Mega‐trials in heart failure: effects of dilution in examination of new therapies

Davison, Beth A.; Takagi, Koji; Senger, Stefanie; Koch, Gary G.; Metra, Marco; Kimmoun, Antoine; Mebazaa, Alexandre; Voors, Adriaan A.; Nielsen, Olav Wendelboe; Chioncel, Ovidiu; Pang, Peter S.; Greenberg, Barry; Maggioni, Aldo P.; Cohen‐Solal, Alain; Ertl, Georg; Sato, Naoki; Teerlink, John R.; Filippatos, Gerasimos; Ponikowski, Piotr; Gayat, Étienne; Edwards, Christopher; Cotter, Gad

doi:10.1002/ejhf.1780

Cited by 11 publications

(14 citation statements)

References 62 publications

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“…The currently used definition is a subjective one (worsening symptoms and signs requiring urgent care), which has been an impediment to distinguishing between patients with ‘true’ AHF vs. those with outpatient HF exacerbations not requiring urgent care. This had led to significant problems in enrolling AHF patients in large studies 4 . Second, related to the lack of ability to define AHF, we also know little of its pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

“…Following a series of neutral studies in which new interventions for AHF were not shown in large studies to be associated with improvements in either patients' symptoms or short‐ and long‐term outcomes, 2 some opinion leaders have raised doubt whether AHF is a separate condition or just a part of the natural course of chronic HF 3 . At the same time doubts have been raised that some of the failure in demonstrating positive effects in large AHF studies relates to dilution of the patient population, 4 i.e. that patients enrolled in larger confirmatory studies may not have ‘true’ AHF but have other disorders, chiefly chronic HF that has slightly deteriorated 4 .…”

Section: Introductionmentioning

confidence: 99%

“…At the same time doubts have been raised that some of the failure in demonstrating positive effects in large AHF studies relates to dilution of the patient population, 4 i.e. that patients enrolled in larger confirmatory studies may not have ‘true’ AHF but have other disorders, chiefly chronic HF that has slightly deteriorated 4 . On the one hand some argue that the decision to admit a patient with AHF is subjective and variable and hence HF deterioration managed in the outpatient setting is not a different entity than AHF leading to hospital admission, while others argue that those are different conditions, the latter having a distinct pathophysiological mechanism – associated with inflammatory activation, more congestion, and end‐organ damage 5 .…”

Section: Introductionmentioning

confidence: 99%

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Is acute heart failure a distinctive disorder? An analysis from BIOSTAT‐CHF

Davison

Senger

Sama

et al. 2021

European J of Heart Fail

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Aims This retrospective analysis sought to identify markers that might distinguish between acute heart failure (HF) and worsening HF in chronic outpatients. Methods and results The 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‐month 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 readmission differed substantially between acute HF and worsening HF in chronic outpatients. Carbohydrate antigen 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. Conclusions This 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Is acute heart failure a distinctive disorder? An analysis from BIOSTAT‐CHF

Davison

Senger

Sama

et al. 2021

European J of Heart Fail

Self Cite

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“…This can be largely explained by differences in study design, cardiac, fibrotic and MMP and TIMP outcome as well as the differences between underlying pathology, animal species and strains. Creating a division between hemodynamic and metabolic-driven pathologies allowed us to analyze both overall data and individual underlying pathologies, in line with the heterogeneity of co-morbidities found in HFpEF patients [92,93]. By including more than one comparison for several studies, controls may be over-analyzed which could affect the pooled outcome but to lesser extent the subgroups.…”

Section: Study Limitationsmentioning

confidence: 99%

Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Extracellular Matrix Remodeling during Left Ventricular Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis

Krebber

Dijk

Vernooij

et al. 2020

IJMS

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Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are pivotal regulators of extracellular matrix (ECM) composition and could, due to their dynamic activity, function as prognostic tools for fibrosis and cardiac function in left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF). We conducted a systematic review on experimental animal models of LVDD and HFpEF published in MEDLINE or Embase. Twenty-three studies were included with a total of 36 comparisons that reported established LVDD, quantification of cardiac fibrosis and cardiac MMP or TIMP expression or activity. LVDD/HFpEF models were divided based on underlying pathology: hemodynamic overload (17 comparisons), metabolic alteration (16 comparisons) or ageing (3 comparisons). Meta-analysis showed that echocardiographic parameters were not consistently altered in LVDD/HFpEF with invasive hemodynamic measurements better representing LVDD. Increased myocardial fibrotic area indicated comparable characteristics between hemodynamic and metabolic models. Regarding MMPs and TIMPs; MMP2 and MMP9 activity and protein and TIMP1 protein levels were mainly enhanced in hemodynamic models. In most cases only mRNA was assessed and there were no correlations between cardiac tissue and plasma levels. Female gender, a known risk factor for LVDD and HFpEF, was underrepresented. Novel studies should detail relevant model characteristics and focus on MMP and TIMP protein expression and activity to identify predictive circulating markers in cardiac ECM remodeling.

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“…In this issue of the Journal, Davison et al 7 . theorize that larger and larger trial sizes have led to the ‘dilution of statistical power.’ Furthermore, the lack of success of medical treatments for HFpEF and AHF may be secondary to these trial design decisions.…”

Section: Figurementioning

confidence: 99%