Physicians' Academy for Cardiovascular Education

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

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


1. Cotter G, Metra M, Weatherley BD, et al. Physician-determined worsening heart failure: a novel definition for early worsening heart failure in patients hospitalized for acute heart failure–association with signs and symptoms, hospitalization duration, and 60-day outcomes. Cardiology 2010; 115:29–36.
2. Metra M, Teerlink JR, Felker GM, et al. Dyspnoea and worsening heart failure in patients with acute heart failure: results from the Pre-RELAX AHF study. Eur J Heart Fail 2010;12:1130–9.
3. Metra M, Cleland JG, Weatherley BD, et al. Dyspnoea in patients with acute heart failure: an analysis of its clinical course, determinants, and relationship to 60-day outcomes in the PROTECT pilot study. Eur J Heart Fail 2010;12:499–507.
4. Torre-Amione G, Milo-Cotter O, Kaluski E, et al. Early worsening heart failure in patients admitted for acute heart failure: time course, hemodynamic predictors, and outcome. J Card Fail 2009;15:639–44.
5. Metra M, O’Connor CM, Davison BA, et al. Early dyspnoea relief in acute heart failure: prevalence, association with mortality, and effect of rolofylline in the PROTECT Study. Eur Heart J 2011;32: 1519–34.
6. Metra M, Cotter G, Davison BA, et al., for the RELAX-AHF Investigators. Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes. J Am Coll Cardiol 2013;61:196–206.
7. Massie BM,O’Connor CM, Metra M, et al., for the PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010;363:1419–28.
8. Cotter G, Dittrich HC, Weatherley BD, et al. The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Card Fail 2008;14:631–40.
9. Teerlink JR, Cotter G, Davison BA, et al., for the RELAX-AHF Investigators. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo controlled trial. Lancet 2013;381:29–39.
10. Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet 2009;373:1429–39.