alimentos. Por su parte, los anticoagulantes orales de acción directa se presentan como una alternativa eficaz y segura con un manejo clínico menos complejo. Existe un considerable debate sobre los criterios de selección de las pautas posológicas de los anticoagulantes orales de acción directa. Las diferencias entre ellos y sus pautas de administración han despertado dudas sobre los criterios de selección clínicos, farmacocinéticos y farmacodinámicos que avalan dicha posología. Esta revisión analiza de forma crítica las evidencias disponibles y su impacto en la selección final del esquema posológic

A Randomized Trial to Evaluate the Impact of Exercise-Based Cardiac Rehabilitation for the Prevention of Chemotherapy-Induced Cardiotoxicity in Patients With Breast Cancer: ONCORE Study Protocol

[Abstract] Background. Anthracyclines and monoclonal antibodies against human epidermal growth factor receptor-2 (HER2) are frequently used to treat breast cancer but they are associated with risk of developing cardiotoxicity. Implementation of cardioprotective strategies as part of breast cancer treatment are needed. To date, a limited number of studies have examined the effectiveness of cardiac rehabilitation programs or exercise programs in the prevention of cardiotoxicity through an integral assessment of cardiac function. The ONCORE study proposes an exercise-based cardiac rehabilitation program as a non-pharmacological tool for the management of chemotherapy-induced cardiotoxicity. Methods. The study protocol describes a prospective, randomized controlled trial aimed to determine whether an intervention through an exercise-based CR program can effectively prevent cardiotoxicity induced by anthracyclines and/or anti-HER2 antibodies in women with breast cancer. Three hundred and forty women with breast cancer at early stages scheduled to receive cardiotoxic chemotherapy will be randomly assigned (1:1) to participation in an exercise-based CR program (intervention group) or to usual care and physical activity recommendation (control group). Primary outcomes include changes in left ventricular ejection fraction and global longitudinal strain as markers of cardiac dysfunction assessed by transthoracic echocardiography. Secondary outcomes comprise levels of cardiovascular biomarkers and cardiopulmonary function through peak oxygen uptake determination, physical performance and psychosocial status. Supervised exercise program-related outcomes including safety, adherence/compliance, expectations and physical exercise in- and out-of-hospital are studied as exploratory outcomes. Transthoracic echocardiography, clinical test and questionnaires will be performed at the beginning and two weeks after completion of chemotherapy. Discussion. The growing incidence of breast cancer and the risk of cardiotoxicity derived from cancer treatments demand adjuvant cardioprotective strategies. The proposed study may determine if an exercise-based CR program is effective in minimizing chemotherapy-induced cardiotoxicity in this population of women with early-stage breast cancer. The proposed research question is concrete, with relevant clinical implications, transferable to clinical practice and achievable with low risk.Instituto de Salud Carlos III; PI17/0168

Thirty-Second Sit-To-Stand Test as an Alternative for Estimating Peak Oxygen Uptake and 6-Min Walking Distance in Women With Breast Cancer: A Cross-Sectional Study

[Abstract] Purpose: To determine whether the 30-s sit-to-stand (30STS) test can be a valid tool for estimating and stratifying peak oxygen uptake (VO2peak) and 6-min walking distance (6MWD) in women with breast cancer. Methods: This cross-sectional study uses data from the ONCORE randomized controlled trial, including 120 women aged 18-70 years with early-stage breast cancer under treatment with anthracycline and/or anti-HER2 antibodies. Participant characteristics were collected at baseline and pooled data from functional assessment (30STS test, relative and absolute VO2peak, and 6MWD) were collected at baseline and post-intervention (comprehensive cardio-oncology rehabilitation program vs. usual care). Bivariate correlations and multivariate linear regression analyses were performed to study the relationship between functional test variables. Results: The number of repetitions in the 30STS test showed (i) a moderate correlation with relative VO2peak (ml/kg/min) (r = 0.419; p < 0.001; n = 126), (ii) a weak correlation with absolute VO2peak (ml/min) (r = 0.241; p = 0.008; n = 120), and (iii) a moderate correlation with the 6MWD (r = 0.440; p < 0.001; n = 85). The ONCORE equations obtained from the multivariate regression models allowed the estimation of VO2peak and 6MWD (r2 = 0.390; r2 = 0.261, respectively) based on the 30STS test, and its stratification into tertiles (low, moderate, and high). Conclusion: The 30STS test was found to be a useful tool to estimate VO2peak and/or 6MWD in women with early-stage breast cancer. Its use may facilitate the assessment and stratification of functional capacity in this population for the implementation of therapeutic exercise programs if cardiopulmonary exercise testing (CPET) or 6MWT are not available.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by a competitive grant from the Asociación Española Contra el Cáncer (AECC) Scientific Foundation — PRDLC21480DÍAZ — and by a competitive grant of the Spanish Health Research Fund of the Carlos III Health Institute (ISCIII) — PI17/01687, co-funded FEDER, through Strategic Action in Healthcare, 2017. The ISCIII is the national and international reference in biomedical research and public health in Spain. The AECC Scientific Foundation and the ISCIII had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Funding for open access charge will be supported by Universidade da Coruña/CISUGFundación Científica Asociación Española Contra el Cáncer; PRDLC21480DÍA

The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile

[Abstract] The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.This work was supported by Boehringer Ingelheim Pharma GmbH and Co., by the National Institute of Health “Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III” Madrid, Spain (PI15/00681, PI17/00409, PI18/00821, PI20/00902, RETICS Programme RD16/0012/0014 and CIBER de Enfermedades Cardiovasculares (CIBERCV)); European Regional Development Fund (FEDER) and European Union framework MSCA-RISE-H2020 Programme (Project number 734899). AH-A was funded by predoctoral research grants from Xunta de Galicia and FPU Program of the Spanish Ministry of Science, Innovation and Universities (Spain); MF-S was funded by the predoctoral research grants “Programa Científico do Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS) (Spain) and Xunta de Galicia; and AV-L was funded by the predoctoral research grant from the PFIS Program of the Spanish Ministry of Science and Instituto de Salud Carlos III (Spain

Prognostic value of discharge heart rate in acute heart failure patients: more relevant in atrial fibrillation?

[Abstract] Aims. The prognostic impact of heart rate (HR) in acute heart failure (AHF) patients is not well known especially in atrial fibrillation (AF) patients. The aim of the study was to evaluate the impact of admission HR, discharge HR, HR difference (admission-discharge) in AHF patients with sinus rhythm (SR) or AF on long- term outcomes. Methods. We included 1398 patients consecutively admitted with AHF between October 2013 and December 2014 from a national multicentre, prospective registry. Logistic regression models were used to estimate the association between admission HR, discharge HR and HR difference and one- year all-cause mortality and HF readmission. Results. The mean age of the study population was 72 ± 12 years. Of these, 594 (42.4%) were female, 655 (77.8%) were hypertensive and 655 (46.8%) had diabetes. Among all included patients, 745 (53.2%) had sinus rhythm and 653 (46.7%) had atrial fibrillation. Only discharge HR was associated with one year all-cause mortality (Relative risk (RR) = 1.182, confidence interval (CI) 95% 1.024–1.366, p = 0.022) in SR. In AF patients discharge HR was associated with one year all cause mortality (RR = 1.276, CI 95% 1.115–1.459, p ≤ 0.001). We did not observe a prognostic effect of admission HR or HRD on long-term outcomes in both groups. This relationship is not dependent on left ventricular ejection fraction. Conclusions. In AHF patients lower discharge HR, neither the admission nor the difference, is associated with better long-term outcomes especially in AF patients

Serum Potassium Dynamics During Acute Heart Failure Hospitalization

[Abstract] Background. Available information about prognostic implications of potassium levels alteration in the setting of acute heart failure (AHF) is scarce. Objectives. We aim to describe the prevalence of dyskalemia (hypo or hyperkalemia), its dynamic changes during AHF-hospitalization, and its long-term clinical impact after hospitalization. Methods. We analyzed 1779 patients hospitalized with AHF who were included in the REDINSCOR II registry. Patients were classified in three groups, according to potassium levels both on admission and discharge: hypokalemia (potassium  5 mEq/L). Results. The prevalence of hypokalemia and hyperkalemia on admission was 8.2 and 4.6%, respectively, and 6.4 and 2.7% at discharge. Hyperkalemia on admission was associated with higher in-hospital mortality (OR = 2.32 [95% CI: 1.04–5.21] p = 0.045). Among patients with hypokalemia on admission, 79% had normalized potassium levels at discharge. In the case of patients with hyperkalemia on admission, 89% normalized kalemia before discharge. In multivariate Cox regression, dyskalemia was associated with higher 12-month mortality, (HR = 1.48 [95% CI, 1.12–1.96], p = 0.005). Among all patterns of dyskalemia persistent hypokalemia (HR = 3.17 [95% CI: 1.71–5.88]; p < 0.001), and transient hyperkalemia (HR = 1.75 [95% CI: 1.07–2.86]; p = 0.023) were related to reduced 12-month survival. Conclusions. Potassium levels alterations are frequent and show a dynamic behavior during AHF admission. Hyperkalemia on admission is an independent predictor of higher in-hospital mortality. Furthermore, persistent hypokalemia and transient hyperkalemia on admission are independent predictors of 12-month mortality.This work is funded by the Instituto de Salud Carlos III (Ministry of Economy, Industry, and Competitiveness) and co-funded by the European Regional Development Fund, through the CIBER in cardiovascular diseases (CB16/11/00502)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Differential clinical characteristics and prognosis of intraventricular conduction defects in patients with chronic heart failure

Intraventricular conduction defects (IVCDs) can impair prognosis of heart failure (HF), but their specific impact is not well established. This study aimed to analyse the clinical profile and outcomes of HF patients with LBBB, right bundle branch block (RBBB), left anterior fascicular block (LAFB), and no IVCDs. Clinical variables and outcomes after a median follow-up of 21 months were analysed in 1762 patients with chronic HF and LBBB (n = 532), RBBB (n = 134), LAFB (n = 154), and no IVCDs (n = 942). LBBB was associated with more marked LV dilation, depressed LVEF, and mitral valve regurgitation. Patients with RBBB presented overt signs of congestive HF and depressed right ventricular motion. The LAFB group presented intermediate clinical characteristics, and patients with no IVCDs were more often women with less enlarged left ventricles and less depressed LVEF. Death occurred in 332 patients (interannual mortality = 10.8%): cardiovascular in 257, extravascular in 61, and of unknown origin in 14 patients. Cardiac death occurred in 230 (pump failure in 171 and sudden death in 59). An adjusted Cox model showed higher risk of cardiac death and pump failure death in the LBBB and RBBB than in the LAFB and the no IVCD groups. LBBB and RBBB are associated with different clinical profiles and both are independent predictors of increased risk of cardiac death in patients with HF. A more favourable prognosis was observed in patients with LAFB and in those free of IVCDs. Further research in HF patients with RBBB is warranted