Table 1

Studies Evaluating WHF as a Clinical Event

First Author (Ref. #)WHF DefinitionIncident WHF, n/N (%)Follow-Up PeriodEndpointsPredictors
Single centerWeatherley et al. (1)WHF was defined as unresolved or recurrent symptoms and signs of HF that required an increase in or institution of intravenous HF-specific therapy, or institution of mechanical ventilatory or circulatory support.99/337 (29)7 daysAssociated with 6-month mortalityNA
Pooled cohorts from small RCTTorre-Amione et al. (14)Occurrence of new pulmonary edema or cardiogenic shock (investigator-defined); in the first 24 h, no resolution of symptoms and signs of HF despite therapy; or worsening of symptoms and signs of HF despite therapy.50/120 (42)30 daysAssociated with 6-month mortalityCO, MAP, CPO, CPO change, and pacemaker
PROTECT-pilotCotter et al. (13)WHF was a pre-specified endpoint that was evaluated daily by the treating physician on the basis of evaluation of the history, physical examination, laboratory evaluations and patients’ medical records for worsening symptoms and/or signs of HF.29/305 (9.6)7 daysIncreased length of stay, 60-day mortality, cardiovascular/renal rehospitalization, and death or cardiovascular/renal rehospitalizationNA
ADHEREDeVore et al. (12)Initiated inotropic medications or an intravenous vasodilator more than 12 h after hospital presentation, transferred to the intensive care unit, or received advanced medical therapy after the first inpatient day.7,032/63,727 (11)During hospitalizationIncreased 30-day and 1-year mortality, and increased 30-day and 1-year heart failure and all-cause readmissionsNA
VERITASMcMurray et al. (3)The development of pulmonary edema, cardiogenic shock, or other evidence of WHF or as lack of improvement in the patient’s HF with treatment (treatment failure). Both definitions required at least 1 of the following: 1) initiation of new intravenous therapy; 2) reinstitution of previous intravenous therapy; 3) increase in current intravenous therapy for HF; 4) implementation of mechanical circulatory (e.g., intra-aortic balloon pump) or ventilatory (including continuous positive airway pressure) support; or 5) use of ultrafiltration, hemofiltration, or hemodialysis.175/1,435 (12)7 daysNANA
REVIVE I and IIPacker et al. (4)If the patient died; experienced persistent or unresponsive symptoms of HF after the first 24 h of randomized therapy or WHF at any time during the first 5 days, which required a rescue intervention specifically to relieve such symptoms; or considered themselves to have moderately or markedly worsened on global assessment at 6 h, 24 h, or 5 days.124/710 (17)5 daysNANA
PROTECTMassie et al. (5)Worsening symptoms and signs of HF occurring more than 24 h after the initiation of the study drug requiring intervention by day 7 or discharge (if earlier).189/2,033 (9.2)3–7 daysNANA
RELAX-AHFTeerlink et al. (7)Defined as worsening signs or symptoms of HF necessitating intensification of intravenous or mechanical HF treatment.157/1,161 (13)5 daysNANA
DOSE-AHFFelker et al. (8)Defined as the need for rescue therapy (additional open-label loop diuretic, addition of thiazide, IV vasoactive agent for HF treatment, ultrafiltration, mechanical circulatory or respiratory support) over 72 h after randomization.72/299 (24)3 daysNANA
ROSE-AHFChen et al. (10)Defined as the need for rescue therapy (additional intravenous vasoactive agent for HF treatment, ultrafiltration, or mechanical or respiratory support).22/360 (6.1)3 daysNANA

ADHERE = Acute Decompensated Heart Failure National Registry; CO = cardiac output; CPO = coproporphyrinogen oxidase; DOSE-AHF = Diuretic Optimization Strategies Evaluation in Acute Heart Failure; HF = heart failure; IV = intravenous; MAP = mean arterial pressure; NA = not applicable; PROTECT = A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function; RCT = randomized controlled trial; RELAX-AHF = Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure; REVIVE = Evaluation of Intravenous Levosimendan Efficacy in the Short Term Treatment of Decompensated Heart Failure; ROSE-AHF = Renal Optimization Strategies Evaluation in Acute Heart Failure; VERITAS = Value of Endothelin Receptor Inhibition With Tezosentan in Acute Heart Failure; WHF = worsening heart failure.