Elena Bignami

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

Objective: Catecholaminergic inotropes have a place in the management of low output syndrome and decompensated heart failure but their effect on mortality is debated. Levosimendan is a calcium sensitizer that enhances myocardial contractility without increasing myocardial oxygen use. A meta-analysis was conducted to determine the impact of levosimendan on mortality and hospital stay. Data Sources: BioMedCentral, PubMed, Embase, and the Cochrane Central Register of clinical trials were searched for pertinent studies. International experts and the manufacturer were contacted. Study Selection: Articles were assessed by four trained investigators, with divergences resolved by consensus. Inclusion criteria were random allocation to treatment and comparison of levosimendan vs. control. There were no restrictions on dose or time of levosimendan administration or on language. Exclusion criteria were: duplicate publications, nonadult studies, oral administration of levosimendan, and no data on main outcomes. Data Extraction: Study end points, main outcomes, study design, population, clinical setting, levosimendan dosage, and treatment duration were extracted. Data Synthesis: Data from 5,480 patients in 45 randomized clinical trials were analyzed. The overall mortality rate was 17.4% (507 of 2,915) among levosimendan-treated patients and 23.3% (598 of 2,565) in the control group (risk ratio 0.80 [0.72; 0.89], p for effect <.001, number needed to treat = 17 with 45 studies included). Reduction in mortality was confirmed in studies with placebo (risk ratio 0.82 [0.69; 0.97], p = .02) or dobutamine (risk ratio 0.68 [0.52–0.88]; p = .003) as comparator and in studies performed in cardiac surgery (risk ratio 0.52 [0.35; 0.76] p = .001) or cardiology (risk ratio 0.75 [0.63; 0.91], p = .003) settings. Length of hospital stay was reduced in the levosimendan group (weighted mean difference = −1.31 [−1.95; −0.31], p for effect = .007, with 17 studies included). A trend toward a higher percentage of patients experiencing hypotension was noted in levosimendan vs. control (risk ratio 1.39 [0.97–1.94], p = .053). Conclusions: Levosimendan might reduce mortality in cardiac surgery and cardiology settings of adult patients.

Reducing Mortality in Cardiac Surgery With Levosimendan: A Meta-analysis of Randomized Controlled Trials

OBJECTIVES The authors performed a meta-analysis to evaluate whether levosimendan is associated with improved survival in patients undergoing cardiac surgery. DESIGN A meta-analysis. SETTING Hospitals. PARTICIPANTS A total of 440 patients from 10 randomized controlled studies were included in the analysis. INTERVENTIONS None. MEASURMENTS AND MAIN RESULTS: Four investigators independently searched BioMedCentral and PubMed. Inclusion criteria were random allocation to treatment, comparison of levosimendan versus control, and cardiac surgery patients. Exclusion criteria were duplicate publications, nonhuman experimental studies, and no mortality data. The primary endpoint was postoperative mortality. Levosimendan was associated with a significant reduction in postoperative mortality (11/235 [4.7%] in the levosimendan group v 26/205 [12.7%] in the control arm, odds ratio = 0.35 [0.18-0.71], p for effect = 0.003, p for heterogeneity = 0.22, I(2) = 27.4% with 440 patients included), cardiac troponin release, and atrial fibrillation. No difference was found in terms of myocardial infarction, acute renal failure, time on mechanical ventilation, intensive care unit, and hospital stay. CONCLUSIONS Levosimendan has cardioprotective effects that could result in a reduced postoperative mortality. A large randomized controlled study is warranted in this setting.

Desmopressin reduces transfusion needs after surgery: a meta-analysis of randomized clinical trials.

Background:Perioperative pathologic microvascular bleeding is associated with increased morbidity and mortality and could be reduced by hemostatic drugs. At the same time, safety concerns regarding existing hemostatic agents include excess mortality. Numerous trials investigating desmopressin have lacked power to detect a beneficial effect on transfusion of blood products. The authors performed a meta-analysis of 38 randomized, placebo-controlled trials (2,488 patients) investigating desmopressin in surgery and indicating at least perioperative blood loss or transfusion of blood products. Methods:Pertinent studies were searched in BioMed Central, CENTRAL, and PubMed (updated May 1, 2008). Further hand or computerized searches involved recent (2003–2008) conference proceedings. Results:In most of the included studies, 0.3 &mgr;g/kg desmopressin was used prophylactically over a 15- to 30-min period. In comparison with placebo, desmopressin was associated with reduced requirements of blood product transfusion (standardized mean difference = −0.29 [−0.52 to −0.06] units per patient; P = 0.01), which were more pronounced in the subgroup of noncardiac surgery and were without a statistically significant increase in thromboembolic adverse events (57/1,002 = 5.7% in the desmopressin group vs. 45/979 = 4.6% in the placebo group; P = 0.3). Conclusions:Desmopressin slightly reduced blood loss (almost 80 ml per patient) and transfusion requirements (almost 0.3 units per patient) in surgical patients, without reduction in the proportion of patients who received transfusions. This meta-analysis suggests the importance of further large, randomized controlled studies using desmopressin in patients with or at risk of perioperative pathologic microvascular bleeding.

Randomized Evidence for Reduction of Perioperative Mortality

OBJECTIVE With more than 220 million major surgical procedures performed annually, perioperative interventions leading to even minor mortality reductions would save thousands of lives per year. This international consensus conference aimed to identify all nonsurgical interventions that increase or reduce perioperative mortality as suggested by randomized evidence. DESIGN AND SETTING A web-based international consensus conference. PARTICIPANTS More than 1,000 physicians from 77 countries participated in this web-based consensus conference. INTERVENTIONS Systematic literature searches (MEDLINE/PubMed, June 8, 2011) were used to identify the papers with a statistically significant effect on mortality together with contacts with experts. Interventions were considered eligible for evaluation if they (1) were published in peer-reviewed journals, (2) dealt with a nonsurgical intervention (drug/technique/strategy) in adult patients undergoing surgery, and (3) provided a statistically significant mortality increase or reduction as suggested by a randomized trial or meta-analysis of randomized trials. MEASUREMENTS AND MAIN RESULTS Fourteen interventions that might change perioperative mortality in adult surgery were identified. Interventions that might reduce mortality include chlorhexidine oral rinse, clonidine, insulin, intra-aortic balloon pump, leukodepletion, levosimendan, neuraxial anesthesia, noninvasive respiratory support, hemodynamic optimization, oxygen, selective decontamination of the digestive tract, and volatile anesthetics. In contrast, aprotinin and extended-release metoprolol might increase mortality. CONCLUSIONS Future research and health care funding should be directed toward studying and evaluating these interventions.

Mortality reduction in cardiac anesthesia and intensive care: results of the first International Consensus Conference

There is no consensus on which drugs/techniques/strategies can affect mortality in the perioperative period of cardiac surgery. With the aim of identifying these measures, and suggesting measures for prioritized future investigation we performed the first International Consensus Conference on this topic. The consensus was a continuous international internet‐based process with a final meeting on 28 June 2010 in Milan at the Vita‐Salute University. Participants included 340 cardiac anesthesiologists, cardiac surgeons, and cardiologists from 65 countries all over the world. A comprehensive literature review was performed to identify topics that subsequently generated position statements for discussion, voting, and ranking. Of the 17 major topics with a documented mortality effect, seven were subsequently excluded after further evaluation due to concerns about clinical applicability and/or study methodology. The following topics are documented as reducing mortality: administration of insulin, levosimendan, volatile anesthetics, statins, chronic β‐blockade, early aspirin therapy, the use of pre‐operative intra‐aortic balloon counterpulsation, and referral to high‐volume centers. The following are documented as increasing mortality: administration of aprotinin and aged red blood cell transfusion. These interventions were classified according to the level of evidence and effect on mortality and a position statement was generated. This International Consensus Conference has identified the non‐surgical interventions that merit urgent study to achieve further reductions in mortality after cardiac surgery: insulin, intra‐aortic balloon counterpulsation, levosimendan, volatile anesthetics, statins, chronic β‐blockade, early aspirin therapy, and referral to high‐volume centers. The use of aprotinin and aged red blood cells may result in increased mortality.

Volatile anesthetics reduce mortality in cardiac surgery.

OBJECTIVES A recent meta-analysis suggested that volatile anesthetics reduce postoperative mortality after cardiac surgery. Nonetheless, whether volatile anesthetics improve the outcome of cardiac surgical patients is still a matter of debate. The authors investigated whether the use of volatile anesthetics reduces mortality in cardiac surgery. DESIGN, SETTING, AND INTERVENTIONS: A longitudinal study of 34,310 coronary artery bypass graft interventions performed in Italy estimated the risk-adjusted mortality ratio for each center. A survey was conducted among these centers to investigate whether the use of volatile anesthetics showed a correlation with mortality. MEASUREMENTS AND MAIN RESULTS All 64 eligible centers provided the required data. The median unadjusted 30-day mortality among participating centers was 2.2% (0.3-8.8), whereas the median risk-adjusted 30-day mortality was 1.8% (0.1-7.2). Risk-adjusted analysis showed that the use of volatile anesthetics was associated with a significantly lower rate of risk-adjusted 30-day mortality (beta = -1.172 [-2.259, -0.085], R(2) = 0.070, p = 0.035). Dichotomization into centers using volatile anesthetics in at least 25% of their cases or in less than 25% yielded even more statistically significant results (p = 0.003). Furthermore, a longer use of volatile anesthetics was associated with a significantly lower death rate (p = 0.022); and exploring the impact of the specific volatile anesthetic agent, the use of isoflurane was associated with significant reductions in risk-adjusted mortality rates (p = 0.039). CONCLUSIONS This survey among 64 Italian centers shows that risk-adjusted mortality may be reduced by the use of volatile agents in patients undergoing coronary artery bypass graft surgery.

Cardiac protection by volatile anaesthetics: A multicentre randomized controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass

Background and objectives: To evaluate the effects of total intravenous anaesthesia vs. volatile anaesthesia on cardiac troponin release in coronary artery bypass grafting with cardiopulmonary bypass, we performed a multicentre randomized controlled study to compare postoperative cardiac troponin release in patients receiving two different anaesthesia plans. Methods: We randomly assigned 75 patients to propofol (intravenous anaesthetic) and 75 patients to desflurane (volatile anaesthetic) in addition to an opiate‐based anaesthesia for coronary artery bypass grafting. Peak postoperative troponin I release was measured as a marker of myocardial necrosis. Results: There was a significant (P < 0.001) difference in the postoperative median (25th‐75th percentiles) peak of troponin I in patients receiving propofol 5,5 (2,3‐9,5) ng dL−1 when compared to patients receiving desflurane 2,5 (1,1‐5,3) ng dL−1. The median (interquartile) troponin I area under the curve analysis confirmed the results: 68 (30.5‐104.8) vs. 36.3 (17.9‐86.6) h ng dL−1 (P = 0.002). Patients receiving volatile anaesthetics had reduced need for postoperative inotropic support (24/75, 32.0% vs. 31/75, 41.3%, P = 0.04), and tends toward a reduction in number of Q‐wave myocardial infarction, time on mechanical ventilation, intensive care unit and overall hospital stay. Conclusions: Myocardial damage measured by cardiac troponin release could be reduced by volatile anaesthetics in coronary artery bypass surgery.

Levosimendan Reduces Cardiac Troponin Release After Cardiac Surgery: A Meta-analysis of Randomized Controlled Studies

OBJECTIVES The authors performed a meta-analysis to investigate the effects of levosimendan in cardiac surgery. Inotropic drugs have never shown beneficial effects on outcome in randomized controlled studies, with the possible exception of levosimendan. DESIGN A meta-analysis. SETTING Hospitals. PARTICIPANTS A total of 139 patients from 5 randomized controlled studies were included in the analysis. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Four investigators independently searched BioMedCentral and PubMed. Inclusion criteria were random allocation to treatment, and comparison of levosimendan versus control performed on cardiac surgery patients. Exclusion criteria were duplicate publications, nonhuman experimental studies, and no outcome data. The endpoint was postoperative cardiac troponin release. Levosimendan was associated with a significant reduction in cardiac troponin peak release (weighted mean difference = 2.5 ng/dL [-3.86, -1.14], p = 0.0003) and in time to hospital discharge (weighted mean difference = -1.38 days [-2.78, 0.03], p = 0.05). No other relevant outcome (mortality, myocardial infarction, atrial fibrillation, time on mechanical ventilation, and intensive care unit stay) was improved in those patients receiving levosimendan. CONCLUSIONS Levosimendan has cardioprotective effects, resulting in reduced postoperative cardiac troponin release.

Epidural analgesia improves outcome in cardiac surgery: a meta-analysis of randomized controlled trials.

OBJECTIVE The authors conducted a review of randomized studies to determine whether there were any advantages for clinically relevant outcomes by adding epidural analgesia in patients undergoing cardiac surgery under general anesthesia. DESIGN Meta-analysis. SETTING Hospitals. PARTICIPANTS A total of 2366 patients from 33 randomized trials. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS DATA SOURCES AND STUDY SELECTION PubMed, BioMedCentral, CENTRAL, EMBASE, Cochrane Central Register of Controlled Trials, and conference proceedings were searched (updated January 2008) for randomized trials that compared general anesthesia with an anesthetic plan including general anesthesia and epidural analgesia in cardiac surgery. Two independent reviewers appraised study quality, with divergences resolved by consensus. Overall analysis showed that epidural analgesia reduced the risk of the composite endpoint mortality and myocardial infarction (30/1125 [2.7%] in the epidural group v 64/1241 [5.2%] in the control arm, odds ratio [OR] = 0.61 [0.40-0.95], p = 0.03 number needed to treat [NNT] = 40), the risk of acute renal failure (35/590 [5.9%] in the epidural group v 54/618 [8.7%] in the control arm, OR = 0.56 [0.34-0.93], p = 0.02, NNT = 36), and the time of mechanical ventilation (weighted mean differences = -2.48 hours [-2.64, -2.32], p < 0.001). CONCLUSIONS This analysis suggested that epidural analgesia on top of general anesthesia reduced the incidence of perioperative acute renal failure, the time on mechanical ventilation, and the composite endpoint of mortality and myocardial infarction in patients undergoing cardiac surgery.

Intraoperative use of tranexamic acid to reduce transfusion rate in patients undergoing radical retropubic prostatectomy: double blind, randomised, placebo controlled trial

Objectives To determine the efficacy of intraoperative treatment with low dose tranexamic acid in reducing the rate of perioperative transfusions in patients undergoing radical retropubic prostatectomy. Design Double blind, parallel group, randomised, placebo controlled trial. Setting One university hospital in Milan, Italy. Participants 200 patients older than 18 years and undergoing radical retropubic prostatectomy agreed to participate in the trial. Exclusion criteria were atrial fibrillation, coronary artery disease treated with drug eluting stent, severe chronic renal failure, congenital or acquired thrombophilia, and known or suspected allergy to tranexamic acid. Interventions Intravenous infusion of tranexamic acid or equivalent volume of placebo (saline) according to the following protocol: loading dose of 500 mg tranexamic acid 20 minutes before surgery followed by continuous infusion of tranexamic acid at 250 mg/h during surgery. Main outcome measures Primary outcome: number of patients receiving blood transfusions perioperatively. Secondary outcome: intraoperative blood loss. Six month follow-up to assess long term safety in terms of mortality and thromboembolic events. Results All patients completed treatment and none was lost to follow-up. Patients transfused were 34 (34%) in the tranexamic acid group and 55 (55%) in the control group (absolute reduction in transfusion rate 21% (95% CI 7% to 34%); relative risk of receiving transfusions for patients treated with tranexamic acid 0.62 (0.45 to 0.85); number needed to treat 5 (3 to 14); P=0.004). At follow-up, no patients died and the occurrence of thromboembolic events did not differ between the two groups. Conclusions Intraoperative treatment with low dose tranexamic acid is safe and effective in reducing the rate of perioperative blood transfusions in patients undergoing radical retropubic prostatectomy. Trial registration ClinicalTrials.gov identifier NCT00670345.