Can Levosimendan after Cardiac Surgery Improve Mortality?

Shoshanna Robinson, Mercer University College of Pharmacy

Acute perioperative left ventricular dysfunction is a complication affecting up to 20% of cardiosurgical patients and may be associated with increased mortality. [1]  Inotropic drugs (catecholamines and phosphodiesterase type 3 inhibitors) are regarded as cornerstones of therapy for postoperative hemodynamic support. [2]  Levosimendan is an inotropic agent that has shown improved survival rates compared to other inotropic drugs. [3]  Randomized, controlled trials that demonstrate the superiority of an individual inotropic agent were determined not to be in existence regarding major cardiac surgery outcomes. [4]

Levosimendan for Hemodynamic Support after Cardiac Surgery [4]
Design Multicenter, randomized, double-blind, placebo-controlled; N= 506
Objective To evaluate levosimendan versus standard inotropic treatment for mortality benefits
Study Groups Placebo (n= 258); levosimendan (n= 248)
Methods Patients with perioperative cardiovascular dysfunction after cardiac surgery received levosimendan (in a continuous infusion at a dose of 0.025 to 0.2 μg per kilogram of body weight per minute) or placebo for up to 48 hours or until discharge from the intensive care unit in addition to standard care.  Telephone follow-up was completed at 30 day.
Duration November 2009 – April 2016
Primary Outcome Measure 30-day mortality
Baseline Characteristics
Levosimendan Placebo
Median age, yrs (IQR) 66 (58–74) 66 (58–72)
Female, n (%) 89 (35.9) 90 (34.9)
Median left ventricular ejection fraction, (%) (IQR) 50 (37–59) 50 (40–60)
NYHA classification, n (%)
I 19 (7.9) 20 (8.0)
II 72 (29.9) 86 (34.5)
III 133 (55.2) 133 (55.2)
IV 17 (7.1) 16 (6.4)
Preoperative left ventricular ejection fraction, n (%) 11 (4.4) 11 (4.3)
Intraaortic balloon pump, n (%) 50 (20.2) 44 (17.1)
High doses of inotropes received for weaning from cardiopulmonary bypass, n (%) 33 (13.3) 28 (10.9)
High doses of inotropes administered in ICU, n (%) 154 (62.1) 175 (67.8)
Preoperative medical therapy, n (%)
Angiotensin-converting enzyme inhibitor 101 (41.4) 111 (43.2)
Angiotensin-receptor blocker 33 (13.5) 35 (13.6)
Diuretic 157 (64.3) 162 (63.0)
Digoxin 21 (8.6) 19 (7.4)
Beta-blocker 153 (62.7) 159 (61.9)
Nitrate 44 (18.1) 49 (19.1)
Amiodarone 15 (6.1) 24  (9.3)
Ivabradine 6 (2.5) 3 (1.2)
Ranolazine 4 (1.6) 1 (0.4)
Results
Levosimendan Placebo 95% CI p-value
30-day mortality, n (%) 32 (12.9) 33 (12.8) 0.1 (−5.7 to 5.9) 0.97
Adverse Events Common Adverse Events:

Levosimendan Placebo 95% CI p-value
Hypotension during infusion, n (%) 62 (25.2) 54 (21.3) 3.9 (−3.6 to 11.3) 0.31
Ventricular Arrhythmias during infusion, n (%) 4 (1.6) 7 (2.8) −1.1 (−3.7 to 1.4) 0.55
Supraventricular arrhythmias during infusion, n (%) 35 (14.2) 43 (16.9) −2.7 (−9.1 to 3.7) 0.41
Serious Adverse Events: composite of myocardial infarction, acute kidney injury (any stage), neurologic damage type 1 or type 2, septic shock, pneumonia, and mediastinitis

Levosimendan, % Placebo, %
43.7 51.6
Levosimendan Placebo Difference (95% CI) p-value
Myocardial infarction, n (%) 105 (42.5) 90 (34.9) —- —-
Acute kidney injury, according to RIFLE criteria, n (%)
Risk 41 (16.6) 55 (21.3) −4.7 (−11.5 to 2.1) 0.18
Injury 26 (10.5) 27 (10.5) 0.1 (−5.3 to 5.4) 0.98
Failure 17 (6.9) 22 (8.5) −1.6 (−6.3 to 3.0) 0.49
Neurologic damage, n (%)
Type 1 11 (4.5) 9 (3.5) 1.0 (−2.4 to 4.4) 0.58
Type 2 30 (12.1) 37 (14.3) −2.2 (−8.1 to 3.7) 0.47
Septic shock, n (%) 6 (2.4) 10 (3.9) −1.5 (−4.6 to 1.6) 0.35
Pneumonia, n (%) 15 (6.2) 15 (5.9) 0.2 (−4.0 to 4.4) 0.37
Mediastinitis, n (%) 1 (0.4) 4 (1.6) −1.2 (−2.9 to 0.6) 0.37
Percentage that Discontinued due to Adverse Events:

Levosimendan, (%) Placebo, (%)
0.8 1.6
Study Author Conclusions In patients who required perioperative hemodynamic support after cardiac surgery, low-dose levosimendan in addition to standard care did not result in lower 30-day mortality compared to placebo.

Previous studies resulting in less mortality due to levosimendan restricted inclusion to patients with left ventricular systolic dysfunction who required cardiopulmonary bypass.  The inclusion of patients with various cardiac procedures may have impacted alternative results in this study.  A review by the data and safety monitoring board (at 25% enrollment) led to a decision to decrease sample size from 1000 to 500 participants due to higher-than-expected overall mortality rate and a lower-than-expected withdrawal rate.   A second review by the board (at 50% of the originally planned enrollment) led to the decision to stop the trial on the grounds of futility of the primary outcome, which may have increased the potential for type II error.  Levosimendan dose adjustments were made under the discretion of the physician; while this could have impeded results, it mocks real world scenarios.

 

References

[1.] Mebazaa A, Pitsis AA, Rudiger A, et al. Clinical review: practical recommendations on the management of perioperative heart failure in cardiac surgery. Crit Care 2010;14:201.

[2.] Gillies M, Bellomo R, Doolan L, Buxton B. Bench-to-bedside review: inotropic drug therapy after adult cardiac surgery — a systematic literature review. Crit Care 2005;9:266-79.

[3.] Landoni G, Biondi-Zoccai G, Greco M, et al. Effects of levosimendan on mortality and hospitalization: a meta-analysis of randomized controlled studies. Crit Care Med 2012;40:634-46

[4.] Landoni G, Lomivorotov VV, Alvaro G, et al. Levosimendan for Hemodynamic Support after Cardiac Surgery. N Engl J Med. 2017; doi: 10.1056/NEJMoa1616325.

 

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