Table 1

Comparison of key inclusion/exclusion criteria and end points

OPTIME CHFSURVIVEVERITASEVERESTPROTECTASCEND-HFRELAX-AHF IdentifierNKNCT00348504NCT00525707 and NCT00524433NCT00071331NCT00328692 and NCT00354458NCT00475852NCT00520806
Enrolment periodJuly 1997–November 1999March 2003–December 2004April 2003–January 2005October 2003–February 2006May 2007–January 2009May 2007–August 2010October 2009–February 2012
Randomised treatmentsMilrinone: placebo (1:1)Levosimendan: dobutamine (1:1)Tezosentan: placebo (1:1)Tolvaptan: placebo (1:1)Rolofylline: placebo (2:1)Nesiritide: placebo (1:1)Serelaxin: placebo (1:1)
Inclusion criteria
 Age, years≥18≥18≥18≥18≥18≥18≥18
 Required history of HFYes*NRNRYes†Yes‡NRNR
 Time from presentation to randomisation, hours<48NR<24<48<24<48<16
 LVEF, %<40≤30<40≤40NR<40Any LVEF
 Dyspnoea requirementsIncorporated into ‘HF score’§At restAt rest+RR ≥24/minAt rest or with minimal exertion¶At rest or with minimal exertionAt rest or with minimal activityAt rest or with minimal exertion
 Other evidence of HF (including symptoms, signs and objective measures)≥3/10 on ‘HF score’§Insufficient response to IV diuretics and/or VD+ ≥1 of: dyspnoea at rest or mechanical ventilation for HF; oliguria not due to hypovolaemia; PCWP ≥18 mm Hg and/or cardiac index ≤2.2 L/min/m2≥2 of: elevated BNP or NT-proBNP; clinical evidence of pulmonary congestion/oedema; pulmonary congestion on CXR; LVSD (EF <40% or wall motion index ≤1.2)≥2 of: dyspnoea; jugular venous distension; pitting oedema (>1+)Requiring IV diuretic therapy+≥1 of: JVP >8 cm; pulmonary rales ≥1/3 above base; peripheral oedema (≥2+); pre-sacral oedema≥1 of: RR ≥20/min; pulmonary rales ≥1/3 above base+≥1 of pulmonary congestion on CXR; BNP ≥400 pg/mL (or NT-proBNP ≥1000); EF <40%; PCWP >20 mm HgPulmonary congestion on CXR+BNP ≥350 pg/mL (or NT-proBNP ≥1400 pg/mL)
 IV diuretic required before randomisationNoNoYesNoYesNoYes
Exclusion criteria
 Systolic BP, mm Hg<80 or >150<85<100 (or <120 if after VD)<90<90 or ≥160<100 (or <110 if after VD) or >180≤125
 Serum creatinine, mg/dL>3.0>5.0≥2.5>3.5NRNRNR
 eGFR, mL/min/1.73 m2NRNRNRNR<20 or >80 mL/min CCNR<30 or >75
 Acute MI/ACSEvidence of unstable angina, myocardial ischaemia, or MI within 3 monthsNRSTEMI; On-going myocardial ischaemia or PCI/CABG during current admissionSTEMI at time of hospitalisationEvidence of ACS in 2 weeks before screeningACS as primary diagnosis; ECG with new ST-elevation >1 mm in 2 consecutive leadsDiagnosis of ACS<45 days before screening; troponin >3 times upper limit of normal
Primary end point(s)
Cumulative days of hospitalisation for CV cause within 60 days after therapyAll-cause mortality in the 180 days after therapyChange from baseline in dyspnoea over 24 h after therapy; Incidence of death or worsening HF at day 7Composite score of changes from baseline in global clinical status and body weight at day 7 or dischargeTreatment success, treatment failure or no change in the patient's conditionChange in dyspnoea 6 and 24 h after therapy; rehospitalisation for HF and all-cause death after therapy to day 30Change in dyspnoea from baseline to day 5; moderately or markedly improved dyspnoea from baseline at 6, 12 and 24 h
Secondary end point(s)‡‡
Proportion of treatment failures due to adverse events 48 h after therapy; proportion of patients achieving target doses of ACE-inhibitor therapyAll-cause mortality during the 31 days following therapy; mean change in plasma BNP level from baseline to 24 hIncidence of death or major CV events at 30 days; length of initial hospital admissionChanges in dyspnoea at day 1 from baseline; global clinical status at day 7 or dischargeAll-cause death and rehospitalisation for CV or renal causes through day 60; proportion of patients who developed persistent renal impairmentSelf-reported overall well-being, measured 6 and 24 h after therapy; composite of worsening HF and all-cause mortality through index hospitalisationRate of combined end point of CV death or rehospitalisation for HF or renal failure to day 60; days alive and out of hospital to day 60
REVIVE IREVIVE IIDOSECARRESSROSE IdentifierNCT00048425NCT00048425NCT00577135NCT00608491NCT01132846
Enrolment periodDecember 2001–December 2004December 2001–December 2004March 2008–November 2009June 2008–January 2012September 2010–March 2013
Randomised treatmentsLevosimendan: placebo (1:1)Levosimendan: placebo (1:1)High-/low dose diuretic IV bolus/IV infusion diuretic (2×2 factorial)Ultrafiltration medical therapy (1:1)Dopamine: nesiritide: placebo (1:1:1)
Inclusion criteria
 Age, years>18>18≥18≥18≥18
 Required history of HFNoNoYes‡NoNo
 Time from presentation to randomisation, hours≤48NR≤24≤168≤24
 LVEF, %≤35≤35NRNRNR
 Dyspnoea requirementsAt restAt restRest/exertionNRNR
 Other evidence of HF (including symptoms, signs and objective measures)Can enrol >48 h if deteriorates after initial improvement with conventional therapyPersisting dyspnoea at rest despite IV diuretic therapy1 symptom and 1 sign of HF daily oral furosemide dose ≥80 ≤240 mgIncrease creatinine >0.3 mg/dL ≥2+peripheral oedema, JVP >10 cm, radiological pulmonary congestion/oedemaeGFR ≥15 ≤60 mL/min/1.73 m2 At least 1 sign and symptom of HF
 IV diuretic required before randomisationYesYesYesYesNR
Exclusion criteria
 Systolic BP, mm Hg≤90≤90<90<90<90
 Serum creatinine, mg/dL>5.0>5.0>3.0>3.5NR
 eGFR, mL/min/1.73 m2NRNRNRNR<15 or >60
 Vasopressors/inotropesNonePDE V inhibitorsBothBothBoth
 Acute MI/ACSAngina in 6 h before randomisationAngina in 6 h before randomisationACS within 4 weeksACS within 4 weeksACS within 4 weeks
Primary end point(s)
Improved/unchanged/worse composite (24 h and 5 days) Clinical composite (6 h, 24 h and 5 days)
  1. Patient global assessment (VAS AUC) at 72 h

  2. change in Cr at 72 h (safety)

Bivariate change in weight/change in creatinine (96 h)
  1. Cumulative urine volume (72 h)

  2. change cystatin C (72 h)

Secondary end point(s)‡‡
Change in BNP at 24 h
Change in PGA at 6 h
Change in dyspnoea at 6 h
Death or worsening HF
NYHA class (day 5)
Mortality (90 day)
Change in BNP at 24 h
Change in PGA at 6 h
Change in dyspnoea at 6 h
Death or worsening HF
NYHA class (day 5)
Mortality (90 day)
Patient dyspnoea report
Change in body weight
Net fluid loss
Proportion of patients congestion free (72 h)
Increase serum Cr >0.3 mg/dL (72 h)
Worsening/persistent HF
Change in biomarkers (72 h/7 days/60 days)
Death/hosp/ER visit (day 60)
Days dead or hospitalised (day 60)
Primary end point days 1–3, day 7
Weight loss and renal function (96 h, 1 week)
Treatment failure (7 days)
Change in renal function (7 days, 30 days, 60 days); peak creatinine
Change in electrolytes (96 h, 1 week)
Change in weight (1 week, 30 days, 60 days)
Proportion with clinical decongestion (96 h, 1 week, 30 days, 60 days)
Total net fluid loss (96 h, 1 week)
Change in biomarkers (96 h, 1 week, 60 days)
Change in global assessment and VAS (96 h, 1 week)
LOS, DAOH, HF hosp, ER visits, unscheduled office visits
Change in diuretic dose from admission (discharge, 30 days, 60 days)
Resource utilisation
Change in Cr (72 h)
Cumulative urinary sodium excretion (72 h)
PGA (72 h)
Dyspnoea (72 h)
Weight (72 h)
Change in BUN/cystatin C ratio (72 h)
Increase in serum Cr >0.3 mg/dL (72 h)
Persistent or worsening HF (72 h)
Treatment failure (72 h)
  • *Prior diagnosis of HF on any oral therapy for same.

  • †A history of CHF (defined as requiring treatment for a minimum of 30d before hospitalisation).

  • ‡A history of HF ≥14 days for which diuretic therapy has been prescribed.

  • §HF Score: dyspnoea (exertional=1 point, nocturnal=2 points, orthopnoea=3 points, rest=4 points)—maximum of four points. HR (91-110 bpm=1 point, >110 bpm=2 points)—maximum of two points. rales (bases only=1 point, >bases=2 points)—maximum of two points. Right heart (JVP >6 cm=1 point, JVP >6 cm with oedema or hepatomegaly=2 points)—maximum of two points.

  • ¶HF symptoms at rest or minimal exertion.

  • **Except dopamine ≤2 μg/kg/min or digitalis during the current hospitalisation.

  • ††Excluded if: received first IV treatment of diuretics, VD or inotropes for HF >24 h before randomisation; treated with levosimendan or milrinone within 30 days before randomisation or anticipated need for these during current hospitalisation; treated with IV vasoactive medication where the dosage is not stable for 3 h before randomisation; treated with dobutamine ≥5 μg/kg/min at the time of randomisation.

  • ‡‡Not exhaustive.

  • ACS, acute coronary syndrome; AHF, acute heart failure; ARB, angiotensin receptor blocker; AUC, area under the curve; ASCEND, acute study of clinical effectiveness of nesiritide in decompensated heart failure; BP, blood pressure; CV, cardiovascular; CABG, coronary artery bypass graft; CHF, heart failure; COPD, chronic obstructive pulmonary disease; CARRES, cardiorenal rescue study in acute decompensated heart failure; CXR, chest x-ray; DAOH, days alive and out of hospital; DOSE, diuretic optimization strategies evaluation; EF, ejection fraction; Egfr, estimated glomerular filtration rate; ER, days alive and out of hospital; EVEREST, the efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan; Hosp, hospital; HF, heart failure; ICD, implantable cardiac defibrillator; IV, intravenous; JVP, jugular venous pressure; LVSD, left ventricular systolic dysfunction; LOS, length of stay; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MRA, mineralocorticoid receptor antagonist; NK, not known; NT, n-terminal; NR, not required; NYHA, new york heart association; OPTIME, the outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure; PDE, phosphodiesterase inhibitor; PCI, percutaneous coronary intervention; PCWP, pulmonary capillary wedge pressure; PGA, patient global assessment; ProBNP, pro b-type natriuretic peptide; PROTECT, placebo-controlled randomised study of the selective A1 adenosine receptor antagonist rolofylline; Pts, patients; STEMI, ST-segment elevation myocardial infarction; SURVIVE, the survival of patients with acute heart failure in need of intravenous inotropic support; RELAX-AHF, the RELAXin in acute heart failure; RR, respiratory rate; REVIVIE, randomized evaluation of intravenous levosimendan efficacy; ROSE, renal optimization strategies evaluation; VAS, visual analogue score; VERITAS, the value of endothelin receptor inhibition with tezosentan in acute heart failure studies; VD, vasodilators.