Physicians' Academy for Cardiovascular Education

Worsening heart failure conveys risk of adverse outcomes, irrespective of severity

Literature - Davison BA et al., JACC Heart Fail. 2015

Worsening Heart Failure Following Admission for Acute Heart Failure: A Pooled Analysis of the PROTECT and RELAX-AHF Studies

Davison BA, Metra M, Cotter G, Massie BM
JACC Heart Fail. 2015 May;3(5):395-403. doi: 10.1016/j.jchf.2015.01.007


For a minority of patients admitted to hospital for acute heart failure (AHF), symptoms are not relieved during hospitalisations. Little is known about factors contributing to lengthy hospital stays, repeat admissions and high mortality in these patients.
Worsening heart failure (WHF) refers to worsening of symptoms and signs of HF that require intensification of intravenous (IV) therapy or initiation of mechanical therapy during hospitalisation for AHF. WHF is associated with adverse outcomes including longer stay in the hospital [1,2], rehospitalisation [1,3] and mortality through 6 months [1, 4-6]. It has been incorporated in the primary efficacy endpoint in several clinical studies of investigational drugs for AHF, including VERITAS, REVIVE, PROTECT and RELAX-AHF. This is a pooled analysis of individual patient (n=3734) data from the PROTECT [7,8] and RELAX-AHF [9,10] studies of AHF to study which patient characteristics and outcomes are associated with WHF.

Main results

  • The strongest multivariable predictors of WHF by day 5 were higher blood urea nitrogen (BUN, HR: 1.78, 95%CI: 1.53-2.09, P<0.0001), respiratory rate (HR: 1.04, 95%CI: 1.02-1.06, P<0.0001), and haematocrit (HR: 1.02, 95%CI: 1.01-1.04, P=0.0042)(C-statistic for the model:  0.67, 95%CI: 0.65-0.70).
  • After multivariable adjustment, the association of WHF with CV death or HF/renal failure (RF) rehospitalisation through day 60 yielded HR: 1.64, 95%CI: 1.34-2.01 (P<0.0001).
  • In the adjusted multivariable model, the HR for the association of WHF with 180-day all-cause mortality was 1.93 (95%CI: 1.55-2.41, P<0.0001).
    This association appeared to decrease over time, as seen by a significant WHF-by-time interaction (P=0.0264). HR was estimated at 2.34 (95%CI: 1.79-3.07) at 30 days, at 2.00 (95%CI: 1.60-2.50) at 60 days, at 1.70 (95%CI: 1.32-2.20) at 90 days, 1.45 (95%CI: 1.03-2.06) at 120 days, and 1.06 (95%CI: 0.59-1.91) at 180 days.
  • Patients in whom WHF was treated with IV loop diuretic alone showed a higher (adjusted HR: 1.80, 95%CI: 1.36-2.36) risk of dying by day 180 as compared with patients who did not experience WHF by day 5. WHF requiring an IV inotrope or mechanical therapy also showed a higher risk (adjusted HR: 3.03, 95%CI: 2.11-4.36), as did WHF treated with other therapy (adjusted HR: 1.23, 95%CI: 0.71-2.16).
  • Larger increases in creatinine and smaller decreases in ALT and AST were seen in patients with, as compared with without WHF.
    Simultaneous adjustment for all laboratory markers weakened the association of WHF with 180-day mortality by 11% from estimated HR: 1.93 to 1.71.
  • Simultaneous adjustment for changes in signs and symptoms of congestion at day 2 hardly affected the association of WHF with CV death or HF/RH rehospitalisation to day 60, but reduced the HR for association with 180-day mortality by 10%, as well as the mean difference in length of stay (-15%).


This study indicates that BUN, a marker of renal dysfunction and hypoperfusion that may also reflect neurohormonal activation in HF, modestly discriminates between patients who develop WHF in the first 5 days of admission and those who do not. Occurrence of WHF in the first 5 days was associated with longer hospital stay, increased CV death risk or HF/RF rehospitalisation at 60 days and about twice the risk of 180-day mortality. Changes in laboratory markers of end-organ damage, worsening metabolic abnormalities or symptoms and signs of HF during the first 2 days of admission only partially explained the increased risks associated with WHF. All types of required therapies conferred a higher mortality risk, albeit to different extents. These data indicate that the occurrence of WHF itself brings about significant risks, irrespective of its severity.
Find this article online at JACC Heart Failure


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