A randomized controlled trial of levosimendan to reduce mortality in high-risk cardiac surgery patients (CHEETAH): Rationale and design

doi:10.1016/j.ahj.2016.03.021

American Heart Journal

Volume 177, July 2016, Pages 66-73

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https://doi.org/10.1016/j.ahj.2016.03.021 Get rights and content

Objective

Patients undergoing cardiac surgery are at risk of perioperative low cardiac output syndrome due to postoperative myocardial dysfunction. Myocardial dysfunction in patients undergoing cardiac surgery is a potential indication for the use of levosimendan, a calcium sensitizer with 3 beneficial cardiovascular effects (inotropic, vasodilatory, and anti-inflammatory), which appears effective in improving clinically relevant outcomes.

Design

Double-blind, placebo-controlled, multicenter randomized trial.

Setting

Tertiary care hospitals.

Interventions

Cardiac surgery patients (n = 1,000) with postoperative myocardial dysfunction (defined as patients with intraaortic balloon pump and/or high-dose standard inotropic support) will be randomized to receive a continuous infusion of either levosimendan (0.05-0.2 μg/[kg min]) or placebo for 24-48 hours.

Measurements and main results

The primary end point will be 30-day mortality. Secondary end points will be mortality at 1 year, time on mechanical ventilation, acute kidney injury, decision to stop the study drug due to adverse events or to start open-label levosimendan, and length of intensive care unit and hospital stay. We will test the hypothesis that levosimendan reduces 30-day mortality in cardiac surgery patients with postoperative myocardial dysfunction.

Conclusions

This trial is planned to determine whether levosimendan could improve survival in patients with postoperative low cardiac output syndrome. The results of this double-blind, placebo-controlled randomized trial may provide important insights into the management of low cardiac output in cardiac surgery.

Section snippets

Study design, approval, and registration

The study was approved by the Ethical Committee of all participating centers and was registered on clinicaltrial.org as NCT00994825.

Study aim

The aim of our study is to confirm the promising results of the above-cited meta-analyses3, 4, 5 that included only single-center trials and to provide clinical evidence from a large prospective, randomized, controlled trial on the impact of levosimendan on survival in patients who develop LCOS after cardiac surgery.

Study population

We will enroll 1,000 patients undergoing cardiac

Expected results

In the present study, we will test the hypothesis that levosimendan would reduce 30-day mortality in critically ill cardiac surgery patients from 10% to 5%. Our trial will help to determine whether this drug in the early treatment of postsurgical LCOS improves outcomes and reduces ICU stay. If levosimendan reduces length of ICU and hospital stay, then it may also significantly reduce costs, and we will therefore perform appropriate cost-benefit analysis.

Discussion

The best medical treatment for patients with LCOS undergoing cardiac surgery is currently debated. None of the drugs currently used have randomized evidence to support its use to improve clinical relevant outcomes such as mortality. On the other hand, “old” inotropic drugs seem to be associated with an increased risk of death and other cardiovascular events.2, 8, 9

Recent studies13, 17, 38, 39 and meta-analyses3, 4, 5, 11, 12, 40 suggested a cardioprotective effect of levosimendan in patients

Conclusions

This will be the first adequately powered randomized controlled trial comparing the effects of levosimendan on survival with standard treatment in cardiac surgery setting. Evidence resulting from this study will be of primary importance in the management of LCOS in patients undergoing cardiac surgery.

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Long-term outcome of perioperative low cardiac output syndrome in cardiac surgery: 1-year results of a multicenter randomized trial
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Perioperative myocardial dysfunction occurs frequently in cardiac surgery, and is a risk factor for morbidity and mortality. Levosimendan has been suggested to reduce mortality of patients with perioperative myocardial dysfunction. However, long-term outcome data on its efficacy in cardiac surgery are lacking.
Cardiac surgery patients with perioperative myocardial dysfunction were randomized to levosimendan or placebo, in addition to standard inotropic care. One-year mortality data were collected.
We randomized 506 patients (248 to levosimendan 258 to placebo). At 1-year follow-up, 41 patients (16.5%) died in the levosimendan group, while 47 (18.3%) died in the placebo group (absolute risk difference −1.8; 95% CI −8.4 to 4.9; P = .60). Female sex, history of chronic obstructive pulmonary disease, previous myocardial infarction, serum creatinine, hematocrit, mean arterial pressure, and duration of cardiopulmonary bypass were independently associated with 1-year mortality.
Levosimendan administration does not improve 1-year survival in cardiac surgery patients with perioperative myocardial dysfunction. One-year mortality in these patients is 17%. Six predictive factors for long-term mortality were identified.
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SEPARATION from cardiopulmonary bypass (CPB) after cardiac surgery is a progressive transition from full mechanical circulatory and respiratory support to spontaneous mechanical activity of the lungs and heart. During the separation phase, measurements of cardiac performance with transesophageal echocardiography (TEE) provide the rationale behind the diagnostic and therapeutic decision-making process. In many cases, it is possible to predict a complex separation from CPB, such as when there is known preoperative left or right ventricular dysfunction, bleeding, hypovolemia, vasoplegia, pulmonary hypertension, or owing to technical complications related to the surgery. Prompt diagnosis and therapeutic decisions regarding mechanical or pharmacologic support have to be made within a few minutes. In fact, a complex separation from CPB if not adequately treated leads to a poor outcome in the vast majority of cases. Unfortunately, no specific criteria defining complex separation from CPB and no management guidelines for these patients currently exist. Taking into account the above considerations, the aim of the present review is to describe the most common scenarios associated with a complex CPB separation and to suggest strategies, pharmacologic agents, and para-corporeal mechanical devices that can be adopted to manage patients with complex separation from CPB. The routine management strategies of complex CPB separation of 17 large cardiac centers from 14 countries in 5 continents will also be described.
Adrenergic Downregulation in Critical Care: Molecular Mechanisms and Therapeutic Evidence
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Citation Excerpt :
Two trials investigated the prophylactic administration of levosimendan to prevent postoperative low cardiac output syndrome and complications (the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass [LEVO-CTS] and Levosimendan in Coronary Artery Revascularization [LICORN] trials).184,185 In addition, one trial focused on the therapeutic role of levosimendan in patients requiring high-dose postoperative inotropic support (Levosimendan to Reduce Mortality in High Risk Cardiac Surgery Patients: A Multicenter Randomized Controlled Trial [CHEETAH]).186 Prophylactic administration of levosimendan resulted in a lower need for catecholamines134,135 and a lower incidence of postoperative low cardiac output syndrome,134,135 but there was no improvement in survival or major clinical outcomes.134,135
Catecholamines remain the mainstay of therapy for acute cardiovascular dysfunction. However, adrenergic receptors quickly undergo desensitization and downregulation after prolonged stimulation. Moreover, prolonged exposure to high circulating catecholamines levels is associated with several adverse effects on different organ systems.
Unfortunately, in critically ill patients, adrenergic downregulation translates into progressive reduction of cardiovascular response to exogenous catecholamine administration, leading to refractory shock. Accordingly, there has been a growing interest in recent years toward use of noncatecholaminergic inotropes and vasopressors.
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Trial DesignA randomized controlled trial of levosimendan to reduce mortality in high-risk cardiac surgery patients (CHEETAH): Rationale and design

Objective

Design

Setting

Interventions

Measurements and main results

Conclusions

Section snippets

Study design, approval, and registration

Study aim

Study population

Expected results

Discussion

Conclusions

J Cardiothorac Vasc Anesth

J Cardiothorac Vasc Anesth

J Cardiothorac Vasc Anesth

J Cardiothorac Vasc Anesth

J Cardiothorac Vasc Anesth

Int J Cardiol

JACC Heart Fail

J Cardiothorac Vasc Anesth

Lancet

J Cardiothorac Vasc Anesth

J Cardiothorac Vasc Anesth

Br J Anaesth

Clinical review: practical recommendations on the management of perioperative heart failure in cardiac surgery

Crit Care

Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies

Crit Care Med

Early administration of levosimendan is associated with improved kidney function after cardiac surgery a retrospective analysis

J Cardiothorac Surg

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

Overview of randomized clinical trials in acute heart failure syndromes

Am J Cardiol

Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes

Am J Cardiol

Levosimendan, a new inotropic and vasodilator agent

Anesthesiology

Trial Design
A randomized controlled trial of levosimendan to reduce mortality in high-risk cardiac surgery patients (CHEETAH): Rationale and design