Topical Versus Intravenous Tranexamic Acid in Patients Undergoing Cardiac Surgery: The DEPOSITION Randomized Controlled Trial.

BACKGROUND: Although intravenous tranexamic acid is used in cardiac surgery to reduce bleeding and transfusion, topical tranexamic acid results in lower plasma concentrations compared with intravenous tranexamic acid, which may lower the risk of seizures. We aimed to determine whether topical tranexamic acid reduces the risk of in-hospital seizure without increasing the risk of transfusion among cardiac surgery patients. METHODS: We conducted a multicenter, double dummy, blinded, randomized controlled trial of patients recruited by convenience sampling in academic hospitals undergoing cardiac surgery with cardiopulmonary bypass. Between September 17, 2019, and November 28, 2023, a total of 3242 patients from 16 hospitals in 6 countries were randomly assigned (1:1 ratio) to receive either intravenous tranexamic acid (control) through surgery or topical tranexamic acid (treatment) at the end of surgery. The primary outcome was seizure, and the secondary outcome was red blood cell transfusion. After the last planned interim analysis, when 75% of anticipated participants had completed follow up, the data and safety monitoring board recommended to terminate the trial, and upon unblinding, the operations committee stopped the trial for safety. RESULTS: Among 3242 randomized patients (mean age, 66.0 years; 77.7% male), in-hospital seizure occurred in 4 of 1624 patients (0.2%) in the topical group, and 11 of 1628 patients (0.7%) in the intravenous group (absolute risk difference, -0.5% [95% CI, -0.9 to 0.03]; P=0.07). Red blood cell transfusion occurred in 570 patients (35.1%) in the topical group and in 433 (26.8%) in the intravenous group (absolute risk difference, 8.3% [95% CI, 5.2-11.5]; P=0.007). The absolute risk difference in transfusion of ≥4 units of red blood cells in the topical group compared with the intravenous group was 8.2% (95% CI, 3.4-12.9). CONCLUSIONS: Among patients undergoing cardiac surgery, topical administration of tranexamic acid resulted in an 8.3% absolute increase in transfusion without reducing the incidence of seizure, compared with intravenous tranexamic acid. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03954314.

Effects of RBT-1 on preconditioning response biomarkers in patients undergoing coronary artery bypass graft or heart valve surgery: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

Background: RBT-1 is a combination drug of stannic protoporfin (SnPP) and iron sucrose (FeS) that elicits a preconditioning response through activation of antioxidant, anti-inflammatory, and iron-scavenging pathways, as measured by heme oxygenase-1 (HO-1), interleukin-10 (IL-10), and ferritin, respectively. Our primary aim was to determine whether RBT-1 administered before surgery would safely and effectively elicit a preconditioning response in patients undergoing cardiac surgery. Methods: This phase 2, double-blind, randomised, placebo-controlled, parallel-group, adaptive trial, conducted in 19 centres across the USA, Canada, and Australia, enrolled patients scheduled to undergo non-emergent coronary artery bypass graft (CABG) and/or heart valve surgery with cardiopulmonary bypass. Patients were randomised (1:1:1) to receive either a single intravenous infusion of high-dose RBT-1 (90 mg SnPP/240 mg FeS), low-dose RBT-1 (45 mg SnPP/240 mg FeS), or placebo within 24-48 h before surgery. The primary outcome was a preoperative preconditioning response, measured by a composite of plasma HO-1, IL-10, and ferritin. Safety was assessed by adverse events and laboratory parameters. Prespecified adaptive criteria permitted early stopping and enrichment. This trial is registered with ClinicalTrials.gov, NCT04564833. Findings: Between Aug 4, 2021, and Nov 9, 2022, of 135 patients who were enrolled and randomly allocated to a study group (46 high-dose, 45 low-dose, 44 placebo), 132 (98%) were included in the primary analysis (46 high-dose, 42 low-dose, 44 placebo). At interim, the trial proceeded to full enrollment without enrichment. RBT-1 led to a greater preconditioning response than did placebo at high-dose (geometric least squares mean [GLSM] ratio, 3.58; 95% CI, 2.91-4.41; p < 0.0001) and low-dose (GLSM ratio, 2.62; 95% CI, 2.11-3.24; p < 0.0001). RBT-1 was generally well tolerated by patients. The primary drug-related adverse event was dose-dependent photosensitivity, observed in 12 (26%) of 46 patients treated with high-dose RBT-1 and in six (13%) of 45 patients treated with low-dose RBT-1 (safety population). Interpretation: RBT-1 demonstrated a statistically significant cytoprotective preconditioning response and a manageable safety profile. Further research is needed. A phase 3 trial is planned. Funding: Renibus Therapeutics, Inc.

Study protocol of a phase 2, randomised, placebo-controlled, double-blind, adaptive, parallel group clinical study to evaluate the efficacy and safety of recombinant alpha-1-microglobulin in subjects at high risk for acute kidney injury following open-chest cardiac surgery (AKITA trial).

INTRODUCTION: Acute kidney injury (AKI) is a common complication after cardiac surgery (CS) and is associated with adverse short-term and long-term outcomes. Alpha-1-microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme binding and mitochondrial-protective mechanisms. RMC-035 is a modified, more soluble, variant of A1M and has been proposed as a novel targeted therapeutic protein to prevent CS-associated AKI (CS-AKI). RMC-035 was considered safe and generally well tolerated when evaluated in four clinical phase 1 studies. METHODS AND ANALYSIS: This is a phase 2, randomised, double-blind, adaptive design, parallel group clinical study that evaluates RMC-035 compared with placebo in approximately 268 cardiac surgical patients at high risk for CS-AKI. RMC-035 is administered as an intravenous infusion. In total, five doses will be given. Dosing is based on presurgery estimated glomerular filtration rate (eGFR), and will be either 1.3 or 0.65 mg/kg.The primary study objective is to evaluate whether RMC-035 reduces the incidence of postoperative AKI, and key secondary objectives are to evaluate whether RMC-035 improves postoperative renal function compared with placebo. A blinded interim analysis with potential sample size reassessment is planned once 134 randomised subjects have completed dosing. An independent data monitoring committee will evaluate safety and efficacy data at prespecified intervals throughout the trial. The study is a global multicentre study at approximately 30 sites. ETHICS AND DISSEMINATION: The trial was approved by the joint ethics committee of the physician chamber Westfalen-Lippe and the University of Münster (code '2021-778 f-A') and subsequently approved by the responsible ethics committees/relevant institutional review boards for the participating sites. The study is conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT05126303.

Fast tracking in cardiac surgery: is it safe?

BACKGROUND: While fast track clinical pathways have been demonstrated to reduce resource utilization in patients undergoing cardiac surgery, it remains unclear as to whether they adversely affect post-operative outcomes. The purpose of this study was to determine the impact of fast tracking on post-operative outcomes following cardiac surgery. METHODS: In a retrospective study, all patients undergoing first-time, on-pump, non-emergent coronary artery bypass grafting, valve, or coronary artery bypass grafting + valve at a single centre between 2010 and 2017 were included. Patients were considered to have been fast tracked if they were extubated and transferred from intensive care to a step-down unit on the same day as their procedure. The risk-adjusted effect of fast tracking on a 30-day composite of all-cause mortality, stroke, renal failure, infection, atrial fibrillation, and readmission to hospital was determined. Furthermore, propensity score matching was used to match fasting track patients in a 1-to-1 manner with their nearest "neighbor" in the control group and subsequently compared in terms of 30-day post-operative outcomes. RESULTS: 3252 patients formed the final study population (fast track: n = 245; control: n = 3007). Patients who were fast tracked experienced reduced time to initial extubation (4.3 vs. 5.6 h, p < 0.0001) and lower median initial intensive care unit length of stay (7.8 vs. 20.4 h, p < 0.0001). Fast tracked patients experienced lower 30-day rates of the composite outcome (42.4% vs. 51.5%, p = 0.008). However, following propensity score matching, fast tracked patients experienced similar 30-day rates of the composite outcome as the control group (42.4% vs. 44.5%, p = 0.72). After risk adjustment using multivariable regression modeling, fast tracking was predictive of an improved 30-day composite outcome (OR 0.75, 95% CI 0.57-0.98, p = 0.03). CONCLUSION: Fast track clinical pathways was associated with reduced intensive care unit, overall length of stay and similar 30-day post-operative outcomes. These results suggest that fast tracking appropriate patients may reduce resource utilization, while maintaining patient safety.

Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study.

BACKGROUND: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI. METHODS: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments. RESULTS: A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P=0.02; odds ratio, 0.58 (95% CI, 0.37-0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment. CONCLUSIONS: The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02610283.

Effect of Continuous Electrocardiogram Monitoring on Detection of Undiagnosed Atrial Fibrillation After Hospitalization for Cardiac Surgery: A Randomized Clinical Trial.

Importance: Postoperative atrial fibrillation (POAF) occurring after cardiac surgery is associated with adverse outcomes. Whether POAF persists beyond discharge is not well defined. Objective: To determine whether continuous cardiac rhythm monitoring enhances detection of POAF among cardiac surgical patients during the first 30 days after hospital discharge compared with usual care. Design, Setting, and Participants: This study is an investigator-initiated, open-label, multicenter, randomized clinical trial conducted at 10 Canadian centers. Enrollment spanned from March 2017 to March 2020, with follow-up through September 11, 2020. As a result of the COVID-19 pandemic, enrollment stopped on July 17, 2020, at which point 85% of the proposed sample size was enrolled. Cardiac surgical patients with CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, prior stroke or transient ischemic attack, vascular disease, age 65-74 years, female sex) score greater than or equal to 4 or greater than or equal to 2 with risk factors for POAF, no history of preoperative AF, and POAF lasting less than 24 hours during hospitalization were enrolled. Interventions: The intervention group underwent continuous cardiac rhythm monitoring with wearable, patch-based monitors for 30 days after randomization. Monitoring was not mandated in the usual care group within 30 days after randomization. Main Outcomes and Measures: The primary outcome was cumulative AF and/or atrial flutter lasting 6 minutes or longer detected by continuous cardiac rhythm monitoring or by a 12-lead electrocardiogram within 30 days of randomization. Prespecified secondary outcomes included cumulative AF lasting 6 hours or longer and 24 hours or longer within 30 days of randomization, death, myocardial infarction, ischemic stroke, non-central nervous system thromboembolism, major bleeding, and oral anticoagulation prescription. Results: Of the 336 patients randomized (163 patients in the intervention group and 173 patients in the usual care group; mean [SD] age, 67.4 [8.1] years; 73 women [21.7%]; median [interquartile range] CHA2DS2-VASc score, 4.0 [3.0-4.0] points), 307 (91.4%) completed the trial. In the intent-to-treat analysis, the primary end point occurred in 32 patients (19.6%) in the intervention group vs 3 patients (1.7%) in the usual care group (absolute difference, 17.9%; 95% CI, 11.5%-24.3%; P < .001). AF lasting 6 hours or longer was detected in 14 patients (8.6%) in the intervention group vs 0 patients in the usual care group (absolute difference, 8.6%; 95% CI, 4.3%-12.9%; P < .001). Conclusions and Relevance: In post-cardiac surgical patients at high risk of stroke, no preoperative AF history, and AF lasting less than 24 hours during hospitalization, continuous monitoring revealed a significant increase in the rate of POAF after discharge that would otherwise not be detected by usual care. Studies are needed to examine whether these patients will benefit from oral anticoagulation therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02793895.

Efficacy of intraoperative cell salvage in decreasing perioperative blood transfusion rates in first-time cardiac surgery patients: a retrospective study.

BACKGROUND: Evidence regarding the safety and efficacy of intraoperative cell salvage (ICS) in transfusion reduction during cardiac surgery remains conflicting. We sought to evaluate the impact of routine ICS on outcomes following cardiac surgery. METHODS: We conducted a retrospective analysis of patients who underwent nonemergent, first-time cardiac surgery 18 months before and 18 months after the implementation of routine ICS. Perioperative transfusion rates, postoperative bleeding, clinical and hematological outcomes, and overall cost were examined. We used multivariable logistic regression modelling to determine the risk-adjusted effect of ICS on likelihood of perioperative transfusion. RESULTS: A total of 389 patients formed the final study population (186 undergoing ICS and 203 controls). Patients undergoing ICS had significantly lower perioperative transfusion rates of packed red blood cells (pRBCs; 33.9% v. 45.3% p = 0.021), coagulation products (16.7% v. 32.5% p < 0.001) and any blood product (38.2% v. 52.7%, p = 0.004). Patients receiving ICS had decreased mediastinal drainage at 12 h (mean 320 [range 230-550] mL v. mean 400 [range 260-690] mL, p = 0.011) and increased postoperative hemoglobin (mean 104.7 ± 13.2 g/L v. 95.0 ± 11.9 g/L, p < 0.001). Following adjustment for other baseline and intraoperative covariates, ICS emerged as an independent predictor of lower perioperative transfusion rates of pRBCs (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.31-0.87), coagulation products (OR 0.41, 95% CI 0.24-0.71) and any blood product (OR 0.47, 95% CI 0.29-0.77). Additionally, ICS was associated with a cost benefit of $116 per patient. CONCLUSION: Intraoperative cell salvage could represent a clinically cost-effective way of reducing transfusion rates in patients undergoing cardiac surgery. Further research on systematic ICS is required before recommending it for routine use.

CONTEXTE: Les résultats d'études portant sur l'innocuité et l'efficacité de l'autotransfusion peropératoire (ATPO) comme mesure de réduction du besoin de transfusion durant une chirurgie cardiaque sont contradictoires. Nous avons cherché à évaluer l'incidence du recours systématique à l'ATPO sur les issues de chirurgies cardiaques. MÉTHODES: Nous avons mené une analyse rétrospective portant sur des patients ayant subi une première chirurgie cardiaque non urgente 18 mois avant et 18 mois après l'introduction de l'ATPO systématique. Les taux de transfusion périopératoire et d'hémorragie postopératoire, les résultats cliniques et hématologiques et le coût total ont été analysés. Nous avons utilisé un modèle de régression logistique multivariée pour déterminer l'incidence ajustée en fonction du risque du recours à l'ATPO sur la probabilité qu'une transfusion périopératoire soit nécessaire. RÉSULTATS: L'échantillon à l'étude était composé de 389 patients (186 dans le groupe ATPO et 203 dans le groupe témoin). Par rapport au groupe témoin, les patients ayant reçu une ATPO ont eu besoin significativement moins souvent d'une transfusion de concentrés de globules rouges (33,9 % c. 45,3 %; p = 0,021), de produits coagulants (16,7 % c. 32,5 %; p < 0,001) et de produits sanguins, tous types confondus (38,2 % c. 52,7 %; p = 0,004). Chez les patients ayant reçu une ATPO, on a constaté un volume de drainage médiastinal après 12 h plus faible (moyenne : 320 mL [étendue de 230-550] c. 400 mL [étendue de 260-690]; p = 0,011) et une hémoglobine postopératoire plus élevée (moyenne : 104,7 ± 13,2 g/L c. 95,0 ± 11,9 g/L; p < 0,001). Après des ajustements pour tenir compte d'autres covariables des mesures de base et peropératoires, nous avons conclu que le recours à l'ATPO était un facteur prédicteur indépendant de taux de transfusion périopératoire plus faibles de concentré de globules rouges (rapport de cotes [RC] : 0,52; intervalle de confiance [IC] à 95 % : 0,31-0,87), de produits coagulants (RC : 0,41; IC à 95 % : 0,24-0,71) et de produits sanguins, tous types confondus (RC : 0,47; IC à 95 % : 0,29-0,77). De plus, l'ATPO a été associée à des économies de 116 $ par patient. CONCLUSION: L'autotransfusion peropératoire pourrait constituer un moyen cliniquement efficace en fonction des coûts de réduire les taux de transfusion des patients subissant une chirurgie cardiaque. D'autres recherches sur le recours systématique à l'ATPO devront être menées avant qu'on puisse recommander son utilisation de routine.

Increased Distance From the Tertiary Cardiac Center Is Associated With Worse 30-Day Outcomes After Cardiac Operations.

BACKGROUND: Numerous studies have examined the effect of geographic place of residence on access to cardiovascular care, but few have examined their effect on outcomes after cardiac operations. This study examined the effect of geographic place of residence on in-hospital and 30-day outcomes after cardiac operations. METHODS: We performed a retrospective analysis of all patients undergoing nonemergency cardiac operations at a single institution between April 2004 and March 2011. Geographic place of residence was defined as the driving distance from the patient's home to the tertiary cardiac care center divided into the following categories: 0 to 50 km, 50 to 100 km, 100 to 150 km, 150 to 200 km, 200 to 250 km, and more than 250 km. Multivariable logistic regression was used to determine the independent effect of driving distance on in-hospital and 30-day outcomes. RESULTS: The final study population included 4,493 patients, of whom 3,897 (86.7%) had 30-day follow-up. After adjusting for differences among patient groups, no consistent relationship existed between distance and in-hospital outcomes. However, increased distance beyond 100 km was significantly associated with a greater risk of adverse outcomes at 30 days (0 to 50 km: referent; 50 to 100 km: odds ratio, 1.16 [95% confidence interval, 0.83 to 1.62]; 100 to 150 km: 1.32 [1.05 to 1.65], 150 to 200 km: 1.68 [1.33 to 2.11], 200 to 250 km: 1.41 [1.06 to 1.88], and >250 km: 1.30 [1.04 to 1.63]). CONCLUSIONS: Patients who live at an increased distance from the tertiary cardiac care center are more likely to have worse 30-day outcomes after cardiac operations. Further study is required to determine the mechanisms underlying this relationship and how such inequalities may be minimized.

Variation in transfusion rates within a single institution: exploring the effect of differing practice patterns on the likelihood of blood product transfusion in patients undergoing cardiac surgery.

OBJECTIVES: Rates of perioperative transfusion vary widely among patients undergoing cardiac surgery. Few studies have examined factors beyond the clinical characteristics of the patients that may be responsible for such variation. The purpose of this study was to determine whether differing practice patterns had an impact on variation in perioperative transfusion at a single center. METHODS: Patients who underwent cardiac surgery at a single center between 2004 and 2011 were considered. Comparisons were made between patients who had received a perioperative transfusion and those who had not from the clinical factors at baseline, intraoperative variables, and differing practice patterns, as defined by the surgeon, anesthesiologist, perfusionist, and the year in which the procedure was performed. The risk-adjusted effect of these factors on perioperative transfusion rates was determined using multivariable regression modeling techniques. RESULTS: The study population comprised 4823 patients, of whom 1929 (40.0%) received a perioperative transfusion. Significant variation in perioperative transfusion rates was noted between surgeons (from 32.4% to 51.5%, P < .0001), anesthesiologists (from 34.4% to 51.9%, P < .0001) and across year (from 28.2% in 2004 to 48.8% in 2008, P < .0001). After adjustment for baseline and intraoperative variables, surgeon, anesthesiologist, and year of procedure were each found to be independent predictors of perioperative transfusion. CONCLUSIONS: Differing practice patterns contribute to significant variation in rates of perioperative transfusion within a single center. Strategies aimed at reducing overall transfusion rates must take into account such variability in practice patterns and account for nonclinical factors as well as known clinical predictors of blood transfusions.