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

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.

Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial.

IMPORTANCE: No effective pharmaceutical agents have yet been identified to treat acute kidney injury after cardiac surgery. OBJECTIVE: To determine whether fenoldopam reduces the need for renal replacement therapy in critically ill cardiac surgery patients with acute kidney injury. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study from March 2008 to April 2013 in 19 cardiovascular intensive care units in Italy. We randomly assigned 667 patients admitted to intensive care units after cardiac surgery with early acute kidney injury (≥50% increase of serum creatinine level from baseline or oliguria for ≥6 hours) to receive fenoldopam (338 patients) or placebo (329 patients). We used a computer-generated permuted block randomization sequence for treatment allocation. All patients completed their follow-up 30 days after surgery, and data were analyzed according to the intention-to-treat principle. INTERVENTIONS: Continuous infusion of fenoldopam or placebo for up to 4 days with a starting dose of 0.1 µg/kg/min (range, 0.025-0.3 µg/kg/min). MAIN OUTCOMES AND MEASURES: The primary end point was the rate of renal replacement therapy. Secondary end points included mortality (intensive care unit and 30-day mortality) and the rate of hypotension during study drug infusion. RESULTS: The study was stopped for futility as recommended by the safety committee after a planned interim analysis. Sixty-nine of 338 patients (20%) allocated to the fenoldopam group and 60 of 329 patients (18%) allocated to the placebo group received renal replacement therapy (P = .47). Mortality at 30 days was 78 of 338 (23%) in the fenoldopam group and 74 of 329 (22%) in the placebo group (P = .86). Hypotension occurred in 85 (26%) patients in the fenoldopam group and in 49 (15%) patients in the placebo group (P = .001). CONCLUSIONS AND RELEVANCE: Among patients with acute kidney injury after cardiac surgery, fenoldopam infusion, compared with placebo, did not reduce the need for renal replacement therapy or risk of 30-day mortality but was associated with an increased rate of hypotension. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00621790.

Mitraclip therapy in patients with functional mitral regurgitation and missing leaflet coaptation: is it still an exclusion criterion?

AIMS: The aim of this study was to investigate the feasibility, safety, and efficacy of Mitraclip therapy in patients with functional mitral regurgitation (MR) and missing leaflet coaptation (MLC). METHODS AND RESULTS: Out of 62 consecutive patients with functional MR undergoing Mitraclip implantation, 22 had MLC defined as the presence of a 'gap' between two mitral leaflets or insufficient coaptation length (<2 mm), according to the EVEREST II criterion. Compared with the control group, the MLC population had a significantly higher effective regurgitant orifice area (0.67 ± 0.31 vs. 0.41 ± 0.13 cm2 ; P = 0.019) and sphericity index (0.80 ± 0.11 vs. 0.71 ± 0.10; P = 0.003). MLC patients were treated with pharmacological/mechanical support in order to improve leaflet coaptation and to prepare the mitral valve apparatus for grasping. Implantation of >1 clip and device time were comparable in patients with and without MLC (61.9% vs. 47.5%; P = 0.284 and 101 ± 39 vs. 108 ± 69 min; P = 0.646, respectively). No significant differences were observed between the two cohorts in technical success (95.5% vs. 97.5%, P = 0.667), 30-day device success (85.7% vs. 78.9%; P = 0.525), procedural success (81.8% vs. 75%; P = 0.842), and 1-year patient success (52.9% vs. 44.1%; P = 0.261), defined according to the MVARC (Mitral Valve Academic Research Consortium) criteria. The long-term composite endpoint of cardiovascular death and heart failure hospitalization was similar in the two groups (49.9% vs. 44.4%; P = 0.348). A significant improvement of MR and NYHA functional class and a lack of reverse remodelling were observed up to 2 years in both arms. CONCLUSION: The Mitraclip procedure could be extended to patients with functional MR who do not fulfil the coaptation length EVEREST II criterion and who would otherwise be excluded from this treatment.