Table 2.

Results of clinical trials involving positive inotropes in heart failure with reduced ejection fraction

Clinical trial	Comparator groups	Year	No. patients	Key inclusion criteria	Results
Amrinone Multicenter Trial40	Amrinone vs. placebo	1985	99	NYHA class III–IV, LVEF ≤ 40%	↑ Adverse events
Xamoterol in Severe Heart Failure41	Xamoterol vs. placebo	1990	516	LVEF < 35%, NYHA class III–IV	↑ Morbidity
PROMISE42	Milrinone vs. placebo	1991	1008	LVEF ≤ 35%, NYHA class III–IV	↑ Morbidity and mortality
PICO43	Pimobendan	1996	317	NYHA class II–III, LVEF ≤ 45%	↑ Exercise tolerance, ↑ mortality
PRIME II44	Ibopamine	1997	1906	NYHA class III–IV, LVEF < 35%	↑ Mortality
VEST45	Vesnarinone	1998	3833	LVEF ≤ 30%, NYHA class III–IV	Dose‐dependent ↑mortality (potentially arrhythmias)
FIRST46	Dobutamine	1999	471	NYHA class IIIB–IV; LVEF < 30%	↑ Mortality
DICE47	Intermittent dobutamine vs. placebo	1999	38	NYHA class III–IV, cardiac index ≤2.2 L/min/m2, and LVEF ≤ 30%	No improvement in functional status
OPTIME‐CHF48	Milrinone	2002	951	ADHF with LVEF < 40%	↑ Adverse events, equivalent mortality
LIDO49	Levosimendan vs. dobutamine	2002	203	ADHF with LVEF < 35%, CI < 2.5 L/min/m2, PCWP > 15 mmHg	↑ Haemodynamics, ↓ mortality with levosimendan
RUSSLAN50	Levosimendan vs. placebo	2002	504	LV failure complicating AMI	Low‐dose levosimendan reduced the risk of worsening HF
SURVIVE51	Levosimendan vs. dobutamine	2007	1327	ADHF with LVEF ≤ 30%	↓ BNP with levosimendan but no impact on clinical outcomes
EMOTE52	Enoximone	2007	201	NYHA class IV, inotrope dependence, LVEF ≤ 25%	No difference is ability to wean patients off inotropes at 30 days
Enoximone Clinical Trials Program14, 53	Enoximone	2009	1854	NYHA class III–IV, LVEF ≤ 35% (two trials)	No difference in mortality, CV hospitalizations, 6MWD, patient global assessment
HORIZON‐HF32	Istaroxime	2008	120	ADHF with LVEF ≤ 35%	↓ PCWP, ↑ SBP, and ↓ diastolic stiffness
CUPID 234	SERCA2a gene	2016	250	Chronic HF, NYHA class II–III, LVEF ≤ 35%, NT‐proBNP > 1200 pg/mLa	No difference in time to recurrent events
REVIVE54	Levosimendan	2013	700	ADHF with LVEF ≤ 35%	↓ HF symptoms, ↑ risk of adverse CV events and 14‐day mortality
ATOMIC‐AHF55	Omecamtiv mecarbil	2016	606	ADHF with LVEF ≤ 40%, BNP > 400 pg/mL or NT‐proBNP > 1600 pg/mLa	No difference in dyspnoea endpoint, ↑ SET, ↓ LVESD, ↑ troponin
COSMIC‐HF56	Omecamtiv mecarbil	2016	448	Chronic HF, NYHA class II–III, LVEF ≤ 40%, NT‐proBNP ≥ 200 pg/mLa	↑ SET, ↑ SV, ↓ LVESD, ↓ LVEDD, ↓ NT‐proBNP
PROFILE57	Flosequinan	2017	2354	NYHA class III–IV, LVEF ≤ 35%	↑ Exercise tolerance, ↑ mortality

6MWD, 6‐min walk distance; ADHF, acute decompensated heart failure; AMI, acute myocardial infarction; BNP, B‐type natriuretic peptide; CI, cardiac index; CV, cardiovascular; HF, heart failure; LV, left ventricular; LVEDD, left ventricular end‐diastolic dimension; LVEF, left ventricular ejection fraction; LVESD, left ventricular end‐systolic dimension; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; PCWP, pulmonary capillary wedge pressure; SBP, systolic blood pressure; SET, systolic ejection time; SV, stroke volume.

^aDifferent cut‐points for atrial fibrillation.