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. Author manuscript; available in PMC: 2016 Oct 1.
Published in final edited form as: Heart Fail Clin. 2015 Aug 11;11(4):603–614. doi: 10.1016/j.hfc.2015.07.004

Table 2.

Observational Studies and Secondary Analyses of Clinical Trials Assessing Worsening Heart Failure

Trial Year Drug WHF Definition Outcome Hazard Ratio (95% Confidence Interval)
PROTECT pilot37 2010 Tezosentan Physician Determined WHF:
Worsening signs and symptoms of HF AND initiation or uptitration of IV treatment or MCS for HF
LOS
60 day CV/RF readmission and death
Mean (SD): WHF vs No WHF 13.8 (6.8) vs 9.3 (5.9)
49.7% vs 19.5% in patients without WHF
PROTECT27 2011 Rolofylline Worsening signs and symptoms of HF with resulting intensification of IV therapy for HF or MCS or ventilator support 14 day all-cause mortality
30 day all-cause mortality
6.84 (4.12, 11.35)
4.78 (3.10, 7.37)
PROTECT30 2015 Rolofylline Worsening signs and symptoms of HF with resulting intensification of therapy: high intensity therapy: initiation of inotropes, vasopressors and inodilators; MCS, ventilator support, and ultrafiltration
low intensity therapy: restarting/increasing diuretics or initiating vasodilators without high intensity interventions
60 day CV/RF rehospitalization and death
60 day all-cause rehospitalization or death
180 day all-cause mortality
60 day CV/RF rehospitalization and death
60 day all-cause rehospitalization or death
180 day all-cause mortality
1.54(1.22, 1.95), p<0.001
1.55(1.25, 1.93) , p<0.001
2.46 (1.87, 3.25) , p<0.001
High vs Low intensity 1.41 (0.88, 2.26), p=0.15
1.32 (0.85, 2.05), p=0.22
1.55 (0.93, 2.60), p=0.096
Pre RELAX-AHF28 2010 Serelaxin Worsening signs or symptoms of HF requiring the increase or re-institution of IV therapy or MCS for HF 60 day HF/RF readmission or death
30 day all-cause mortality
60 day CV mortality
60 day all-cause mortality
180 day CV death
3.93 (1.72-8.98), p=0.001
7.70 (1.72-34.41), p=0.008
4.56 (1.02-20.20), p=0.05
3.76 ( 1.23-11.50), p=0.02
6.04 (1.75-20.87), p=0.004
RELAX-AHF38 2013 Serelaxin Worsening signs or symptoms of HF requiring reinstitution or intensification of IV therapy or MCS for HF 180 day all-cause mortality 1.90 (1.11-3.22), p=0.016
PROTECT and RELAX-AHF29 2015 Physician assessment of worsening signs or symptoms of HF requiring intensification of IV therapy or MCS
The treatment required was categorized as IV loop diuretic alone, IV inotrope (e.g., dobutamine, norepinephrine, levosimendan, phenylephrine) or mechanical therapy (e.g., mechanical ventilation, MCS, ultrafiltration), or other treatment (e.g., IV nitrates, nesiritide, nonloop diuretic)
60 day HF/RF rehospitalization or CV death
180 day all-cause mortality
2.19 (1.80-2.67), p=0.58
2.61 (2.20-3.10, p = 0.45
VERITAS26 2014 Tezosentan WHF could occur during the index admission or after discharge.
In-hospital: either: (i) the development of pulmonary edema, cardiogenic shock, or other evidence of WHF; or (ii) failure of the patient's HF condition to improve with treatment (treatment failure)
Required at least one of the following: (i) initiation of new IV therapy; (ii) re-institution of prior IV therapy; (iii) increase in current IV therapy for HF; (iv) implementation of MCS or ventilatory support; or (v) use of ultrafiltration, hemofiltration, or hemodialysis.
LOS
30 day HF rehospitalization or death
90 day mortality
4.33 (3.54-5.13), p<0.001
2.45 (1.75-3.40), p<0.001
2.57 (1.81-3.65), p<0.001
ADHERE31 2014 Registry Any of the following criteria: initiated inotropic medications or an IV vasodilator more than 12 hours after hospital presentation, were transferred to the ICU, or received advanced medical therapy after the first inpatient day. 30 day mortality
1 year mortality
30 day all-cause readmission
1 year all-cause readmission
30 day HF readmission
1 year HF readmission
30 day Medicare payments
1 year Medicare payments
Hazard Ratio (99% CI)
2.78 (2.55-3.04), p<0.001
1.84 (1.75-1.93), p<0.001
1.47 (1.35-1.59), p<0.001
1.27 (1.21-1.34), p<0.001
1.62 (1.43-1.84), p<0.001
1.36 (1.26-1.47), p<0.001
Cost Ratio (99% CI) 1.70 (1.57-1.84), p<0.001
1.43 (1.37-1.49), p<0.001
ASCEND7 2015 Nesiritide At least 1 sign, symptom, or radiologic evidence of new, persistent, or worsening acute HF requiring addition of a new IV therapy (inotrope or vasodilator) or mechanical support during index hospitalization targeted specifically at HF symptoms. 30 day all-cause mortality or HF hospitalization
30 day all-cause mortality
180 day all-cause mortality
8.43 (6.70-10.60), p<0.001
16.56 (12.58-21.79), p<0.001
5.05 (4.23-6.03), p<0.001
ADHERE6 2015 Registry Any of the following criteria: use of IV inotropes or vasodilators; mechanical support including ventilator, dialysis, IABP or LVAD; or an ICU stay during the index hospitalization
Early WHF: occurred during day 1 of hospitalization
Late WHF: occurred after day 1 of hospitalization
Early WHF vs Late WHF
30 day mortality
1 year mortality
30 day all-cause readmission
1 year all-cause readmission
30 day HF readmission
1 year HF readmission
30 day Medicare payments
1 year Medicare payments
Hazard Ratio (99% CI)
0.69 (0.57-0.83), p<0.001
0.84 (0.75-0.94), p<0.001
1.04 (0.91-1.20), p=0.44
1.08(1.01-1.16), p=0.003
0.95 (0.75-1.19), p=0.54
0.99 (0.86-1.13), p=0.81
Cost Ratio (99% CI) 1.09(0.94-1.28), p=0.14
1.26 (1.16-1.37), p<0.001

Abbreviations: CPAP continuous positive airway pressure, HF heart failure, IABP intra-aortic balloon pump, ICU intensive care unit, IV intravenous, LVAD left ventricular assist device, MCS mechanical circulatory support, RF renal failure, WHF worsening heart failure