Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction

International audienceAims: The lack of effective therapies for patients with heart failure with preserved ejection fraction (HFpEF) is often ascribed to the heterogeneity of patients with HFpEF. We aimed to identify distinct pathophysiologic clusters of HFpEF based on circulating biomarkers.Methods and results: We performed an unsupervised cluster analysis using 363 biomarkers from 429 patient with HFpEF. Relative differences in expression profiles of the biomarkers between clusters were assessed and used for pathway over-representation analyses. We identified four distinct patients subgroups based on their biomarker profiles : cluster 1 with the highest prevalence of diabetes mellitus and renal disease; cluster 2 with oldest age and frequent age-related comorbidities; cluster 3 with youngest age, largest body size, least symptoms and lowest NT-proBNP levels; and cluster 4 with highest prevalence of ischemic aetiology, smoking and chronic lung disease, most symptoms, as well as highest NT-proBNP and troponin levels. Over a median follow-up of 21 months, the occurrence of death or HF hospitalization was highest in clusters 1 and 4 (62.1% and 62.8% respectively) and lowest in cluster 3 (25.6%). Pathway over-representation analyses revealed that the biomarker profile of patients in cluster 1 was associated with activation of inflammatory pathways while the biomarker profile of patients in cluster 4 was specifically associated with pathways implicated in cell proliferation regulation and cell survival.Conclusion: Unsupervised cluster analysis based on biomarker profiles identified mutually exclusive subgroups of patients with HFpEF with distinct biomarker profiles, clinical characteristics and outcomes, suggesting different underlying pathophysiological pathway

Is Acute heart failure a distinctive disorder? An analysis from BIOSTAT-CHF

AimsThis retrospective analysis sought to identify markers that might distinguish between acute heart failure (HF) and worsening HF in chronic outpatients.Methods and ResultsThe BIOSTAT‐CHF index cohort included 2516 patients with new or worsening HF symptoms: 1694 enrolled as inpatients (acute HF) and 822 as outpatients (worsening HF in chronic outpatients). A validation cohort included 935 inpatients and 803 outpatients. Multivariable models were developed in the index cohort using clinical characteristics, routine laboratory values, and proteomics data to examine which factors predict adverse outcomes in both conditions and to determine which factors differ between acute HF and worsening HF in chronic outpatients, validated in the validation cohort.Patients with acute HF had substantially higher morbidity and mortality (6 months mortality was 12..3% for acute HF and 4..7% for worsening HF in chronic outpatients). Multivariable models predicting 180‐day mortality and 180‐day HF re‐admission differed substantially between acute HF and worsening HF in chronic outpatients. CA‐125 was the strongest single biomarker to distinguish acute HF from worsening HF in chronic outpatients, but only yielded a C‐index of 0..71. A model including multiple biomarkers and clinical variables achieved a high degree of discrimination with a C‐index of 0..913 in the index cohort and 0..901 in the validation cohort.ConclusionThe study identifies different characteristics and predictors of outcome in acute HF patients as compared to outpatients with chronic HF developing worsening HF. The markers identified may be useful in better diagnosing acute HF and may become targets for treatment development.</h4

Public Information about Clinical Trials and Research

Be it to restore the confused image of clinical research in relation to the lay public, or to develop new ways of accruing healthy volunteers or patients for clinical trials, there is a need to draft some guidance on how best to provide information on research. Although the French legal and regulatory armamentarium in this area is essentially liberal, there is currently little-justified reluctance among study sponsors to advertise publicly. A group of academic and pharmaceutical industry researchers, assembled for a workshop, together with regulators, journalists, representatives from ethics committees, social security, patient and health consumer groups and other French institutional bodies, has suggested the following series of recommendations: – there is no need for additional legal or regulatory constraints; – sponsors should be aware of and make use of direct public information on trials; – a `good practice charter' on public communication about clinical trials should be developed; – all professionals should be involved in this communication platform; – communication in the patient's immediate vicinity should be preferred (primary-care physician, local press); – clinical databases and websites accessible to professionals, but also to patients and non-professionals, should be developed; – genuine instruction on clinical trials for physicians and health professionals unfamiliar with such trials should be developed and disseminated; – media groups should receive at least some training in the fundamentals of clinical research

Information du public sur les essais cliniques et la recherche

Que ce soit pour restaurer l'image ternie de la recherche clinique vis-à-vis du grand public ou pour développer de nouvelles méthodes de recrutement des volontaires sains ou des patients dans les essais cliniques, il existe un besoin de recommandations permettant in fine d'optimiser l'information sur la recherche. Alors que l'arsenal légal et réglementaire français serait plutôt libéral en la matière, il existe actuellement et sans justification réelle une réticence des promoteurs d'essais à recourir à la publicité pour les essais. Un groupe de chercheurs cliniciens universitaires publics et industriels a tenu une table ronde en présence de représentants des autorités de santé, de journalistes, de membres des Comités Consultatifs de Protection des Personnes dans la Recherche Biomédicale, de représentants de la Sécurité Sociale, d'associations de malades et de consommateurs et d'autres instances administratives françaises afin d'émettre un certain nombre de recommandations qui peuvent s'énoncer comme suit : – il n'y a pas nécessité d'augmenter les contraintes légales ou réglementaires; – les promoteurs d'essais doivent être informés sur les possibilités de recourir à l'information directe du grand public sur les essais cliniques et en faire usage; – une "charte professionnelle de bonne pratique" de communication sur les essais devrait être développée; – toute la chaîne des professionnels devrait être incluse dans la plate-forme de communication; – l'information de proximité du patient devrait être privilégiée (médecin traitant et presse régionale); – le développement de répertoires et de sites internet dédiés devrait être encouragé, qu'ils soient accessibles non seulement aux professionnels mais aussi aux patients et aux non-professionnels; – une vraie pédagogie pour les médecins, personnels de santé non-professionnels de l'essai clinique, devrait être mise en place; – les médias devraient être formés aux bases de la recherche clinique

Élaboration de recommandations de pratique clinique : les inhibiteurs de l'enzyme de conversion dans l'insuffisance cardiaque

Les inhibiteurs de l'enzyme de conversion (IEC) constituent la classe thérapeutique incontournable du traitement de l'insuffisance cardiaque. Cependant, de la littérature internationale aux données régionales, il est fait état de leur sous-prescription en pratique cardiologique. Malgré l'abondance des conférences de consensus, aucune ne cible en particulier la stratégie thérapeutique par IEC. Dans ce contexte, des recommandations de pratique clinique sur la prise en charge de l'insuffisance cardiaque par IEC ont été formalisées par des cardiologues hospitaliers lorrains. Cette formalisation s'est déroulée selon une méthode standardisée combinant l'analyse de la littérature et les opinions d'experts. Au final, 17 recommandations ont été adoptées et classées en quatre rubriques : indications et contre-indications ; posologies et modalités de surveillance ; gestion des effets indésirables ; et associations déconseillées. La formalisation de ces recommandations est l'étape clé d'une démarche d'amélioration de la qualité, initiée en 1999 dans les services de cardiologie de la région

Évaluation de différentes modalités de traitement de l'hypertension artérielle : association faiblement dosée perindopril/indapamide versus traitement séquentiel ou traitement pas à pas

Etude randomisée, en double aveugle, comparant trois modalités de traitement, chez 533 patients présentant une hypertension artérielle, sur une période de 6–9 mois. L'administration quotidienne de l'association faiblement dosée de perindopril/indapamide (PER/IND) [respectivement 2,0 et 0,625 mg] a entraîné un contrôle de la pression artérielle et une réduction de la pression artérielle systolique significativement supérieurs. De plus, l'association faiblement dosée PER/IND a présenté un critère composite efficacité/tolérance supérieur à celui du traitement séquentiel de l'aténolol (50 mg) puis du losartan (50 mg) puis de l'amlodipine (5 mg), et à celui du traitement pas à pas avec du valsartan (40 mg – 80 mg – 80 mg plus de l'hydrochlorothiazide 12,5 mg)

Association of Serum Phosphate with Efficacy of Statin Therapy in Hemodialysis Patients

International audienceBACKGROUND AND OBJECTIVES: Statins are less efficacious in reducing cardiovascular disease risk in patients on dialysis than in the general population. Recent experimental data showed that phosphate excess promotes cellular de novo cholesterol synthesis through 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activation. Whether this mechanism might account for the resistance of patients on dialysis to statins has not yet been explored. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this post hoc analysis, we examined the efficacy of statin treatment according to serum phosphate levels in the patients on dialysis who were participants of the A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) trial using serum phosphate levels at baseline and during the trial course. We first classified the patients by groups of similar phosphate trajectories over time and tested whether phosphate as a longitudinal exposure (summarized by the identified trajectory groups) modulated the occurrence of major adverse cardiovascular events and all-cause death. We replicate the analysis in the Deutsche Diabetes Dialyze Studie (4D) trial. RESULTS: In the AURORA trial, using multivariable analysis, we found that the treatment effect of statin on major adverse cardiovascular events and all-cause death was significant and protective effects in patients with low values of serum phosphate gradually faded for higher phosphate levels >5 mg/dl. A similar lack of statin treatment efficacy for both outcomes was observed with high baseline phosphate levels (>5 mg/dl). In the 4D trial, we found a comparable but not significant trend toward losing treatment efficacy in the presence of high serum phosphate levels for both outcomes. CONCLUSIONS: Our results demonstrated the limited treatment efficacy of statins in patients on dialysis in the presence of hyperphosphatemia. Copyrigh

Combined baseline and one-month changes in big endothelin-1 and brain natriuretic peptide plasma concentrations predict clinical outcomes in patients with left ventricular dysfunction after acute myocardial infarction: Insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study.

OBJECTIVE: Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI. METHODS: In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients. RESULTS: When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint). CONCLUSIONS: Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies. KEY MESSAGES: In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies