OPTIME CHF | SURVIVE | VERITAS | EVEREST | PROTECT | ASCEND-HF | RELAX-AHF | |
---|---|---|---|---|---|---|---|
Clinicaltrials.gov Identifier | NK | NCT00348504 | NCT00525707 and NCT00524433 | NCT00071331 | NCT00328692 and NCT00354458 | NCT00475852 | NCT00520806 |
Enrolment period | July 1997–November 1999 | March 2003–December 2004 | April 2003–January 2005 | October 2003–February 2006 | May 2007–January 2009 | May 2007–August 2010 | October 2009–February 2012 |
Randomised treatments | Milrinone: 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 HF | Yes* | NR | NR | Yes† | Yes‡ | NR | NR |
Time from presentation to randomisation, hours | <48 | NR | <24 | <48 | <24 | <48 | <16 |
LVEF, % | <40 | ≤30 | <40 | ≤40 | NR | <40 | Any LVEF |
Dyspnoea requirements | Incorporated into ‘HF score’§ | At rest | At rest+RR ≥24/min | At rest or with minimal exertion¶ | At rest or with minimal exertion | At rest or with minimal activity | At 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 Hg | Pulmonary congestion on CXR+BNP ≥350 pg/mL (or NT-proBNP ≥1400 pg/mL) |
IV diuretic required before randomisation | No | No | Yes | No | Yes | No | Yes |
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 | >3.5 | NR | NR | NR |
eGFR, mL/min/1.73 m2 | NR | NR | NR | NR | <20 or >80 mL/min CC | NR | <30 or >75 |
Vasopressors/inotropes | Both | Inotropes** | None | None | Both | Both†† | Both |
Acute MI/ACS | Evidence of unstable angina, myocardial ischaemia, or MI within 3 months | NR | STEMI; On-going myocardial ischaemia or PCI/CABG during current admission | STEMI at time of hospitalisation | Evidence of ACS in 2 weeks before screening | ACS as primary diagnosis; ECG with new ST-elevation >1 mm in 2 consecutive leads | Diagnosis 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 therapy | All-cause mortality in the 180 days after therapy | Change from baseline in dyspnoea over 24 h after therapy; Incidence of death or worsening HF at day 7 | Composite score of changes from baseline in global clinical status and body weight at day 7 or discharge | Treatment success, treatment failure or no change in the patient's condition | Change in dyspnoea 6 and 24 h after therapy; rehospitalisation for HF and all-cause death after therapy to day 30 | Change 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 therapy | All-cause mortality during the 31 days following therapy; mean change in plasma BNP level from baseline to 24 h | Incidence of death or major CV events at 30 days; length of initial hospital admission | Changes in dyspnoea at day 1 from baseline; global clinical status at day 7 or discharge | All-cause death and rehospitalisation for CV or renal causes through day 60; proportion of patients who developed persistent renal impairment | Self-reported overall well-being, measured 6 and 24 h after therapy; composite of worsening HF and all-cause mortality through index hospitalisation | Rate 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 I | REVIVE II | DOSE | CARRESS | ROSE | |
---|---|---|---|---|---|
Clinicaltrials.gov Identifier | NCT00048425 | NCT00048425 | NCT00577135 | NCT00608491 | NCT01132846 |
Enrolment period | December 2001–December 2004 | December 2001–December 2004 | March 2008–November 2009 | June 2008–January 2012 | September 2010–March 2013 |
Randomised treatments | Levosimendan: 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 HF | No | No | Yes‡ | No | No |
Time from presentation to randomisation, hours | ≤48 | NR | ≤24 | ≤168 | ≤24 |
LVEF, % | ≤35 | ≤35 | NR | NR | NR |
Dyspnoea requirements | At rest | At rest | Rest/exertion | NR | NR |
Other evidence of HF (including symptoms, signs and objective measures) | Can enrol >48 h if deteriorates after initial improvement with conventional therapy | Persisting dyspnoea at rest despite IV diuretic therapy | 1 symptom and 1 sign of HF daily oral furosemide dose ≥80 ≤240 mg | Increase creatinine >0.3 mg/dL ≥2+peripheral oedema, JVP >10 cm, radiological pulmonary congestion/oedema | eGFR ≥15 ≤60 mL/min/1.73 m2 At least 1 sign and symptom of HF |
IV diuretic required before randomisation | Yes | Yes | Yes | Yes | NR |
Exclusion criteria | |||||
Systolic BP, mm Hg | ≤90 | ≤90 | <90 | <90 | <90 |
Serum creatinine, mg/dL | >5.0 | >5.0 | >3.0 | >3.5 | NR |
eGFR, mL/min/1.73 m2 | NR | NR | NR | NR | <15 or >60 |
Vasopressors/inotropes | None | PDE V inhibitors | Both | Both | Both |
Acute MI/ACS | Angina in 6 h before randomisation | Angina in 6 h before randomisation | ACS within 4 weeks | ACS within 4 weeks | ACS 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) |
| Bivariate change in weight/change in creatinine (96 h) |
| |
Secondary end point(s)‡‡ | |||||
Change in BNP at 24 h Change in PGA at 6 h Change in dyspnoea at 6 h DAOH 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 DAOH 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.