Table 1.

Worsening Heart Failure as a Clinical Trial Endpoint

Trial	Year	Drug	WHF Endpoint	Definition/Time Course/Clinical Events	Treatment
Low dose Tezosentan study8	2004	Tezosentan	Secondary endpoint: Incidence and time to WHF or death up to 30 days after the start of treatment	Persistent signs or symptoms of HF in initial 24 hours of treatment or Recurrent signs of symptoms of HF, pulmonary edema, or cardiogenic shock after initial stabilization with 30 day of randomization	Initiation or increase of IV therapy Implementation of MCS or ventilator
VERITAS I and II12	2007	Tezosentan	Primary endpoint: Death or WHF at 7 days (WHF during admission or after discharge)	Persistent signs or symptoms of HF with treatment or Development of pulmonary edema, cardiogenic shock, or other evidence of WHF	IV treatment for HF (diuretic, vasodilator, or inotrope) Implementation of MCS, ventilator, or CPAP Use of ultrafiltration, hemofiltration, or hemodialysis.
PROTECT Pilot25	2008	Rolofylline	Primary endpoint: Treatment success, treatment failure, or no change in condition	Worsening symptoms or signs of HF occurring > 24 hours after start of study drug to day 7 or discharge, whichever occurred first
PROTECT13	2010	Rolofylline	Primary endpoint: Treatment success, treatment failure, or no change in condition	Death or readmission for HF through day 7 or Worsening symptoms and signs of HF occurring > 24 hours after start of study drug requiring intervention by day 7 or discharge
ASCEND15	2011	Nesiritide	Secondary endpoint: Composite of persistent or WHF and all-cause death	Typical clinical manifestations of worsening heart failure from randomization through hospital discharge	Addition or increase of IV pharmacologic agent Mechanical or surgical intervention Ultrafiltration, hemofiltration, or dialysis
REVIVE17	2013	Levosimendan	Primary endpoint: Characterization of clinical course as improved, unchanged, or worse	Death through day 5 Persistent symptoms of HF from >24 after start of study drug through day 5	Rescue intervention specifically to relieve HF symptoms or Moderately or markedly worsened global assessment at 6 h, 24 h, or 5 days.
Pre-RELAX36	2009	Serelaxin	Exploratory endpoint: In-hospital WHF from baseline to day 5	Physician-determined assessment on the basis of worsening symptoms or signs of HF	Addition or institution of IV medications or mechanical support to treat acute HF
RELAX-AHF19	2013	Serelaxin	Additional endpoint: Time to WHF through day 5 and through day 14	Worsening signs or symptoms of HF	Institution or uptitration of IV therapy (furosemide, nitrates, other HF medications) Institution of MCS or ventilatory support
DOSE16	2011	Furosemide	Secondary endpoint: Worsening or persistent heart failure	Need for rescue therapy within 72 hours from randomization	Additional loop diuretic, addition of thiazide, IV vasoactive agent for HF Ultrafiltration MCS or respiratory support
ROSE-AHF20	2013	Dopamine or Nesiritide	Secondary endpoint: Worsening or persistent heart failure	Need for rescue therapy within 72 hours from randomization	Additional IV vasoactive agent for HF Ultrafiltration MCS or respiratory support
BLAST-AHF21 ClinicalTrials.gov NCT01966601	Ongoing	TRV027	Composite primary endpoint: Time from randomization to WHF through day 5	Worsening signs or symptoms of HF during hospitalization, or rehospitalization for HF after discharge	Intensification of IV therapy including loop diuretics, nitrates, or other medications for HF MCS or ventilator support (including CPAP/BiPAP if used for HF).
TRUE-AHF22 ClinicalTrials.gov NCT01661634	Ongoing	Ularitide	Co-primary endpoint: Improvement in a clinical composite including WHF	Persistent or worsening HF requiring an intervention	Initiation or intensification of IV therapy MCS or ventilatory support, surgical intervention, ultrafiltration, hemofiltration, or dialysis

Abbreviations: CPAP continuous positive airway pressure, HF heart failure, IV intravenous, MCS mechanical circulatory support, WHF worsening heart failure