Abstract The present paper systematically reviews and compares existing prediction models in order to establish the strongest variables, models, and model characteristics in patients with heart ...failure predicting outcome. To improve decision making accurately predicting mortality and heart-failure hospitalization in patients with heart failure can be important for selecting patients with a poorer prognosis or nonresponders to current therapy, to improve decision making. MEDLINE/PubMed was searched for papers dealing with heart failure prediction models. To identify similar models on the basis of their variables hierarchical cluster analysis was performed. Meta-analysis was used to estimate the mean predictive value of the variables and models; meta-regression was used to find characteristics that explain variation in discriminating values between models. We identified 117 models in 55 papers. These models used 249 different variables. The strongest predictors were blood urea nitrogen and sodium. Four subgroups of models were identified. Mortality was most accurately predicted by prospective registry-type studies using a large number of clinical predictor variables. Mean C-statistic of all models was 0.66 ± 0.0005, with 0.71 ± 0.001, 0.68 ± 0.001 and 0.63 ± 0.001 for models predicting mortality, heart failure hospitalization, or both, respectively. There was no significant difference in discriminating value of models between patients with chronic and acute heart failure. Prediction of mortality and in particular heart failure hospitalization in patients with heart failure remains only moderately successful. The strongest predictors were blood urea nitrogen and sodium. The highest C-statistic values were achieved in a clinical setting, predicting short-term mortality with the use of models derived from prospective cohort/registry studies with a large number of predictor variables.
Aims
Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)‐α were largely unsuccessful. Interleukin (IL)‐6 is an important ...inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL‐6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations.
Methods and results
Interleukin‐6 was measured in 2329 patients 89.4% with a left ventricular ejection fraction (LVEF) ≤ 40% of the BIOSTAT‐CHF cohort. The primary outcome was all‐cause mortality and HF hospitalization during 2 years, with all‐cause, cardiovascular (CV), and non‐CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL‐6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N‐terminal pro‐brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF‐α/IL‐1‐related biomarkers, or having iron deficiency, atrial fibrillation and LVEF > 40% independently predicted elevated IL‐6 levels. IL‐6 independently predicted the primary outcome HR (95% confidence interval) per doubling: 1.16 (1.11–1.21), P < 0.001, all‐cause mortality 1.22 (1.16–1.29), P < 0.001 and CV as well as non‐CV mortality 1.16 (1.09–1.24), P < 0.001; 1.31 (1.18–1.45), P < 0.001, but did not improve discrimination in previously published risk models.
Conclusions
In a large, heterogeneous cohort of HF patients, elevated IL‐6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL‐6 as a potential therapeutic target in specific HF subpopulations.
Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), β blockers, and mineralocorticoid receptor antagonists (MRAs) are of proven benefit and are recommended by ...guidelines for management of patients with heart failure and reduced ejection fraction (HFrEF). We aimed to examine the first prospective multinational data from Asia on prescribing patterns of guideline-directed medical therapies and analyse its effect on outcomes.
In the prospective multinational ASIAN-HF registry (with enrolment from 46 centres in 11 countries in Asia), we enrolled patients aged 18 years or older, with symptomatic heart failure (stage C, with at least one episode of decompensated heart failure in the past 6 months that resulted in admission to hospital or was treated in an outpatient clinic) and left ventricular systolic dysfunction (ejection fraction ≤40% on baseline echocardiography, consistent with 2016 European Society of Cardiology guidelines). We excluded patients with heart failure caused by severe valvular heart disease, life-threatening comorbidity with a life expectancy of less than 1 year, who were unable or unwilling to give consent, or who had concurrent participation in a clinical trial. Patients were followed up for 3 years for the outcomes of death and cause-specific admittance to hospital. Primary outcomes were uptake of guideline-directed medical therapies (as proportions) by therapeutic class, achieved doses as proportions of guideline-recommended doses, and their association with 1-year composite outcome of all-cause death or admittance to hospital because of heart failure. This study is registered with ClinicalTrials.gov, number NCT01633398.
Between Oct 1, 2012, and Dec 31, 2015, we enrolled 5276 patients with HFrEF (mean age 59·6 years SD 13·2, 77% men, body-mass index 24·9 kg/m2 5·1, 33% New York Heart Association class III or IV). Follow-up data were available for 4544 (90%) of 5061 eligible patients taking medication for heart failure, with median follow-up of 417 days (IQR 214–735). ACE inhibitors or ARBs were prescribed to 3868 (77%) of 5005 patients, β blockers to 3975 (79%) of 5061, and MRAs to 2998 (58%) of 5205, with substantial regional variation. Guideline-recommended dose was achieved in only 17% of cases for ACE inhibitors or ARB, 13% for β blockers, and 29% for MRAs. Country (all three drug classes), increasing body-mass index (ACE inhibitors or ARBs and MRAs), and in-patient recruitment (ACE inhibitors or ARBs and β blockers) were associated with attainment of guideline-recommended dose (all p<0·05). When adjusted for indication bias, increasing drug doses, from low dose (1–<25% of guideline-recommended dose) upwards were associated with lower hazards of a 1-year composite outcome for ACE inhibitors or ARBs and β blockers compared with non-users. The lowest adjusted hazards were in the group that attained guideline-recommended doses above 50% (hazard ratio HR 0·54, 95% CI 0·50–0·58 for ACE inhibitors or ARBs 50–99·9%; HR 0·47, 0·46–0·50 for β blockers, and HR 0·77, 0·72–0·81 for MRAs ≥100%).
Guideline-directed medical therapies at recommended doses are underutilised in patients with HFrEF. Improved uptake and uptitration of guideline-directed medical therapies are needed for better patient outcomes.
National Medical Research Council (Singapore), A*STAR Biomedical Research Council ATTRaCT program, Boston Scientific Investigator Sponsored Research program, and Bayer.
Comorbidities are common in patients with heart failure (HF) and complicate treatment and outcomes. We identified patterns of multimorbidity in Asian patients with HF and their association with ...patients' quality of life (QoL) and health outcomes.
We used data on 6,480 patients with chronic HF (1,204 with preserved ejection fraction) enrolled between 1 October 2012 and 6 October 2016 in the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry. The ASIAN-HF registry is a prospective cohort study, with patients prospectively enrolled from in- and outpatient clinics from 11 Asian regions (Hong Kong, Taiwan, China, Japan, Korea, India, Malaysia, Thailand, Singapore, Indonesia, and Philippines). Latent class analysis was used to identify patterns of multimorbidity. The primary outcome was defined as a composite of all-cause mortality or HF hospitalization within 1 year. To assess differences in QoL, we used the Kansas City Cardiomyopathy Questionnaire. We identified 5 distinct multimorbidity groups: elderly/atrial fibrillation (AF) (N = 1,048; oldest, more AF), metabolic (N = 1,129; obesity, diabetes, hypertension), young (N = 1,759; youngest, low comorbidity rates, non-ischemic etiology), ischemic (N = 1,261; ischemic etiology), and lean diabetic (N = 1,283; diabetic, hypertensive, low prevalence of obesity, high prevalence of chronic kidney disease). Patients in the lean diabetic group had the worst QoL, more severe signs and symptoms of HF, and the highest rate of the primary combined outcome within 1 year (29% versus 11% in the young group) (p for all <0.001). Adjusting for confounders (demographics, New York Heart Association class, and medication) the lean diabetic (hazard ratio HR 1.79, 95% CI 1.46-2.22), elderly/AF (HR 1.57, 95% CI 1.26-1.96), ischemic (HR 1.51, 95% CI 1.22-1.88), and metabolic (HR 1.28, 95% CI 1.02-1.60) groups had higher rates of the primary combined outcome compared to the young group. Potential limitations include site selection and participation bias.
Among Asian patients with HF, comorbidities naturally clustered in 5 distinct patterns, each differentially impacting patients' QoL and health outcomes. These data underscore the importance of studying multimorbidity in HF and the need for more comprehensive approaches in phenotyping patients with HF and multimorbidity.
ClinicalTrials.gov NCT01633398.
Heart failure is a global public health problem, affecting a large number of individuals from low-income and middle-income countries. REPORT-HF is, to our knowledge, the first prospective global ...registry collecting information on patient characteristics, management, and prognosis of acute heart failure using a single protocol. The aim of this study was to investigate differences in 1-year post-discharge mortality according to region, country income, and income inequality.
Patients were enrolled during hospitalisation for acute heart failure from 358 centres in 44 countries on six continents. We stratified countries according to a modified WHO regional classification (Latin America, North America, western Europe, eastern Europe, eastern Mediterranean and Africa, southeast Asia, and western Pacific), country income (low, middle, high) and income inequality (according to tertiles of Gini index). Risk factors were identified on the basis of expert opinion and knowledge of the literature.
Of 18 102 patients discharged, 3461 (20%) died within 1 year. Important predictors of 1-year mortality were old age, anaemia, chronic kidney disease, presence of valvular heart disease, left ventricular ejection fraction phenotype (heart failure with reduced ejection fraction HFrEF vs preserved ejection fraction HFpEF), and being on guideline-directed medical treatment (GDMT) at discharge (p<0·0001 for all). Patients from eastern Europe had the lowest 1-year mortality (16%) and patients from eastern Mediterranean and Africa (22%) and Latin America (22%) the highest. Patients from lower-income countries (ie, ≤US$3955 per capita; hazard ratio 1·58, 95% CI 1·41–1·77), or with greater income inequality (ie, from the highest Gini tertile; 1·25, 1·13–1·38) had a higher 1-year mortality compared with patients from regions with higher income (ie, >$12 235 per capita) or lower income inequality (ie, from the lowest Gini tertile). Compared with patients with HFrEF, patients with HFpEF had a lower 1-year mortality with little variation by income level (pinteraction for HFrEF vs HFpEF <0·0001).
Acute heart failure is associated with a high post-discharge mortality, particularly in patients with HFrEF from low-income regions with high income inequality. Regional differences exist in the proportion of eligible patients discharged on GDMT, which was strongly associated with mortality and might reflect lack of access to post-discharge care and prescribing of GDMT.
Novartis Pharma.
Immune checkpoint inhibitors (ICIs), which target CTLA-4 or PD-(L)1 molecules, have shown impressive therapeutic results. Durable responses, however, are only observed in a segment of the patient ...population and must be offset against severe off-target immune toxicity and high costs. This calls for biomarkers that predict response during ICI treatment. Although many candidate biomarkers exist, as yet, there has been no systematic overview of biomarkers predictive during. Here, we provide a systematic review of the current literature of ICI treatment to establish an overview of candidate predictive biomarkers during ICI treatment in melanoma patients. We performed a systematic Medline search (2000-2018, 1 January) on biomarkers for survival or response to ICI treatment in melanoma patients. We retrieved 735 publications, of which 79 were finally included in this systematic review. Blood markers were largely studied for CTLA-4 ICI, whereas tumor tissue markers were analyzed for PD-(L)1 ICI. Blood cytology and soluble factors were more frequently correlated to overall survival (OS) than response, indicating their prognostic rather than predictive nature. An increase in tumor-infiltrating CD8 + T-cells and a decrease in regulatory T-cells were correlated to response, in addition to mutational load, neoantigen load, and immune-related gene expression. Immune-related adverse events were also associated frequently with a favorable response and OS. This review shows the great variety of potential biomarkers published to date, in an attempt to better understand response to ICI therapy; it also highlights the candidate markers for future research. The most promising biomarkers for response to ICI treatment are the occurrence of immune-related adverse events (especially vitiligo), lowering of lactate dehydrogenase, and increase in activated CD8 + and decrease in regulatory T-cells.
Aims
Several studies have shown that older patients with heart failure with reduced ejection fraction (HFrEF) are undertreated. The aim of this study was to evaluate the association of up‐titration ...of angiotensin‐converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) and beta‐blockers on outcome across the age spectrum in HFrEF patients.
Methods and results
We analysed HFrEF patients on sub‐optimal doses of ACEI/ARB and/or beta‐blockers from the BIOSTAT‐CHF study stratified by age. Patients underwent a 3‐month up‐titration period. We used inverse probability weighting to adjust for the likelihood of successful up‐titration to determine the association of achieved dose with mortality and/or heart failure hospitalisation, testing for an interaction with age. Over a median follow‐up of 21 months in 1720 HFrEF patients (76.5% male, mean age 67 years), the primary outcome occurred in 558 patients. Increased percentage of target dose of ACEI/ARB and beta‐blocker achieved at 3 months were both significantly associated with reduced incidence of the primary outcome, ACEI‐ARB: hazard ratio (HR) per 12.5% increase in dose: 0.92, 95% confidence interval (CI) 0.91–0.94, P < 0.001; beta‐blocker: HR 0.98, 95% CI 0.95–1.00, P = 0.046, with a significant interaction with age seen for beta‐blockers but not ACEI/ARB (P = 0.034 and P = 0.22, respectively).
Conclusions
Achieving higher doses of ACEI/ARB was associated with improved outcome regardless of age. However, achieving higher doses of beta‐blockers was only associated with improved outcome in younger, but not in older patients.
Aims
Heart failure (HF) patients are at high‐risk of cardiovascular (CV) events, including CV death. Nonetheless, a substantial proportion of these patients die from non‐CV causes. Identifying ...patients at higher risk for each individual event may help selecting patients for clinical trials and tailoring cardiovascular therapies. The aims of the present study are to: (i) characterize patients according to CV vs. non‐CV death; (ii) develop models for the prediction of the respective events; (iii) assess the models' performance to differentiate CV from non‐CV death.
Methods and results
This study included 2309 patients with HF from the BIOSTAT‐CHF (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Competing‐risk models were used to assess the best combination of variables associated with each cause‐specific death. Results were validated in an independent cohort of 1738 HF patients. The best model to predict CV death included low blood pressure, estimated glomerular filtration rate ≤ 60 mL/min, peripheral oedema, previous HF hospitalization, ischaemic HF, chronic obstructive pulmonary disease, elevated N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), and troponin (c‐index = 0.73). The non‐CV death model incorporated age > 75 years, anaemia and elevated NT‐proBNP (c‐index = 0.71). Both CV and non‐CV death rose by quintiles of the risk scores; yet these models allowed the identification of patients in whom absolute CV death rates clearly outweigh non‐CV death ones. These findings were externally replicated, but performed worse in a less severely diseased population.
Conclusions
Risk models for predicting CV and non‐CV death allowed the identification of patients at higher absolute risk of dying from CV causes (vs. non‐CV ones). Troponin helped in predicting CV death only, whereas NT‐proBNP helped in the prediction of both CV and non‐CV death. These findings can be useful both for tailoring therapies and for patient selection in HF trials in order to attain CV event enrichment.
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