Husebye 2013.

Study characteristics
Methods	Study design: single‐centre, 2‐arm parallel group RCT (Norway) Recruitment period: April 2006 – December 2010 Follow‐up: 6 months
Participants	n = 61 (randomised), n = 61 (enrolled; subgroup of n = 9 with CS) Inclusion criteria: acute STEMI complicated with clinically heart failure within 48 h after percutaneous coronary intervention (PCI) (signs of decreased wall motion in at least 3 of 16 segments of the left ventricle; dyspnoea at rest at screening and at least one of the following signs: pulmonary oedema, signs of marked pulmonary congestion on chest X‐ray, need for continuous positive airway pressure or mechanical ventilation, need for intravenous diuretics due to symptoms of congestion or persistent oliguria after volume therapy); included a subgroup of participants with CS Exclusion criteria: age < 20 years; heart rate > 120 bpm; septic shock; acute respiratory distress syndrome; creatinine > 450 µmol/L; severe hepatic failure; significant mechanical outflow obstruction; allergy against study medication or one of its components; anaemia (haemoglobin < 8 g/dL), pregnancy CS definition: SBP < 90 mmHg after 60 min of adequate volume therapy or SBP between 90 and 100 mmHg in spite of inotropic support by catecholamine infusion; signs of organ hypoperfusion (oliguria, cold and clammy extremities, reduced consciousness) Characteristics: (levosimendan/placebo, median with IQR) Age (years): 66 (56 – 74)/62 (56 – 74) Sex (male, %): 60/81 Diabetes (%): 17/3 Hypertension (%): 33/36 Smoker (%): 41/33 Prior AMI (%): 23/13 MAP (mmHg): 78 (72 – 85)/80 (73 – 84) HR (bpm): ‐ SBP (mmHg): 102 (93 – 114)/107 (93 – 115) DBP (mmHg): 67 (59 – 72)/66 (58 – 70) CI (L/min/m2): ‐ PCWP (mmHg): ‐ LVEF (%): 43 (38 – 49)/40 (33 – 47) SVRI (dyne.s/cm5/m2)/SVR (dyne.s/cm5): ‐ Timetable: treatment for 25 h; observation at 0/25 h, 5/42 days and 6 months
Interventions	Levosimendan (n = 30; subgroup of 4 with CS): 0.2 µg/kg/min for 1 h followed by 0.1 µg/kg/min for 24 h Placebo (n = 31; subgroup of 5 with CS): infusion for 25 h matching size, colour of solution and packaging Procedure in case of hypotension: volume therapy given according to the clinicians` decision; if SBP dropped < 80 mmHg or MAP dropped > 10 mmHg in participants with intra‐aortic balloon pump (IABP), the infusion rate was reduced to 0.05 µg/kg/min; if a further drop in blood pressure occurred, an infusion of noradrenaline was started and eventually the study drug infusion was aborted. Concomitant medication: volume therapy; intravenous diuretics; standard medical therapy according to national and international guidelines (the use of intravenous inotropic drugs was restricted to participants with CS except noradrenaline in the setting of hypotension) Concomitant intervention: continuous positive airway pressure or mechanical ventilation Intervention before baseline: percutaneous coronary intervention (PCI); intra‐aortic balloon pump (IABP)
Outcomes	Primary: change in wall motion score index (WMSI) from baseline to day 5 Secondary: changes in N‐terminal‐pro‐B‐type natriuretic peptide (NT‐pro‐BNP) (25 h, 5 days, 42 days), WMSI (25 h, 42 days), clinical score (25 h and 5 days); use of inotropic or vasopressor drugs in participants without CS; infarct size at 42 days; time to major adverse cardiac events (death, non‐fatal myocardial infarction, revascularisation of infarct‐related artery, rehospitalisation for heart failure) Safety: number of participants developing hypotension, sinus tachycardia, atrial fibrillation, ventricular arrhythmia or ischaemic episodes
Notes	Funding: unrestricted educational grant from Orion Pharma Contact: T. Husebye (phone: 47‐40452621; mail: http://tr‐huse@online.no / trygve.husebye@ous‐hf.no) Trial registration: NCT00324766 Other: ‐
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated code; block randomisation
Allocation concealment (selection bias)	Low risk	Code was kept in a safe at the hospital pharmacy.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study medication was prepared with matching size, colour of solution and packaging by the hospital pharmacy.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind trial; all investigating doctors, nurses and study personnel were blinded throughout the study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	Pre‐planned endpoints were reported.
Other bias	High risk	Cross‐over: no Baseline differences: yes (male sex in 60% versus 81%; prior AMI in 23% versus 13%; diabetes in 17% versus 3%; smoking in 41% versus 33%; dyslipidaemia in 10% versus 32%) Influence of interim results on the conduct of the study: no Deviation from study protocol: no Inappropriate administration of an intervention: yes (reduction of study drug infusion in 6 participants (4 in overall levosimendan group, 2 in overall placebo group) due to episodes of hypotension or atrial fibrillation) Contra‐active or similar supporting pre‐randomisation intervention: yes (volume therapy, intravenous diuretics, standard medical therapy according to national and international guidelines, intravenous inotropic drugs in CS subgroup, noradrenaline in the setting of hypotension)
Adverse effects	Low risk	Definitions of AEs given: yes Monitoring of AEs: report of all predefined adverse effects at 5 days; report of all‐cause mortality at 6 months Participants excluded from AE analysis: no Numerical data by intervention: yes