Slawsky 2000.

Study characteristics
Methods	Study design: multicentre, 2‐arm parallel group RCT (USA) Recruitment period: ‐ Follow‐up: 6 h
Participants	n = 146 (randomised), n = 146 (enrolled) Inclusion criteria: systolic left ventricular dysfunction (ejection fraction ≤ 30% documented by echocardiogram or radionuclide ventriculogram in the proceeding 6 months); symptoms of NYHA class III or IV; decompensated heart failure; treatment with diuretics and ACE inhibitors Exclusion criteria: significant ischaemic heart disease (angina‐limited exercise or unstable angina); documented AMI within the previous 8 weeks; uncorrected primary stenotic valve disease; uncorrected thyroid disease; obstructive cardiomyopathy; pericardial disease; amyloidosis; active myocarditis; malfunctioning artificial heart valve; symptomatic primary pulmonary disease; obstructive pulmonary disease requiring long‐term treatment with β‐agonists, theophylline or corticosteroids; serious arrhythmias defined as a history of ventricular flutter or fibrillation other than occurring within 24 h after acute AMI; history of sudden cardiac death or symptomatic ventricular tachycardia within 3 months before study entry (patients with a history of symptomatic ventricular tachycardia or cardiac arrest who had implantable defibrillators that had not discharged within the preceding 6 months were allowed in the study); resting HR > 115 bpm for at least 10 min on repeated measurements; second‐ or third‐degree atrioventricular block unless the patient had a functioning implanted pacemaker; supine SBP < 85 mmHg or > 200 mmHg; primary renal or hepatic impairment (creatinine > 2.5 mg/dL or aspartate aminotransferase/alanine aminotransferase > 2 times upper limit of normal); uncorrected hypokalaemia or hyperkalaemia (potassium < 3.5 mmol/L or > 5.5 mmol/L); treatment with another investigational agent within 30 days before study entry LCOS definition: CI ≤ 2.5 L/min/m2; PCWP ≥ 15 mmHg Characteristics: (levosimendan/placebo, mean ± SEM) Age (years): 58 ± 1/56 ± 2 Sex (male, %): 81/83 Diabetes (%): ‐ Hypertension (%): ‐ Smoker (%): ‐ Prior AMI/vascular intervention (%): ‐ MAP (mmHg): 84 ± 2/84 ± 2 HR (bpm): 80 ± 2/84 ± 2 SBP (mmHg): ‐ DBP (mmHg): ‐ CI (L/min/m2): 1.8 ± 0.1/1.9 ± 0.1 PCWP (mmHg): 27 ± 1/28 ± 1 LVEF (%): 21 ± 1/20 ± 1 SVR (dyne.s/cm5): 1753 ± 65/1621 ± 92 Timetable: treatment for 6 h; observation at 0/1/2/3/4/6 h
Interventions	Levosimendan (n = 98): bolus of 6 µg/kg followed by a continuous infusion initially at a rate of 0.1 µg/kg/h; at hourly intervals a repeated bolus (6 µg/kg) was given and the infusion rate was increased by increments of 0.1 µg/kg; up‐titration was continued until a maximum rate of 0.4 µg/kg/min was achieved or a dose‐limiting event occurred (HR > 130 bpm or an increase in HR of > 15 bpm above baseline for 10 min; symptomatic hypotension or a drop in SBP to < 75 mmHg; decrease in PCWP to ≤ 10 mmHg; any adverse event that in the opinion of the site investigator required drug dose modification); if a dose‐limiting event occurred the study drug was discontinued until the event resolved and was then restarted at the next lower dose. Placebo (n = 48): no information given Concomitant medication: amiodarone Concomitant intervention: ‐ Intervention before baseline: ACE inhibitors/digoxin at stable doses; diuretics; nitrates; antiarrhythmics; calcium channel blockers; beta blockers
Outcomes	Primary: proportion of participants with an increase in stroke volume or a decrease in PCWP of ≥ 25% at 6 h Secondary: change in stroke volume and PCWP over time; change in the symptoms of dyspnoea or fatigue Safety: adverse events
Notes	Funding: no potential conflict of interest reported Contact: W.S Colucci (mail: Wilson.colucci@bmc.org) Trial registration: ‐ Other: ‐
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information provided
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding was performed for the duration of haemodynamic measurements and symptoms evaluation.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding was opened at 6 h after haemodynamic measurements and the symptom evaluation was completed.
Incomplete outcome data (attrition bias) All outcomes	High risk	Exclusion of 4 (levosimendan group) and 2 (placebo group) participants due to (1) failure to respond, (2) increased pulmonary congestion and decreased cardiac output, (3) increase in HR ≥ 15 bpm, (4) throat pain with ischaemic ECG changes, (5) worsening clinical condition; no data reported for these participants.
Selective reporting (reporting bias)	Low risk	Pre‐planned endpoints were reported.
Other bias	High risk	Cross‐over: no Baseline differences: no Influence of interim results on the conduct of the study: no Deviation from study protocol: no Inappropriate administration of an intervention: yes (in 10 participants from levosimendan group up‐titration was ended because of dose‐limiting events, investigator judgement or by mistake) Contra‐active or similar supporting pre‐randomisation intervention: yes (ACE inhibitors/digoxin at stable doses; diuretics; nitrates; antiarrhythmics; calcium channel blockers; beta blockers)
Adverse effects	Low risk	Definitions of AEs given: no Monitoring of AEs: report of adverse events within 6 h Participants excluded from AE analysis: no Numerical data by intervention: yes