Real-world experience of therapeutic drug monitoring and PK/PD achievement of ceftaroline administered by different infusion regimens in patients with confirmed infections caused by Gram-positive bacteria.

BACKGROUND: Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For ß-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic drug monitoring (TDM) are used for dosage optimization based on their pharmacokinetics/pharmacodynamics (PK/PD). OBJECTIVES: To describe our experience with TDM and PK/PD target attainment of ceftaroline administered by intermittent and prolonged infusion in a cohort of patients with MDR-GP bacterial infections. METHODS: Patients treated with ceftaroline administered by continuous (24 h), extended (3 h/6 h) and intermittent infusion (1 h) and undergoing TDM of plasma concentrations were included. A 100%fT>4×MIC was the pre-specified PK/PD target and 100%fT>10×MIC was considered overexposure. Dose recommendations were made based on TDM results and each patient's clinical condition. RESULTS: Twelve patients [83.3% male, median age of 73 (38-83) years] were included. Nine patients (75%) achieved 100%fT>4×MIC, all under prolonged infusions. In one patient, the 100%fT was >10×MIC but no toxicity was observed. Based on TDM results, initial doses were recommended to be maintained in eight patients, decreased in three and increased in one. CONCLUSIONS: The administration of ceftaroline by prolonged infusion together with TDM may be a useful strategy for achieving the desired PK/PD target in these patients. However, more studies evaluating the relationship between PK/PD attainment and clinical outcomes are needed.

Long-term LVEF trajectories in patients with type 2 diabetes and heart failure: diabetic cardiomyopathy may underlie functional decline.

BACKGROUND: Left ventricular ejection fraction (LVEF) trajectories and functional recovery with current heart failure (HF) management is increasingly recognized. Type 2 diabetes mellitus (T2D) leads to a worse prognosis in HF patients. However, it is unknown whether T2D interferes with LVEF trajectories. The aim of this study was to prospectively assess very long-term (up to 15 years) LVEF trajectories in patients with and without T2D and underlying HF. METHODS: Ambulatory patients admitted to a multidisciplinary HF clinic were prospectively evaluated by scheduled two-dimensional echocardiography at baseline, 1 year, and then every 2 years afterwards, up to 15 years. Statistical analyses of LVEF change with time were performed using the linear mixed effects (LME) models, and locally weighted error sum of squares (Loess) curves were plotted. RESULTS: Of the 1921 patients, 461 diabetic and 699 non-diabetic patients with LVEF < 50% were included in the study. The mean number of echocardiography measurements performed in diabetic patients was 3.3 ± 1.6. Early LVEF recovery was similar in diabetic and non-diabetic patients, but Loess curves showed a more pronounced inverted U shape in diabetics with a more pronounced decline after 9 years. LME analysis showed a statistical interaction between T2D and LVEF trajectory over time (p = 0.009), which was statistically significant in patients with ischemic etiologies (p < 0.001). Other variables that showed an interaction between LVEF trajectories and T2D were male sex (p = 0.04) and HF duration (p = 0.008). CONCLUSIONS: LVEF trajectories in T2D patients with depressed systolic function showed a pronounced inverted U shape with a marked decline after 9 years. Diabetic cardiomyopathy may underlie the functional decline observed.

Telomere attrition in heart failure: a flow-FISH longitudinal analysis of circulating monocytes.

BACKGROUND: Cross-sectional investigations report shorter telomeres in patients with heart failure (HF); however, no studies describe telomere length (TL) trajectory and its relationship with HF progression. Here we aimed to investigate telomere shortening over time and its relationship to outcomes. METHODS: Our study cohort included 101 ambulatory patients with HF. Blood samples were collected at baseline (n = 101) and at the 1-year follow-up (n = 54). Using flow-FISH analysis of circulating monocytes, we simultaneously measured three monocyte subsets-classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++)-and their respective TLs based on FITC-labeled PNA probe hybridization. The primary endpoints were all-cause death and the composite of all-cause death or HF-related hospitalization, assessed at 2.3 ± 0.6 years. All statistical analyses were executed by using the SPSS 15.0 software, and included Student's t test and ANOVA with post hoc Scheffe analysis, Pearson or Spearman rho correlation and univariate Cox regression when applicable. RESULTS: We found high correlations between TL values of different monocyte subsets: CD14++CD16+ vs. CD14++CD16-, R = 0.95, p < 0.001; CD14++CD16+ vs. CD14+CD16++, R = 0.90, p < 0.001; and CD14++CD16- vs. CD14+CD16++, R = 0.89, p < 0.001. Mean monocyte TL exhibited significant attrition from baseline to the 1-year follow-up (11.1 ± 3.3 vs. 8.3 ± 2.1, p < 0.001). TL did not significantly differ between monocyte subsets at either sampling time-point (all p values > 0.1). Cox regression analyses did not indicate that TL or ΔTL was associated with all-cause death or the composite endpoint. CONCLUSIONS: Overall, this longitudinal study demonstrated a ~ 22% reduction of TL in monocytes from ambulatory patients with HF within 1 year. TL and ΔTL were not related to outcomes over long-term follow-up.

Importance of iron deficiency in patients with chronic heart failure as a predictor of mortality and hospitalizations: insights from an observational cohort study.

BACKGROUND: Iron deficiency (ID) in patients with chronic heart failure (CHF) is considered an adverse prognostic factor. We aimed to evaluate if ID in patients with CHF is associated with increased mortality and hospitalizations. METHODS: We evaluated ID in patients with CHF at 3 university hospitals. ID was defined as absolute (ferritin < 100 µg/L) or functional (transferrin Saturation index < 20% and ferritin between 100 and 299 µg/L). We excluded patients who received treatment with intravenous Iron or Erythropoietin during follow-up. We evaluated if ID was a predictor of death or hospitalization due to heart failure or any cause using univariate and multivariate cox regression analysis. RESULTS: We included 1684 patients, 65% males, 38% diabetics, median age of 72 years, 37% in functional class III-IV and 30% of patients with a left ventricular ejection fraction > 45%. Patients were well treated, with 87% and 88% of patients receiving renin-angiotensin inhibitors and beta-blockers, respectively. Median transferrin saturation index was 20%, median ferritin 155 ng/mL and median haemoglobin 13 g/dL. ID was present in 53% of patients; in 35% it was absolute and in 18% functional. Median follow-up was 20 months. ID was a predictor of death, hospitalization due to heart failure or to any cause in univariate analysis but not after multivariate analysis. No differences were found between absolute or functional ID regarding prognosis. CONCLUSION: In a real life population of patients with CHF and a high prevalence of heart failure with preserved ejection fraction, ID did not predict mortality or hospitalizations after adjustment for comorbidities, functional class and neurohormonal treatment.

Predictive biomarkers for death and rehospitalization in comorbid frail elderly heart failure patients.

BACKGROUND: Heart failure (HF) is associated with a high rate of readmissions within 30 days post-discharge and in the following year, especially in frail elderly patients. Biomarker data are scarce in this high-risk population. This study assessed the value of early post-discharge circulating levels of ST2, NT-proBNP, CA125, and hs-TnI for predicting 30-day and 1-year outcomes in comorbid frail elderly patients with HF with mainly preserved ejection fraction (HFpEF). METHODS: Blood samples were obtained at the first visit shortly after discharge (4.9 ± 2 days). The primary endpoint was the composite of all-cause mortality or HF-related rehospitalization at 30 days and at 1 year. All-cause mortality alone at one year was also a major endpoint. HF-related rehospitalizations alone were secondary end-points. RESULTS: From February 2014 to November 2016, 522 consecutive patients attending the STOP-HF Clinic were included (57.1% women, age 82 ± 8.7 years, mean Barthel index 70 ± 25, mean Charlson comorbidity index 5.6 ± 2.2). The composite endpoint occurred in 8.6% patients at 30 days and in 38.5% at 1 year. In multivariable analysis, ST2 [hazard ratio (HR) 1.53; 95% CI 1.19-1.97; p = 0.001] was the only predictive biomarker at 30 days; at 1 year, both ST2 (HR 1.34; 95% CI 1.15-1.56; p < 0.001) and NT-proBNP (HR 1.19; 95% CI 1.02-1.40; p = 0.03) remained significant. The addition of ST2 and NT-proBNP into a clinical predictive model increased the AUC from 0.70 to 0.75 at 30 days (p = 0.02) and from 0.71 to 0.74 at 1 year (p < 0.05). For all-cause death at 1 year, ST2 (HR 1.50; 95% CI 1.26-1.80; p < 0.001), and CA125 (HR 1.41; 95% CI 1.21-1.63; p < 0.001) remained independent predictors in multivariable analysis. The addition of ST2 and CA125 into a clinical predictive model increased the AUC from 0.74 to 0.78 (p = 0.03). For HF-related hospitalizations, ST2 was the only predictive biomarker in multivariable analyses, both at 30 days and at 1 year. CONCLUSIONS: In a comorbid frail elderly population with HFpEF, ST2 outperformed NT-proBNP for predicting the risk of all-cause mortality or HF-related rehospitalization. ST2, a surrogate marker of inflammation and fibrosis, may be a better predictive marker in high-risk HFpEF.

Depression as Measured by PHQ-9 Versus Clinical Diagnosis as an Independent Predictor of Long-Term Mortality in a Prospective Cohort of Medical Inpatients.

BACKGROUND: Depression has been associated with higher rates of mortality in medical patients. The aim of the study was to evaluate the impact of depression in medical inpatients on the rate of mortality during a prolonged follow-up period. METHOD: This is a prospective follow-up study of a cohort of medical inpatients assessed during 1997-1998 in medical and surgical units at a tertiary university hospital in Spain and followed-up for a period ranging between 16.5 and 18 years. Eight hundred three patients were included; 420 (52.3%) were male, and the mean (SD) age was 41.7 (13.8) years. Main outcome was death for any cause during follow-up. The original full Patient Health Questionnaire (PHQ) was administered at baseline as self-report from which the PHQ-9 was derived. Depressive disorders were assessed using PHQ-9 and a structured clinical interview (Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition). RESULTS: Depressive disorders as defined by PHQ-9 were detected in 206 patients (25.7%), 122 (15.2%) of them fulfilling criteria for major depression. During follow-up, 152 patients (18.9%) died. A PHQ score indicating the presence of major depressive disorder predicted increased mortality (hazard ratio [HR], 2.44; 95% CI, 1.39-4.29), even after adjusting for important demographic and clinical variables. Similarly, the PHQ-9 score as a continuous measure of depression severity predicted increased mortality (HR, 1.06; 95% CI, 1.02-1.10). Results were similar for clinical interview diagnoses of major depression (HR, 2.07; 95% CI, 1.04-4.09). CONCLUSIONS: Medical inpatients with a PHQ depressive disorder had a nearly 2-fold higher risk of long-term mortality, even after adjustment for several confounders. Depression severity as represented by the PHQ-9 score was also a risk factor.

Impact of diabetes on the predictive value of heart failure biomarkers.

BACKGROUND: Patients with diabetes mellitus (DM) have an increased risk of developing heart failure (HF). Further, DM is associated with poor prognosis in patients with HF. Our aim was to determine whether DM has any impact on the predictive value of a multi-biomarker panel in patients with HF. METHODS: We included 1069 consecutive ambulatory HF patients in the study: age 66.2 ± 12.8 years, 33.5 ± 13.3 left ventricular ejection fraction, 36% diabetic patients. We measured serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), ST2, galectin-3, high-sensitivity C reactive protein (hs-CRP), cystatin-C, soluble transferrin receptor (sTfR), and neprilysin and followed patients for 4.9 ± 2.8 years. Primary endpoints were all-cause and cardiovascular death. RESULTS: During follow-up, 534 patients died; 283 died of cardiovascular causes. Diabetic subjects had higher mortality (57.7 vs. 45.6%, p < 0.001). NTproBNP (p = 0.07), hs-TnT (p < 0.001), galectin-3 (p < 0.001), and cystatin-C (p = 0.001) concentrations were higher in diabetic patients, whereas sTfR levels were lower (p = 0.005). There were no interactions between DM and NTproBNP, hs-TnT, galectin-3, hs-CRP, cystatin-C, sTfR, and neprilysin relative to risk prediction for all-cause or cardiovascular death. By contrast, ST2 significantly interacted with DM for all-cause (p = 0.02) and cardiovascular (p = 0.03) death. In diabetic patients, HRs for ST2 were 1.27 (95% CI 1.16-1.40, p < 0.001) and 1.23 (95% CI 1.09-1.39, p = 0.001) for all-cause and cardiovascular death, respectively. In nondiabetic patients, HRs for ST2 were 1.53 (95% CI 1.35-1.73, p < 0.001) and 1.64 (95% CI 1.31-2.05, p < 0.001) for all-cause and cardiovascular death, respectively. The multivariable Cox regression analysis showed that hs-TnT and ST2 were the only markers that were independently associated with both all-cause and cardiovascular mortality in patients with HF and diabetes. Moreover, in these patients, the combination of these two markers significantly increased discrimination as assessed by the area under the curve. CONCLUSIONS: Biomarkers used in the general population to predict the clinical course of heart failure are also useful in patients with diabetes. In these patients, among all the biomarkers analysed only hs-TnT and ST2 were independently associated with both all-cause and cardiovascular mortality.

The real-life value of ST2 monitoring during heart failure decompensation: impact on long-term readmission and mortality.

CONTEXT: Prognostic value of ST2 levels and dynamics has not been investigated in acute heart failure (AHF) using prospective real-life measurements. OBJECTIVE: The objective of this study is to investigate the prognostic value of ST2 in AHF. METHODS: ST2 levels were determined at admission (n = 182) and discharge (n = 85). Primary endpoint was the composite of all-cause death and HF rehospitalisation at one year. RESULTS: Discharge ST2 (HR 2.42 [95% CI 1.46-4], p = 0.001) and ΔST2 (HR 2.32 [95% CI 1.21-4.57], p = 0.01) but not admission ST2, remained independently prognostic for the primary endpoint after comprehensive multivariable adjustment. ST2 significantly improved prognosis stratification on top of clinical variables and NTproBNP. CONCLUSIONS: Routine clinical use of discharge ST2 and ST2 dynamics provide independent prognostic information.

ST2 pathogenetic profile in ambulatory heart failure patients.

BACKGROUND: Soluble ST2 is involved in multiple pathogenic pathways, including cardiac strain, inflammation, and myocardial necrosis with remodeling. The relative weight of ST2 and the point at which its prognostic value in heart failure (HF) is affected by different degrees of myocardial strain, inflammation, necrosis, and remodeling is unknown. METHODS AND RESULTS: We examined whether soluble ST2 levels improves HF risk stratification relative to other biomarkers representative of multiple pathogenic pathways-N-terminal pro-B-type natriuretic peptide (NT-proBNP; strain), high-sensitivity C-reactive protein (hsCRP; inflammation), and galectin-3 and high-sensitivity troponin T (hsTnT; necrosis and remodeling)-in 1,015 patients with mean left ventricular ejection fraction (LVEF) 33.5%. Mean follow-up was 4.2 ± 2.1 years. The correlation with soluble ST2 was highest with NT-proBNP (r = 0.32; P < .001) and lowest with galectin-3 (r = 0.15; P < .001). ST2 levels increased with increasing concentrations of the other biomarkers (P < .001 in all cases). During follow-up, 467 patients died. Soluble ST2 remained an independent prognosticator of risk at every tertile of each biomarker. This was observed even after adjusting for clinical parameters. CONCLUSIONS: Soluble ST2 may be regarded as a 3-in-1 prognosis biomarker in HF. ST2 provides valuable long-term risk stratification information in HF beyond that reported by other biomarkers of stretch, inflammation, necrosis, and remodeling.

Long-term prognostic value for patients with chronic heart failure of estimated glomerular filtration rate calculated with the new CKD-EPI equations containing cystatin C.

BACKGROUND: Correct estimation of renal function is crucial in assessing prognosis of patients with heart failure (HF). Recently, two new equations have been proposed to calculate estimated glomerular filtration rate (eGFR) with cystatin C alone or both creatinine and cystatin C. We assessed the prognostic value of eGFR estimated by these new equations in outpatients with HF. METHODS: The study included 879 patients with median age, 70.4 years; main etiology of HF ischemic heart disease, 52.7%; and median LVEF, 34%. RESULTS: eGFR estimates by the new equations correlated significantly with eGFR estimates from previous equations, with the best correlation observed between the 2 equations containing cystatin C [intraclass correlation coefficient 0.95 (95% confidence interval 0.94-0.95)]. During a median follow-up of 3.94 years, 371 patients died. The Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations containing cystatin C were found to be best for predicting death [area under the ROC curve 0.685 for CKD-EPI-cystatin C and 0.672 for CKD-EPI-creatinine-cystatin C vs 0.632 for simplified Modification of Diet in Renal Disease Study traceable to isotope dilution mass spectrometry and 0.643 for CKD-EPI (all P < 0.001)]. The CKD-EPI-cystatin C equations also showed significantly better calibration and reclassification measurements for both integrated discrimination improvement and net reclassification improvement in predicting death (P < 0.001). Reclassification with these new equations was particularly better in the subgroup with intermediate eGFR [45-74 mL · min(-1) · (1.73 m(2))(-1)]. CONCLUSIONS: The two new CKD-EPI equations containing cystatin C are useful for HF risk stratification and show better prognostic performance than creatinine-only based eGFR equations, mostly in patients with intermediate eGFR. These equations seem appropriate for assessing prognosis of HF patients with moderate renal insufficiency.

Complementary and alternative medicine in HIV care: frequency of consumption, risks and interactions with antiretroviral therapy.

OBJECTIVES: People living with HIV (PLWH) are common users of complementary and alternative medicine (CAM). The main objective of this study was to study the frequency and patterns of CAM natural products use in a large cohort of PLWH and to identify potential drug-drug interactions (DDIs) and the impact on their antiretroviral treatment (ART) adherence and efficacy. METHODS: This was a cross-sectional multicenter survey including 420 PLWH from different Spanish hospitals. Participants completed a face-to-face questionnaire on CAM consumption and different sociodemographic and clinical data were collected. DDIs between CAM and ART were identified and classified according to the Liverpool University Database and patient factors related to CAM consumption were assessed. RESULTS: 420 participants were included (82.6% male, mean age 47 years); 209 patients (49.8%) were taking at least one CAM. The most consumed CAM were green, black and red tea (n=146, 25.4%), ginger (n=26, 4.5%), fish oil (n=25, 4.4%) and cannabis (n=24, 4.2%). An ART based on integrase inhibitors was the only factor independently associated with CAM consumption (OR 1.54, 95% CI 1.04 to 2.26). 50 potential CAM-ART interactions in 43 (20.6%) patients taking CAM were identified, being clinically significant in 80% of the cases. CAM products most frequently involved with a potential significant DDI were supplements containing divalent cations (n=11) and garlic (n=7). No differences in ART efficacy and adherence were observed between patients with and without CAM consumption. CONCLUSIONS: Almost 50% of patients were taking at least one CAM product and its use was associated with an integrase inhibitor based ART. One out of every six patients was at risk of presenting with an interaction between a CAM and their ART, confirming the need to review continuously the use of CAM as part of the medication review process.

Soluble ST2 serum concentration and renal function in heart failure.

BACKGROUND: Soluble ST2 (sST2) provides important prognostic information in patients with heart failure (HF). How sST2 serum concentration is related to renal function is uncertain. We evaluated the association between sST2 and renal function and compared its prognostic value in HF patients with renal insufficiency. METHODS AND RESULTS: Patients (n = 879; median age 70.4 years; 71.8% men) were divided into 3 subgroups according to estimated glomerular filtration rate (eGFR): ≥60 mL/min/1.73 m(2) (n = 337); 30-59 mL/min/1.73 m(2) (n = 352); and <30 mL/min/1.73 m(2) (n = 190). sST2 (rho = -0.16; P < .001), N-terminal pro-B-type natriuretic peptide (rho = -0.40; P < .001), and high-sensitivity cardiac troponin T (rho = -0.47; P < .001) inversely correlated with eGFR. All-cause mortality was the primary end point. During a median follow-up of 3.46 years, 312 patients (35%) died, 246 of them from the subgroup of 542 patients with eGFR <60 mL/min/1.73 m(2) (45%). Biomarker combination including sST2 showed best discrimination, calibration, and reclassification metrics in renal insufficiency patients (net reclassification improvement 16.6 [95% confidence interval (CI) 8.1-25; P < .001]; integrated discrimination improvement 4.2 [95% CI 2.2-6.2; P < .001]). Improvement in reclassification was higher in these patients than in the total cohort. CONCLUSIONS: The prognostic value of sST2 was not influenced by renal function. On top of other biomarkers, sST2 improved long-term prediction in patients with renal insufficiency even more than in the total cohort.

Therapeutic Drug Monitoring of Vancomycin Concentrations for the Management of Bone and Joint Infections: An Urgent Need.

Vancomycin is used for the treatment of bone and joint infections (BJI), but scarce information is available about its pharmacokinetic/pharmacodynamic (PK/PD) characteristics. We aimed to identify the risk factors associated with the non-achievement of an optimal PK/PD target in the first therapeutic drug monitoring (TDM). Methods: A retrospective study was conducted in a tertiary hospital from January 2020 to January 2022. Patients with BJI and TDM of vancomycin on day 2 of treatment were included. Initial vancomycin fixed doses (1 g every 8 h or 12 h) was decided by the responsible doctors. According to TDM results, dosage adjustments were performed. An AUC24h/MIC < 400 mg × h/L, between 400 and 600 mg × h/L and >600 mg × h/L, were defined as suboptimal, optimal and supratherapeutic, respectively. Patients were grouped into these three categories. Demographic, clinical and PK characteristics were compared between groups. Nephrotoxicity at the end of treatment was assessed. Results: A total of 94 patients were included: 22 (23.4%), 42 (44.7%) and 30 (31.9%) presented an infratherapeutic, optimal and supratherapeutic PK/PD targets, respectively. A younger age and initial vancomycin dose <40 mg/kg/day were predictive factors for achieving a suboptimal PK/PD target, while older age, higher serum-creatinine and dose >40 mg/kg/day were associated with overexposure. The nephrotoxicity rate was 22.7%. More than 50% of patients did not achieve an optimal PK/PD. Considering age, baseline serum-creatinine and body weight, TDM is required to readily achieve an optimal and safe exposure.

Combined use of high-sensitivity cardiac troponin T and N-terminal pro-B type natriuretic peptide improves measurements of performance over established mortality risk factors in chronic heart failure.

BACKGROUND: Heart failure still maintains a high mortality. Biomarkers reflecting different pathophysiological pathways are under evaluation to better stratify the mortality risk. The objective was to assess high-sensitivity cardiac troponin T (hs-cTnT) in combination with N-terminal pro-B type natriuretic peptide (NT-proBNP) for risk stratification in a real-life cohort of ambulatory heart failure patients. METHODS: We analyzed 876 consecutive patients (median age 70.3 years, median left ventricular ejection fraction 34%) treated at a heart failure unit. A combination of biomarkers reflecting myocyte injury (hs-cTnT) and myocardial stretch (NT-proBNP) was used in addition to an assessment based on established mortality risk factors (age, sex, left ventricular ejection fraction, New York Heart Association functional class, diabetes, estimated glomerular filtration rate, ischemic etiology, sodium, hemoglobin, ß-blocker treatment, and angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment). RESULTS: During a median follow-up of 41.4 months, 311 patients died. In the multivariable Cox proportional hazards model, hs-cTnT and NT-proBNP were independent prognosticators (P = .003 each). The combined elevation of both biomarkers above cut-off values significantly increased the risk of death (HR 7.42 [95% CI, 5.23-10.54], P < .001). When hs-cTnT and NT-proBNP were individually included in a model with established mortality risk factors, measurements of performance significantly improved. Results obtained for hs-cTnT compared with NT-proBNP were superior according to comprehensive discrimination, calibration, and reclassification analysis (net reclassification indices of 7.7% and 1.5%, respectively). CONCLUSIONS: hs-cTnT provides significant prognostic information in a real-life cohort of patients with chronic heart failure. Simultaneous addition of hs-cTnT and NT-proBNP into a model that includes established risk factors improves mortality risk stratification.

Comprehensive Multimorbidity Patterns in Older Patients Are Associated with Quality Indicators of Medication-MoPIM Cohort Study.

Multimorbidity is increasing and poses a challenge to the clinical management of patients with multiple conditions and drug prescriptions. The objectives of this work are to evaluate if multimorbidity patterns are associated with quality indicators of medication: potentially inappropriate prescribing (PIP) or adverse drug reactions (ADRs). A multicentre prospective cohort study was conducted including 740 older (≥65 years) patients hospitalised due to chronic pathology exacerbation. Sociodemographic, clinical and medication related variables (polypharmacy, PIP according to STOPP/START criteria, ADRs) were collected. Bivariate analyses were performed comparing previously identified multimorbidity clusters (osteoarticular, psychogeriatric, minor chronic disease, cardiorespiratory) to presence, number or specific types of PIP or ADRs. Significant associations were found in all clusters. The osteoarticular cluster presented the highest prevalence of PIP (94.9%) and ADRs (48.2%), mostly related to anxiolytics and antihypertensives, followed by the minor chronic disease cluster, associated with ADRs caused by antihypertensives and insulin. The psychogeriatric cluster presented PIP and ADRs of neuroleptics and the cardiorespiratory cluster indicators were better overall. In conclusion, the associations that were found reinforce the existence of multimorbidity patterns and support specific medication review actions according to each patient profile. Thus, determining the relationship between multimorbidity profiles and quality indicators of medication could help optimise healthcare processes. Trial registration number: NCT02830425.

Clinical Determinants and Prognosis of Left Ventricular Reverse Remodelling in Non-Ischemic Dilated Cardiomyopathy.

AIMS: Non-ischaemic dilated cardiomyopathy (NIDCM) is characterized by left ventricular (LV) chamber enlargement and systolic dysfunction in the absence of coronary artery disease. Left ventricular reverse remodelling (LVRR) is the ability of a dilated ventricle to restore its normal size, shape and function. We sought to determine the frequency, clinical predictors and prognostic implications of LVRR, in a cohort of heart failure (HF) patients with NIDCM. METHODS: We conducted a multicentre observational, retrospective cohort study of patients with NIDCM, with prospective serial echocardiography evaluations. LVRR was defined as an increase of ≥15% in left ventricular ejection fraction (LVEF) or as a LVEF increase ≥ 10% plus reduction of LV end-systolic diameter index ≥ 20%. We used multivariable logistic regression analyses to identify the baseline clinical predictors of LVRR and evaluate the prognostic impact of LVRR. RESULTS: LVRR was achieved in 42.5% of 527 patients with NIDCM during the first year of follow-up (median LVEF 49%, median change +22%), Alcoholic aetiology, HF duration, baseline LVEF and the absence of LBBB (plus NT-proBNP levels when in the model), were the strongest predictors of LVRR. During a median follow-up of 47 months, 134 patients died (25.4%) and 7 patients (1.3%) received a heart transplant. Patients with LVRR presented better outcomes, regardless of other clinical conditions. CONCLUSIONS: In patients with NIDCM, LVRR was frequent and was associated with improved prognosis. Major clinical predictors of LVRR were alcoholic cardiomyopathy, absence of LBBB, shorter HF duration, and lower baseline LVEF and NT-proBNP levels. Our study advocates for clinical phenotyping of non-ischaemic dilated cardiomyopathy and intense gold-standard treatment optimization of patients according to current guidelines and recommendations in specialized HF units.

Body mass index and outcomes in ischaemic versus non-ischaemic heart failure across the spectrum of ejection fraction.

AIMS: Obesity is related to better prognosis in heart failure with either reduced (HFrEF; left ventricular ejection fraction (LVEF) < 40%) or preserved LVEF (HFpEF; LVEF ≥50%). Whether the obesity paradox exists in patients with heart failure and mid-range LVEF (HFmrEF; LVEF 40-49%) and whether it is independent of heart failure aetiology is unknown. Therefore, we aimed to test the prognostic value of body mass index (BMI) in ischaemic and non-ischaemic heart failure patients across the whole spectrum of LVEF. METHODS: Consecutive ambulatory heart failure patients were enrolled in two tertiary centres in Italy and Spain and classified as HFrEF, HFmrEF or HFpEF, of either ischaemic or non-ischaemic aetiology. Patients were stratified into underweight (BMI < 18.5 kg/m2), normal-weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25-29.9 kg/m2), mild-obese (BMI 30-34.9 kg/m2), moderate-obese (BMI 35-39.9 kg/m2) and severe-obese (BMI ≥40 kg/m2) and followed up for the end-point of five-year all-cause mortality. RESULTS: We enrolled 5155 patients (age 70 years (60-77); 71% males; LVEF 35% (27-45); 63% HFrEF, 18% HFmrEF, 19% HFpEF). At multivariable analysis, mild obesity was independently associated with a lower risk of all-cause mortality in HFrEF (hazard ratio, 0.78 (95% confidence interval (CI) 0.64-0.95), p = 0.020), HFmrEF (hazard ratio 0.63 (95% CI 0.41-0.96), p = 0.029), and HFpEF (hazard ratio 0.60 (95% CI 0.42-0.88), p = 0.008). Both overweight and mild-to-moderate obesity were associated with better outcome in non-ischaemic heart failure, but not in ischaemic heart failure. CONCLUSIONS: Mild obesity is independently associated with better survival in heart failure across the whole spectrum of LVEF. Prognostic benefit of obesity is maintained only in non-ischaemic heart failure.

Lung ultrasound in outpatients with heart failure: the wet-to-dry HF study.

AIMS: In ambulatory patients with chronic heart failure (HF), congestion and decongestion assessment may be challenging. The aim of this study is to assess the value of lung ultrasound (LUS) in outpatients with HF in characterizing decompensation and recompensation, and in outcomes prediction. METHODS AND RESULTS: Heart failure outpatients attended to establish HF decompensation were included. LUS was blindly performed at baseline (LUS1) and at clinical recompensation (LUS2). B-lines were counted in eight scanned areas. Diagnosis of no HF decompensation vs. right-sided, left-sided, or global HF decompensation, and patients' management were performed by physicians blinded to LUS1. Outcome was the composite of all-cause death or HF-related hospitalization. Two hundred and thirty-three suspicions of HF decompensation were included in 187 patients (71.4 ± 11.3 years, 66.8% men). Mean B-line (LUS1) was 17.6 ± 11.2 vs. 3.7 ± 4.5 for episodes with and without HF decompensation, respectively (P < 0.001). Global HF decompensation showed the highest number of B-lines (20.6 ± 11), followed by left-sided (19.7 ± 11.6) and right-sided (13.5 ± 9.8). B-lines declined to 6.9 ± 6.7 (LUS2) (P < 0.001 vs. LUS1) after treatment, within a mean time of 24.2 ± 23.7 days [median 13.5 days (interquartile range 6-40)]. B-lines were significantly associated with the composite endpoint at 30 days (hazard ratio [HR] 1.04 [95% confidence interval 1.01-1.07], P = 0.02), but not at 60 (P = 0.22) or 180 days (P = 0.54). In multivariable analysis, B-line number remained as an independent predictor of the composite endpoint at 30 days, [HR 1.04 (1.01-1.07), P = 0.014], with a 4% increase risk per B-line added. B-lines correlated significantly with CA125 (R = 0.30, P = 0.001). CONCLUSIONS: Lung ultrasound supports the diagnostic work-up of congestion and decongestion in chronic HF outpatients and identifies patients at high risk of short-term events.

Prognostic value of lung ultrasound in chronic stable ambulatory heart failure patients.

INTRODUCTION AND OBJECTIVES: The role of lung ultrasound (LUS) in acute heart failure (HF) has been widely studied, but little is known about its usefulness in chronic HF. This study assessed the prognostic value of LUS in a cohort of chronic HF stable ambulatory patients. METHODS: We included consecutive outpatients who attended a scheduled follow-up visit in a HF clinic. LUS was performed in situ. The operators were blinded to clinical data and examined 8 thoracic areas. The sum of B-lines across all lung zones and the quartiles of this addition were used for the analyses. Linear regression and Cox regression analyses were performed. The main clinical outcomes were a composite of all-cause death or hospitalization for HF and mortality from any cause. RESULTS: A total of 577 individuals were included (72% men; 69± 12 years). The mean number of B-lines was 5±6. During a mean follow-up of 31±7 months, 157 patients experienced the main clinical outcome and 111 died. Having ≥ 8 B-lines (Q4) doubled the risk of experiencing the composite primary event (P <.001) and increased the risk of death from any cause by 2.6-fold (P <.001). On multivariate analysis, the total sum of B-lines remained independent predictive factor of the composite endpoint (HR, 1.04; 95%CI, 1.02-1.06; P=.002) and of all-cause death (HR, 1.04; 95%CI, 1.02-1.07; P=.001), independently of whether or not N-terminal pro-B-type natriuretic peptide (NT-proBNP) was included in the model (P=.01 and P=.008, respectively), with a 3% to 4% increased risk for each 1-line addition. CONCLUSIONS: LUS identified patients with stable chronic HF at high risk of death or HF hospitalization.