Levy 2018.

Study characteristics
Methods	Study design: multicentre, 2‐arm parallel group RCT (France) Recruitment period: September 2011 – August 2016 Follow‐up: 60 days
Participants	n = 163 (randomised), n = 57 (enrolled) Inclusion criteria: CS due to AMI successfully revascularised by percutaneous coronary intervention (PCI) Exclusion criteria: shock of other origin; immediate indication for extracorporeal life support; age < 18 years; cardiac arrest with early signs of cerebral anoxia; septic/toxic/obstructive cardiomyopathy; missing medical insurance; patient under legal protection; moribund status (state of imminent death with no medical therapeutic option); missing inserted pulmonary artery catheter; open‐label vasopressor therapy more than 6 h before the introduction of the study drug CS definition: SBP < 90 mmHg or MAP < 65 mmHg without a vasopressor agent or need for vasopressor therapy to correct hypotension; CI < 2.2 L/min/m2 in the absence of vasopressor or inotrope therapy; PCWP > 15 mmHg or echocardiographic evidence of high pressure; echocardiographic ejection fraction < 40% without inotrope support; evidence of tissue hypoperfusion (e.g. skin mottling, oliguria, elevated lactate level, altered consciousness) Characteristics: (epinephrine/norepinephrine, median with IQR) Age (years): 68 (55 – 79)/66 (55 – 77) Sex (male, %): 52/80 Diabetes (%): 7/13 Hypertension (%): 30/20 Smoker (%): ‐ Prior AMI (%): 7/7 MAP (mmHg): 72 (69 – 79)/71 (66 – 83) HR (bpm): 100 (70 – 118)/88 (75 – 110) SBP (mmHg): 109 (93 – 125)/98 (95 – 116) DBP (mmHg): 54 (44 – 61)/57 (51 – 65) CI (L/min/m2): 1.8 (1.6 – 2.7)/2.1 (1.8 – 2.5) PCWP (mmHg): 14 (11 – 18)/15 (10 – 20) LVEF (%): 34 (24 – 48)/34 (26 – 40) SVRI (dyne.s/cm5/m2): 2611 (2080 – 3388)/2330 (1833 – 2729) Timetable: treatment for at least 24 h (as long as clinically indicated); observation at 0/2/4/6/12/24/48/72 h
Interventions	Epinephrine (n = 27): continuous infusion increased by 0.02 µg/kg/min (or higher in emergency cases) to the targeted MAP of 65 – 70 mmHg; a participant was considered to be weaned from vasopressor therapy after 24 h of haemodynamic stability without vasopressor support – during this time lag, if MAP decreased to < 65 – 70 mmHg, the study drug was reintroduced; the study period lasted a maximum of 60 days. Norepinephrine (n = 30): continuous infusion increased by 0.02 µg/kg/min (or higher in emergency cases) to the targeted MAP of 65 – 70 mmHg; a participant was considered to be weaned from vasopressor therapy after 24 h of haemodynamic stability without vasopressor support – during this time lag, if MAP decreased to < 65 – 70 mmHg, the study drug was reintroduced; the study period lasted a maximum of 60 days. Concomitant medication: in case of failure to reach a MAP of 65 – 70 mmHg or in case of arrhythmias refractory to therapy during treatment with the study drug, an open‐label vasopressor (dobutamine) was used. Concomitant intervention: mechanical ventilation, intra‐aortic balloon pump Intervention before baseline: percutaneous coronary intervention (PCI)
Outcomes	Primary: change in CI Secondary: changes in other haemodynamic variables over time; cardiac power index; use of inotropes; lactate level and lactate clearance; biomarker levels; SOFA score evolution during the first 72 h Safety: incidence of refractory CS; arrhythmias (i.e. ventricular tachycardia, ventricular fibrillation, atrial fibrillation)
Notes	Funding: The study was supported by a grant from INSERM‐DHOS. Dr. Levy received lecture fees from Pulsion, Baxter, Orion, Lilly and has received consultant fees from Novartis, Orion, Baxter. Dr. Leone has served as a consultant of Aguettant. Dr. Kimmoun has received fees from Baxter, Merck Sharp and Dohme, Gilead. Dr. Rossignol has received personal fees (consulting) from Novartis, Relypsa, AstraZeneca, Grünenthal, Stealth Peptides, Fresenius, Vifor Fresenius Medical Care Renal Pharma, Vifor, CTMA, lecture fees from Bayer, CVRx and is cofounder of CardioRenal. Dr. Girerd has received board fees from Novartis and honoraria from Servier. Dr. Mebazaa has received speaker honoraria from Abbott, Orion, Roche, Servier and has received fees as a member of advisory boards and/or steering committees and/or research grants from Bristol Myers Squibb, Adrenomed, Neurotronik, Roche, Sanofi, Sphyngotec. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Contact: B. Levy (mail: blevy5463@gmail.com) Trial registration: NCT01367743 Other: ‐
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated code; block randomisation with a block size of 4
Allocation concealment (selection bias)	Low risk	Treatment assignments and participant reference number were placed in sealed, opaque envelopes which were opened by an independent pharmacist in charge of the preparation of the study drugs.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Drug syringes were prepared extemporaneously by the pharmacist and labelled with the participant`s number only and were indistinguishable.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind trial; 2 participants from the epinephrine group were switched to open‐label norepinephrine due to sustained ventricular tachycardia.
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 52% versus 80%; diabetes in 7% versus 13%) Influence of interim results on the conduct of the study: yes (given the higher incidence of refractory shock in the epinephrine group, the data and safety monitoring board terminated the study prematurely) Deviation from study protocol: no Inappropriate administration of an intervention: no Contra‐active or similar supporting pre‐randomisation intervention: yes (open‐label vasopressor (dobutamine))
Adverse effects	Low risk	Definitions of AEs given: yes Monitoring of AEs: report of serious adverse events (refractory shock, arrhythmia, need for extracorporeal life support); report of all‐cause mortality at 7/28/60 days Participants excluded from AE analysis: no Numerical data by intervention: yes