Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery
Rajendra H Mehta, Jeffrey D Leimberger, Sean van Diepen, James Meza, Alice Wang, Rachael Jankowich, Robert W Harrison, Douglas Hay, Stephen Fremes, Andra Duncan, Edward G Soltesz, John Luber, Soon Park, Michael Argenziano, Edward Murphy, Randy Marcel, Dimitri Kalavrouziotis, Dave Nagpal, John Bozinovski, Wolfgang Toller, Matthias Heringlake, Shaun G Goodman, Jerrold H Levy, Robert A Harrington, Kevin J Anstrom, John H Alexander, LEVO-CTS Investigators, John Kelley, Bertram Pitt, T Bruce Ferguson, Steven Goodman, Kenneth W Mahaffey, Vandana Sundaram, Sandra Tourt-Uhlig, Deborah Drosdick, Merri Swartz, Ann Schutte, Gail Beaulieu, Chiara Melloni, Charlene Trotter, Alicia Lowe, Joni O’Briant, Daniel B Mark, Linda Davidson-Ray, Karen P Alexander, Sana M Al-Khatib, Bradley J Kolls, David F Kong, Ann Marie Navar, Thomas J Povsic, Tiffany C Randolph, Amit N Vora, Jodi Parrotta, Vickie Altman, John P Kelley, Thomas Washburn Jr, Manesh Parikshak, Michael England, Robert Kramer, Allen Morris, Daniel Gunn, Francis Downey, Clarence Owen, Andrew Pruitt, Julie Huffmyer, Michael Wait, Chandrashekhar Ramaiah, James Wudel, Michael Essandoh, Mark Groh, James Slater, Robert Hagberg, Robert Pearl, Vincent Scavo, Andrew Shaw, Mark Slaughter, James Wu, Keith Allen, Keki Balsara, Alexander Kulik, Kevin Accola, Benjamin Mackie, Carmelo Milano, Goya Raikar, Geoffrey Answini, Reza Dabir, Alexandros Karavas, Ludmil Mitrev, Liem Nguyen, Thomas Beaver, Nirav Patel, Cornelius Dyke, David Hockmuth, Michael Moront, Duc Pham, Robin Varghese, Luigino Nascimben, Prakash Patel, Ahmed Zaky, Manuel Fontes, Daniel Goldfaden, Robert Hunsaker, Newell Robinson, Ronald Zolty, H Edward Garrett Jr, Chirag Badami, Phillip Lumb, Jay Pal, James Ramsay, Kevin Teoh, David Mazer, Benoit de Varennes, Richard Whitlock, Steven Meyer, Rakesh Arora, Louis Perrault, Rajendra H Mehta, Jeffrey D Leimberger, Sean van Diepen, James Meza, Alice Wang, Rachael Jankowich, Robert W Harrison, Douglas Hay, Stephen Fremes, Andra Duncan, Edward G Soltesz, John Luber, Soon Park, Michael Argenziano, Edward Murphy, Randy Marcel, Dimitri Kalavrouziotis, Dave Nagpal, John Bozinovski, Wolfgang Toller, Matthias Heringlake, Shaun G Goodman, Jerrold H Levy, Robert A Harrington, Kevin J Anstrom, John H Alexander, LEVO-CTS Investigators, John Kelley, Bertram Pitt, T Bruce Ferguson, Steven Goodman, Kenneth W Mahaffey, Vandana Sundaram, Sandra Tourt-Uhlig, Deborah Drosdick, Merri Swartz, Ann Schutte, Gail Beaulieu, Chiara Melloni, Charlene Trotter, Alicia Lowe, Joni O’Briant, Daniel B Mark, Linda Davidson-Ray, Karen P Alexander, Sana M Al-Khatib, Bradley J Kolls, David F Kong, Ann Marie Navar, Thomas J Povsic, Tiffany C Randolph, Amit N Vora, Jodi Parrotta, Vickie Altman, John P Kelley, Thomas Washburn Jr, Manesh Parikshak, Michael England, Robert Kramer, Allen Morris, Daniel Gunn, Francis Downey, Clarence Owen, Andrew Pruitt, Julie Huffmyer, Michael Wait, Chandrashekhar Ramaiah, James Wudel, Michael Essandoh, Mark Groh, James Slater, Robert Hagberg, Robert Pearl, Vincent Scavo, Andrew Shaw, Mark Slaughter, James Wu, Keith Allen, Keki Balsara, Alexander Kulik, Kevin Accola, Benjamin Mackie, Carmelo Milano, Goya Raikar, Geoffrey Answini, Reza Dabir, Alexandros Karavas, Ludmil Mitrev, Liem Nguyen, Thomas Beaver, Nirav Patel, Cornelius Dyke, David Hockmuth, Michael Moront, Duc Pham, Robin Varghese, Luigino Nascimben, Prakash Patel, Ahmed Zaky, Manuel Fontes, Daniel Goldfaden, Robert Hunsaker, Newell Robinson, Ronald Zolty, H Edward Garrett Jr, Chirag Badami, Phillip Lumb, Jay Pal, James Ramsay, Kevin Teoh, David Mazer, Benoit de Varennes, Richard Whitlock, Steven Meyer, Rakesh Arora, Louis Perrault
Abstract
Background: Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery.
Methods: In a multicenter, randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive 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. The two primary end points were a four-component composite of death through day 30, renal-replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5.
Results: A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention-to-treat population. The four-component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two-component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups.
Conclusions: Prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass. (Funded by Tenax Therapeutics; LEVO-CTS ClinicalTrials.gov number, NCT02025621 .).
Source: PubMed