Levosimendan for Hemodynamic Support after Cardiac Surgery

Landoni. NEJM 2017; published online 21st March. doi:10.1056/NEJMoa1616325

Clinical Question

• In patients undergoing cardiac surgery with left ventricular dysfunction, does levosimendan compared to placebo reduce mortality?

Design

• Multi-centre, randomised trial
• Placebo-controlled, parallel group design
• Computer generated permuted block randomisation sequence, stratifying according to study centre
• Concealed allocation using opaque, sealed envelopes
• Blinding of patients, clinicians and study personnel
• Powered at 80% with two-sided alpha significance defined at 0.05
  • Requiring 435 patients per group (set at 500 to allow for losses)
  • Expected mortality of 10% in control group and 5% in levosimendan group (based on meta-analysis of small trials)
• Terminated after 2nd interim analysis on grounds of futility

Setting

• 14 cardiac surgery centres in Italy, Russia and Brazil
• November 2009 – April 2016

Population

• Inclusion: Patients scheduled for cardiac surgery with peri-operative cardiovascular dysfunction
  • Pre-operative left ventricular ejection fraction (LVEF) < 25%
  • Pre-operative intra-aortic balloon pump (IABP)
  • Intra- or post-operative (within 24 hours) IABP or significant inotropic requirement
• Exclusion: Adverse reaction to study drug; levosimendan administration in previous 30 days; kidney or liver transplant; liver cirrhosis; ECMO; not for resuscitation order
• 6478 screened; 4725 consented pre-operatively; 647 met inclusion criteria; 506 randomised (126 excluded at discretion of attending physician); all 506 analysed (none lost to follow-up)
• Baseline characteristics were similar between groups (levosimendan vs placebo)
  • Median age: 66 yrs vs 66 yrs
  • Previous cardiac surgery: 18% vs 14%
  • Cardiogenic shock: 2.4% vs 2.7%
  • Median LVEF: 50% vs 50%
  • First reason for trial inclusion
    • Pre-op LVEF < 50%: 4.4% vs 4.3%
    • IABP: 20.2% vs 17.1%
    • Intra-op high-dose inotropes: 13.3% vs 10.9%
    • Post-op high-dose inotropes: 62.1% vs 67.8%

Intervention

• Levosimendan infusion
  • Initially 0.05 µg/kg/min
  • Titrated at attending physician’s discretion up to 0.2 µg/kg/min
  • Continued for up to 48 hours or until ICU discharge

Control

• Placebo infusion
  • Indistinguishable from levosimendan infusion
  • Consisted of yellow vitamin mix with no cardiovascular effect
  • Titrated and continued in same way as levosimendan

Management common to both groups

• All clinical decisions, except for the study drug, were at the treating physician’s discretion
• An advisory flowchart provided guidance for inotropic management

Outcome

• Primary outcome: Mortality at 30 days was not different between the groups
  • Levosimendan 12.9% vs Placebo 12.8%
  • Absolute risk reduction -0.1% (95% CI -5.7 to 5.9, P=0.97)
• Secondary outcome: There were no significant differences in the secondary outcomes
  • Survival over time: hazard ratio 1.02 (95% CI 0.65 to 1.59, P=0.94)
  • Requirement of renal replacement therapy: Levo 9.7% vs Placebo 12.8%
  • Median duration of mechanical ventilation: Levo 19 hours vs Placebo 21 hours
  • Median hospital stay: Levo 14 days vs Placebo 14 days
  • Interruptions due to adverse events: Levo 3.8% vs Placebo 1.6%

Authors’ Conclusions

• A low-dose infusion of levosimendan did not improve survival in patients with left ventricular dysfunction undergoing cardiac surgery compared to a placebo

Strengths

• Appropriate methodology for study question
• Excellent methods of randomisation, concealment of allocation and blinding, which will minimise biases and provide good internal validity
• Broad inclusion criteria compared to other trials investigating levosimendan in cardiac surgery, improving the generalisability of the results
• Ethically appropriate early termination

Weaknesses

• Dosage of levosimendan is smaller than other trials
  • The lack of routine cardiac output data collection means that the physiological efficacy of this smaller dose cannot be shown
• The wide confidence intervals do not exclude a clinically relevant absolute risk reduction of 5% – is this a ‘negative’ trial or a ‘null’ trial?
  • The authors designed the study to attempt to demonstrate an absolute risk reduction (ARR) of 5%, but the study was terminated early as this trial would not have been able to demonstrate this with the remaining intended recruitment
  • The 95% CI -5.7 to 5.9 so there may be a clinically relevant benefit (or harm) from levosimendan (although it appears unlikely)
  • Concluding that there is no clinically relevant difference may be a type 2 error (false negative)

The Bottom Line

• In patients undergoing cardiac surgery with peri-operative left ventricular dysfunction, it appears that a low-dose infusion of levosimendan is not beneficial
• Although there is a possibility of a type 2 error (false negative) in this conclusion, this finding is in keeping with other levosimendan trials

External Links

• [article] Levosimendan for Hemodynamic Support after Cardiac Surgery
• [further reading] LEVO-CTS summary by TBL
• [further reading] LeoPARDS summary by TBL
• [further reading] Levosimendan by LITFL

Metadata

Summary author: Duncan Chambler
Summary date: 12 April 2017
Peer-review editor: Adrian Wong