LEVO-CTS Trial: Should Cardiac Surgery Patients Use Levosimendan?

Sandy Liu, Mercer University College of Pharmacy

Utilizing a heart-lung machine, cardiopulmonary bypass replaces the heart’s pumping action and adds oxygen to blood, allowing the heart and lungs to be still prior to cardiac surgeries. [1]  Morbidity and mortality have demonstrated to be associated with this surgery, as is low cardiac output syndrome. [2]  Despite being managed with inotropic agents and mechanical cardiac assist devices, it has been suggested that short-term mortality is higher compared to patients without this syndrome. [3]  Some available inotropic agents may still have unknown safety profiles or known adverse effects.  [4]

Levosimendan is a calcium-sensitizing inotrope and an adenosine triphosphate (ATP) sensitive potassium channel opener used to enhance cardiac contractility and vasodilation.  This medication increases the sensitivity of cardiac myofilament to calcium, rather than increasing intracellular concentrations of free calcium.  By binding to cardiac troponin C in a calcium-dependent manner, levosimendan stabilizes troponin C and the kinetics of actin-myosin cross-bridges without increasing myocardial consumption of ATP. [5]

Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery [6]
Design Multicenter, randomized, double-blind, placebo-controlled, phase 3;

N= 849

Objective To evaluate the safety and efficacy of prophylactic levosimendan in patients undergoing cardiac surgery with cardiopulmonary bypass
Study Groups Levosimendan (n= 428); placebo (n= 421)
Methods Patients received either intravenous levosimendan (at a dose of 0.2 µg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 µg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery, with no stratification.

Eligible patients were scheduled to undergo cardiac surgery with the use of cardiopulmonary bypass and had a left ventricular ejection fraction of 35% or less as assessed within 60 days before surgery.  The cardiac surgical procedures included coronary artery bypass graft (CABG), CABG plus aortic valve surgery, isolated mitral valve surgery, or any combination of these procedures.  The use of concomitant medications, including other inotropes and vasopressors, were not controlled.

Blood samples for the analysis of creatine kinase (CK) and CK-MB isoenzyme levels were obtained and analyzed within 8 hours before surgery and at 3 and 5 days after surgery.  Electrocardiograms were recorded at baseline and after surgery on days 0, 1, 2, 3, and 5 as well as on the day of and the day after any suspected ischemic event through 30 days.

Renal-replacement therapy (RRT) included hemodialysis (HD), peritoneal dialysis, or continuous venovenous HD.  Perioperative myocardial infarction (MI) was defined as a CK-MB level of more than 100 ng per milliliter or a level that was more than 10 times the upper limit of the normal range, or a level more than 50 ng per milliliter or a level that was more than 5 times the upper limit of the normal range, with new Q waves that were more than 30 msec in duration in two contiguous leads or new left bundle branch block.  Use of a mechanical cardiac assist device included the use of an intraaortic balloon pump, extracorporeal membrane oxygenator, or ventricular assist device.

Duration July 2014 to November 2016
Primary Outcome Measure 1) Four-component composite of death through day 30, RRT through day 30, perioperative MI through day 5, or use of a mechanical cardiac assist device through day 5

2) Two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5

Baseline Characteristics
Levosimendan Placebo
Mean age, year 65 65
Female, n (%) 81 (18.9) 89 (21.1)
Race, n (%)
    White 385 (91.0) 375 (89.5)
    Black 21 (5.0) 23 (5.5)
    Other 17 (4.0) 21 (5.0)
Medical history, n (%)
    Hypertension 344 (81.3) 340 (81.1)
    Diabetes mellitus 214 (50.1) 212 (50.4)
    Hypercholesterolemia 333 (78.9) 331 (79.2)
    Chronic lung disease 118 (28.4) 120 (29.4)
    Chronic kidney disease 131 (31.2) 134 (32.4)
    MI 223 (52.5) 213 (50.6)
    MI within previous 7 days 67 (15.8) 62 (14.7)
    Stroke 30 (7.1) 33 (7.9)
    Peripheral vascular disease 60 (14.3) 64 (15.3)
    Cerebrovascular disease 58 (13.7) 49 (11.7)
    Cardiac surgery 50 (11.7) 48 (11.4)
    Heart failure 332 (80.6) 339 (81.7)
Preoperative cardiac status, beats/min (IQR)
    Mean heart rate 74 (64-84) 75 (66-85)
Systolic blood pressure (SBP), mmHg (IQR)
    Median 122 (111-136) 123 (111-139)
Left ventricular ejection fraction, % (IQR)
    Median 26 (24-32) 27 (22-31)
Preoperative medication, n (%)
    Aspirin 287 (70.2) 284 (69.3)
    Beta-blocker 325 (79.5) 333 (81.2)
    ACE inhibitor or ARB 171 (41.8) 195 (47.6)
Results
Levosimendan Placebo Odds ratio (95% CI) p-value
Primary end points, n (%)
Four-component end point 105 (24.5) 103 (24.5) 1.00

(0.66-1.54)

0.98
Two-component end point 56 (13.1) 48 (11.4) 1.18

(0.76-1.82)

0.45
Components of primary end points, n (%)
Death at 30 days 15 (3.5) 19 (4.5) 0.77

(0.38-1.53)

0.45
RRT at 30 days 9 (2.1) 16 (3.8) 0.54

(0.24-1.24)

0.15
MI at 5 days 67 (15.7) 63 (15.0) 1.06

(0.73-1.53)

0.78
Use of mechanical cardiac assist devices at 5 days 47 (11.0) 38 (9.0) 1.24

(0.79-1.95)

0.34
Adverse Events Common Adverse Events: hypotension (36.2%); atrial fibrillation (38.1%); ventricular tachycardia or fibrillation (10.7%)
Serious Adverse Events: stroke (3.5%); deep venous thrombosis (0.7%); congestive heart failure (10.7%)
Percentage that Discontinued due to Adverse Events: 1.4%
Study Author Conclusions Prophylactic levosimendan did not decrease short-term composite end point compared with placebo.

Although levosimendan has been associated with higher rates of weaning from cardiopulmonary bypass and lower rates of inotrope use, it may only benefit patients who have severe left ventricular dysfunction at baseline.  Due to its multiple mechanisms of actions, levosimendan’s effects may differ between patients who have left ventricular function due to ischemic heart disease versus those with pressure or volume overload.  Unlike other inotropic agents, levosimendan is able to exerts its effects for up several days due to its long-acting metabolites.  Not only can this lead to an increase in adverse effects, but it can also harm cardiac patients requiring the use of these medications.  With limited data available to suggest levosimendan is superior to other available agents, it is critical for healthcare providers to be cautious with its use, as long-term safety has yet to be established.

 

References

[1] National Heart, Lung, and Blood Institute: Heart Surgery.  https://www.nhlbi.nih.gov/health/health-topics/topics/hs/during.  Accessed on April 3, 2017.

[2] Algarni KD, Maganti M, Yau TM.  Predictors of low cardiac output syndrome after isolated coronary artery bypass surgery: trends over 20 years.  Ann Thorac Surg.  2011;92(5):1678-84.

[3] Nishimura RA, Otto CM, Bonow RO, et al.  2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  Circulation. 2014;129(23):2440-92.

[4] Thackray S, Easthaugh J, Freemantle N, Cleland JG.  The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure-a meta-regression analysis.  Eur J Heart Fail.  2002;4(4):515-29.

[5] Ersoy O, Boysan E, Unal EU, et al.  Effectiveness of prophylactic levosimendan in high-risk valve surgery patients.  Cardiovasc J Afr.  2013;24(7):260-4.

[6] Mehta RH, Leimberger JD, Van diepen S, et al. Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery. N Engl J Med. 2017.

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