Physicians' Academy for Cardiovascular Education

Worsening heart failure associated with higher risk of morbidity and mortality in PROTECT study

Mallick A et al., J Am Coll Cardiol HF 2016

The Importance of Worsening Heart Failure in Ambulatory Patients
Definition, Characteristics, and Effects of Amino-Terminal Pro-B Type Natriuretic Peptide Guided Therapy

Mallick A, Gandhi PU, Gaggin HK, et al.
J Am Coll Cardiol HF 2016; published online ahead of print


Despite the significant advances in the diagnosis and management, heart failure HF is associated with high morbidity and mortality [1,2]. Reasons for that encompass the complex underlying pathophysiology, as well as the heterogeneous and often unpredictable manifestations and outcomes [3]. Although the identification of HF has been improved with the introduction of prognostic biomarkers and implantable hemodynamic monitoring, the clinical history and physical examination remain important and less developed in this setting [4,5].
Worsening HF may be a predictor of unfavourable prognosis and is used as an inclusion criterion and endpoint in clinical trials. However, there is no standardised definition or evidence-based treatment for it [6-8].
In this study, the hypothesis of the association between worsening HF and adverse outcomes was tested, by analysing data from 151 symptomatic patients with chronic HFrEF in the PROTECT study, in which worsening HF was strictly and prospectively defined as follows [9]: new or progressive symptoms and/or signs of decompensated HF and unplanned intensification of diuretic therapy. Moreover, it was assessed whether biomarker-guided (NT-proBNP) therapy would improve worsening HF.

Main results

Over a mean follow-up of 10 months, 45 subjects developed worsening HF. At baseline, patients developing worsening HF:
  • had higher EF (31% vs. 25%; P = 0.03)
  • were more likely to have jugular venous distension and edema (P < 0.02)
  • were less likely to receive ACE inhibitors or received these agents at lower doses (P < 0.04)
  • received higher loop diuretic doses (P < 0.001)
  • had worse renal function (estimated glomerular filtration rate 50.2 ml/min/m2 vs. 63.7 ml/min/m2; P < 0.001)
  • had higher concentrations of known prognostic markers, including NT-proBNP, hsTnT, sST2, and galectin-3 (all P < 0.05)
Only log-transformed sST2 and higher baseline LVEF were significant predictors in a multivariate logistic regression analysis (HR: 4.6, 95% CI 2.4-8.8, p < 0.001 resp. HR: 3.1, 95% CI 1.1-8.7, p = 0.03).
Patients with worsening HF had a significantly higher rate of subsequent HF hospitalisation compared with patients without: 53% vs. 1%; P < 0.001
Worsening HF was strongly associated with subsequent HF hospitalisation/cardiovascular death: landmark analysis HR: 18.8; 95% CI: 5.7 - 62.5; P < 0.001
NT-proBNP-guided therapy:
  • Frequency of worsening HF: 23% of NT-proBNP-guided patients compared with 37% of patients in the standard-of-care arm (HR: 0.50, 95% CI 0.25-1.0, p=0.06)
Incidence of worsening HF: NT-proBNP–guided care reduced the incidence in adjusted analyses (HR: 0.52; P = 0.04, log-rank p=0.03)


In symptomatic patients with chronic HFrEF, worsening HF was common, and was associated with substantial risk for HF hospitalisation and CV death, suggesting that worsening HF may be useful to identify patients at higher risk for these adverse outcomes. NT-proBNP–guided care reduced the risk of worsening HF. Elevated sST2 serum concentrations and higher baseline LVEF were independent predictors of worsening HF.
Find this article online at JACC HF


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