OBJECTIVES:Rivaroxaban 2.5mg twice daily with aspirin 100mg daily was superior to aspirin 100mg daily in the COMPASS trial but the cost-effectiveness in Scandinavia is unknown. DESIGN:Mean lifetime costs (USDs) and quality-adjusted life-years were determined from a Scandinavian perspective using a 2-state Markov model with US mortality data. Subgroup and sensitivity analyses were performed. RESULTS:Over a lifetime adding rivaroxaban to aspirin had lower costs (-$3791USD/-23675DKK/-27410NOK/-29200SEK) and gained 1.17 QALYs versus ASA alone. CONCLUSION:Rivaroxaban 2.5mg twice daily with aspirin is a dominant strategy compared to aspirin alone in COMPASS participants from a Scandinavian perspective.

Background and Aims New-onset atrial fibrillation (AF) is the most common complication of cardiac surgery. We aimed to describe the incidence of postoperative AF (POAF), its management, and its relationship to long-term outcomes in a prospective multi-centre cohort, as our current understanding comes primarily from registries and single-centre studies.Methods VISION Cardiac Surgery was a prospective cohort of adults who underwent cardiac surgery in 12 countries. The association of POAF with outcomes occurring between 30 days and 1 year postoperatively was estimated using a multivariable Cox model adjusted for patient and operative characteristics and for antithrombotic therapies.Results Among 12 234 patients (55.3% isolated coronary artery bypass grafting), 31.8% had POAF within 30 days of surgery. The proportion of participants with POAF who received anticoagulation alone at hospital discharge was 15.6%, 54.3% received antiplatelets alone, 23.9% received anticoagulation and antiplatelets, and 6.3% received neither; 48.8% were receiving amiodarone. At 1 year, clinical AF was detected in 6.9% of patients with POAF compared to 0.6% in those without [adjusted hazard ratio (aHR), 11.30; 95% confidence interval (CI) 8.17-15.70]. The primary composite outcome of stroke or vascular death occurred in 2.3% of patients with POAF and 1.5% in those without POAF (aHR 1.32; 95% CI 0.99-1.77). Patients with POAF had a higher risk of all-cause death (3.0% vs 1.7%; aHR 1.54; 95% CI 1.18-2.00).Conclusions New-onset POAF occurs in a third of patients after cardiac surgery; its antithrombotic and antiarrhythmic management varies. Patients with POAF have increased risks of both clinical AF and of all-cause death in the year following surgery.

OBJECTIVES:We aimed to determine whether high-sensitivity cardiac troponin I (hs-cTnI) thresholds associated with increased 30-day mortality isolated coronary artery bypass grafting (CABG) differed between those undergoing off-pump (OPCAB) and on-pump (ONCAB) CABG. METHODS:We conducted a subanalysis of patients who underwent isolated CABG in the Vascular Events in Surgery Patients Cohort Evaluation (VISION) Cardiac Surgery Study. Cox regression was used to determine the hazard ratios (HRs) for mortality based on postoperative day 1 log-transformed hs-cTnI adjusted by EuroSCORE II, with OPCAB versus ONCAB as an interaction term. HRs were modelled as a function of hs-cTnI, and the lowest troponin associated with HR ≥ 1.00 was identified for each group. RESULTS:Of the original VISION cohort, 6505 patients underwent isolated CABG (OPCAB = 1141, ONCAB = 5364). Median hs-cTnI after CABG was 2446 ng/L (interquartile range [IQR] 1164-5654), and lower after OPCAB (640 ng/L [264-1689]) than ONCAB (2972 ng/L [1536-6448], P < .001). There were no differences in 30-day mortality between OPCAB and ONCAB (1.7% vs 1.4%, P = .5). Increased log-peak hs-cTnI was associated with greater mortality after CABG (adjusted HR = 1.7 [95% CI, 1.4-2.1]). The hs-cTnI threshold associated with HR ≥ 1.00 for isolated CABG was 6549 ng/L (95% CI, 3609-8381). OPCAB versus ONCAB had a significant interaction effect on the association between hs-cTnI and mortality (interaction P = .002). The hs-cTnI threshold associated with mortality after OPCAB was ≥4708 ng/L (95% CI, 581-7177), compared to ≥6806 ng/L (95% CI, 4001-13 993) after ONCAB. CONCLUSIONS:The clinically significant hs-cTnI threshold after CABG associated with an increased risk of 30-day mortality above the baseline is substantially higher than defined by current guidelines, but lower in patients undergoing OPCAB compared to ONCAB.

OBJECTIVES:The most prognostically important complications after cardiac surgery to target for prevention remain uncertain. We aimed to assess the relationship between postoperative complications and mortality at 30 days and 1 year after cardiac surgery and rank the complications by their contribution to mortality. METHODS:We completed an analysis of 15,550 patients from the Vascular Events in Surgery Patients Cohort Evaluation (VISION) Cardiac Surgery Prospective Cohort Study, which enrolled 15,971 patients who underwent cardiac surgery from 24 centers in 12 countries. The primary outcome was all-cause mortality at 30 days and 1 year. Population attributable fractions (PAFs) were calculated to estimate the proportion of deaths potentially attributable to each complication. RESULTS:All-cause mortality occurred in 460 patients (3.0%) at 30 days and in 399 (2.6%) between 31 days and 1 year, totaling 859 deaths (5.5%) at 1 year. The 4 complications occurring within 30 days with the largest PAFs for 30-day mortality were acute kidney injury (2612 patients [16.8%]; adjusted hazard ratio [aHR], 4.47; 95% CI, 3.52-5.67; PAF, 37%), bleeding (1491 patients [9.6%]; aHR, 2.39; 95% CI, 1.87-3.06; PAF, 12%), infection (2260 [14.5%]; aHR, 1.95; 95% CI, 1.47-2.57; PAF, 12%), and myocardial injury after cardiac surgery (1686 patients [10.8%]; aHR, 2.01; 95% CI, 1.58-2.54; PAF, 10%). CONCLUSIONS:This international study suggests that approximately 1 in 3 deaths after cardiac surgery are associated with acute kidney injury. Targeted prevention of acute kidney injury, infections, bleeding, and myocardial injury holds promise for reducing mortality in patients after cardiac surgery.

ObjectivesApproximately two-thirds of patients undergoing cardiac surgery experience postoperative complications, which may lead to significant clinical consequences. RBT-1, an investigational drug with anti-inflammatory and antioxidant properties, elicits a preconditioning response and was shown to improve clinical outcomes when administered within 24-48 hours prior to surgery (modified intention-to-treat population). The current post hoc analysis evaluated the efficacy of RBT-1 in reducing postoperative complications in the entire study population without excluding patients based on when surgery occurred relative to study drug administration.MethodsA total of 135 patients were randomized to receive a single infusion of RBT-1 (n = 91) or placebo (n = 44) at least 1 day before undergoing nonemergent coronary artery bypass graft (CABG) and/or heart valve surgery on cardiopulmonary bypass (CPB) and were followed for 90 days postsurgery. Clinical outcomes assessed included ventilator time, intensive care unit (ICU) and hospital length of stay (LOS), cardiopulmonary readmission, and other clinical events of interest.ResultsIn this analysis, RBT-1 reduced ventilator time, ICU, and hospital LOS by 0.98 days (NS), 2.59 days (p = 0.026), and 1.35 days (NS), respectively, compared with placebo. The incidence of 30-day cardiopulmonary readmission was significantly reduced by RBT-1 (4.6% vs. 17.5%, placebo; p = 0.035). Additionally, RBT-1 showed a trend in reductions in several clinical events of interest, including anemia, atrial fibrillation, and fluid overload.ConclusionsTrends in improved clinical outcomes were seen with RBT-1 treatment in this post hoc analysis that included all patients enrolled in a Phase 2 clinical study regardless of surgery delay beyond 2 days posttreatment. A Phase 3 study is underway to confirm these improved clinical outcomes in a larger study population. Trial Registration: ClinicalTrials.gov identifier: NCT06021457ConclusionsTrends in improved clinical outcomes were seen with RBT-1 treatment in this post hoc analysis that included all patients enrolled in a Phase 2 clinical study regardless of surgery delay beyond 2 days posttreatment. A Phase 3 study is underway to confirm these improved clinical outcomes in a larger study population. Trial Registration: ClinicalTrials.gov identifier: NCT06021457

Importance:Delirium is common after cardiac surgery and associated with adverse outcomes. Intraoperative benzodiazepines may increase postoperative delirium but restricting intraoperative benzodiazepines has not yet been evaluated in a randomized trial. Objective:To determine whether an institutional policy of restricted intraoperative benzodiazepine administration reduced the incidence of postoperative delirium. Design, Setting, and Participants:This pragmatic, multiperiod, patient- and assessor-blinded, cluster randomized crossover trial took place at 20 North American cardiac surgical centers. All adults undergoing open cardiac surgery at participating centers during the trial period were included through a waiver of individual patient consent between November 2019 and December 2022. Intervention:Institutional policies of restrictive vs liberal intraoperative benzodiazepine administration were compared. Hospitals (clusters) were randomized to cross between the restricted and liberal benzodiazepine policies 12 to 18 times over 4-week periods. Main Outcomes and Measures:The primary outcome was the incidence of delirium within 72 hours of surgery as detected in routine clinical care, using either the Confusion Assessment Method-Intensive Care Unit or the Intensive Care Delirium Screening Checklist. Intraoperative awareness by patient report was assessed as an adverse event. Results:During the trial, 19 768 patients (mean [SD] age, 65 [12] years; 14 528 [73.5%] male) underwent cardiac surgery, 9827 during restricted benzodiazepine periods and 9941 during liberal benzodiazepine periods. During restricted periods, clinicians adhered to assigned policy in 8928 patients (90.9%), compared to 9268 patients (93.2%) during liberal periods. Delirium occurred in 1373 patients (14.0%) during restricted periods and 1485 (14.9%) during liberal periods (adjusted odds ratio [aOR], 0.92; 95% CI, 0.84-1.01; P = .07). No patient spontaneously reported intraoperative awareness. Conclusions and Relevance:In intention-to-treat analyses, restricting benzodiazepines during cardiac surgery did not reduce delirium incidence but was also not associated with an increase in the incidence of patient-reported intraoperative awareness. Given that smaller effect sizes cannot be ruled out, restriction of benzodiazepines during cardiac surgery may be considered. Research is required to determine whether restricting intraoperative benzodiazepines at the patient level can reduce the incidence of postoperative delirium. Trial Registration:ClinicalTrials.gov Identifier: NCT03928236.

AIMS:Apixaban was superior to aspirin for the prevention of stroke or systemic embolism in participants with subclinical atrial fibrillation (SCAF) in the Apixaban for the Reduction of Thromboembolism in Patients With Device-Detected Subclinical Atrial Fibrillation trial. This was especially true for those with CHA2DS2-VASc score > 4. Understanding the cost-effectiveness of treating SCAF is important for decision-makers. METHODS AND RESULTS:Canadian, UK, German, and US direct healthcare costs [in 2023 US dollars (USD)] were applied to hospitalized events (including strokes and bleeds) and study drugs for all participants with a CHA2DS2-VASc score > 4 to determine the mean cost per participant during the trial (mean follow-up 3.5 years). A daily cost of $0.63, $0.11, $2.26, and $6.06 for apixaban in Canada, the UK, Germany, and the USA was used. If in-trial results were not cost-saving (below $0), the prospective plan was to perform a lifetime cost-effectiveness analysis using a Markov model and a willingness-to-pay of 50 000 USD per quality-adjusted life year (QALY). After considering the cost of study medication and clinical events over 3.5 years, apixaban was dominant (cost-saving and more effective) in Canada (-$2301) and the UK (-$902) but cost more in Germany and the USA ($600 and $1990, respectively). Over a lifetime, treatment with apixaban produced a net gain of 0.107 QALYs, but with costs in both Germany ($2623 more) and the USA ($9110 more), yielding an incremental cost-effectiveness ratio of $24 514 per QALY for Germany and $85 140 for the USA. CONCLUSION:In patients with SCAF and a CHA2DS2-VASc score > 4, apixaban is cost saving in Canada and the UK and cost-effective in Germany. Apixaban was not cost-effective in the USA under the base cost assumption but would be cost-effective at a daily cost of $4.35 and cost saving at $3.59.

Cardiac procedures, particularly those requiring cardiopulmonary bypass (CPB), are associated with the development of cardiac surgery-associated acute kidney injury (CSA-AKI). Development of CSA-AKI occurs as a result of inflammation, uncontrolled complement activation, and kidney cell damage. In patients with preoperative renal impairment, such as those with chronic kidney disease (CKD), there is an increased risk of both CSA-AKI and poorer clinical outcomes. Currently, there are limited effective, targeted pharmacological interventions for the prevention or treatment of CSA-AKI, although emerging therapies are being investigated, particularly in patients with existing CKD. The ARTEMIS (RAvulizumab to PRotect PaTients with Chronic Kidney DisEase froM CSA-AKI and Subsequent Major Adverse Kidney Events) trial will assess the efficacy and safety of ravulizumab (a complement C5 inhibitor) in reducing the risk of major adverse kidney events (MAKE) in patients with preoperative CKD undergoing non-emergent cardiac surgery with CPB. This trial is currently recruiting patients with CKD who have planned cardiac surgery requiring CPB including coronary artery bypass grafting, valve replacement or repair, or combined procedures. This is a phase 3, randomized, double-blind, placebo-controlled, global study assessing the efficacy and safety of a single preoperative dose of ravulizumab. These outcomes will be assessed using the occurrence of MAKE and its components, as well as the occurrence and severity of CSA-AKI throughout the study period. Complement activation is known to occur during and after cardiac procedures as a result of CPB and ischemia–reperfusion injury, leading to a cycle of cell damage and death. Therefore, it is hypothesized that preoperative administration of ravulizumab will provide immediate and complete complement inhibition, which will be sustained throughout the surgical period, preventing the uncontrolled complement activation associated with the development of CSA-AKI, thus minimizing poor outcomes for patients. ClinicalTrials.gov NCT05746559. Registered on February 27, 2023.

Background: Delirium is an acute state of confusion associated with adverse postoperative outcomes. Delirium is diagnosed clinically using screening tools; most cases go undetected. Identifying a delirium biomarker would allow for accurate diagnosis, application of therapies, and insight into causal pathways. To agnostically discover novel biomarkers of delirium, we conducted a case-control sub-study using the VISION-Cardiac Surgery biobank. Our objective was to identify candidate biomarkers to investigate in future studies. Methods: We obtained a convenience sample of 30 patients with delirium on postoperative day 1 matched to 30 matched controls by age, sex, ethnicity, center and cardiopulmonary bypass time. The Olink Explore 3K platform was used to identify blood protein alterations on postoperative day 3. Protein concentrations were expressed as normalized protein expression (NPx) units (log2 fold scale). We compared protein expression between cases and controls using a paired t-test and reported significantly different biomarkers based on a False Discovery Rate (FDR)-adjusted p-value<0.05. Results: Of 2,865 unique serum proteins, 26 (0.9%) were significantly associated with delirium status; all were elevated in cases versus controls at an FDR<0.05. Pathway analysis identified “calcium-release channel activity” (Padj=0.02) and “Guanosine 5’ triphosphate (GTP)-binding” (Padj=0.005) functions as characteristic of proteins associated with delirium. The top three differentially expressed biomarkers were FKBP1B (Padj=0.003), C2CD2L (Padj=0.004), and RAB6B (Padj=0.004). The inflammatory biomarker IL-8 (CXCL8) (mean difference = 2.36; P=3.6x10-4) was also associated with delirium. Discussion: We identified 26 biomarkers significantly associated with delirium; all are novel except for IL-8. We did not identify an association between delirium and recognized neuro-inflammatory proteins and markers of brain injury, which supports using biomarkers to differentiate between delirium and other neurological conditions. While exploratory, our findings support using biomarkers to diagnose postoperative delirium and validate using agnostic screens to identify potential delirium biomarkers.

ImportanceDelirium is common after cardiac surgery and associated with adverse outcomes. Intraoperative benzodiazepines may increase postoperative delirium but restricting intraoperative benzodiazepines has not yet been evaluated in a randomized trial.ObjectiveTo determine whether an institutional policy of restricted intraoperative benzodiazepine administration reduced the incidence of postoperative delirium.Design, Setting, and ParticipantsThis pragmatic, multiperiod, patient- and assessor-blinded, cluster randomized crossover trial took place at 20 North American cardiac surgical centers. All adults undergoing open cardiac surgery at participating centers during the trial period were included through a waiver of individual patient consent between November 2019 and December 2022.InterventionInstitutional policies of restrictive vs liberal intraoperative benzodiazepine administration were compared. Hospitals (clusters) were randomized to cross between the restricted and liberal benzodiazepine policies 12 to 18 times over 4-week periods.Main Outcomes and MeasuresThe primary outcome was the incidence of delirium within 72 hours of surgery as detected in routine clinical care, using either the Confusion Assessment Method–Intensive Care Unit or the Intensive Care Delirium Screening Checklist. Intraoperative awareness by patient report was assessed as an adverse event.ResultsDuring the trial, 19 768 patients (mean [SD] age, 65 [12] years; 14 528 [73.5%] male) underwent cardiac surgery, 9827 during restricted benzodiazepine periods and 9941 during liberal benzodiazepine periods. During restricted periods, clinicians adhered to assigned policy in 8928 patients (90.9%), compared to 9268 patients (93.2%) during liberal periods. Delirium occurred in 1373 patients (14.0%) during restricted periods and 1485 (14.9%) during liberal periods (adjusted odds ratio [aOR], 0.92; 95% CI, 0.84-1.01; P = .07). No patient spontaneously reported intraoperative awareness.Conclusions and RelevanceIn intention-to-treat analyses, restricting benzodiazepines during cardiac surgery did not reduce delirium incidence but was also not associated with an increase in the incidence of patient-reported intraoperative awareness. Given that smaller effect sizes cannot be ruled out, restriction of benzodiazepines during cardiac surgery may be considered. Research is required to determine whether restricting intraoperative benzodiazepines at the patient level can reduce the incidence of postoperative delirium.Trial RegistrationClinicalTrials.gov Identifier: NCT03928236

BACKGROUND:The relationship between myocardial injury after cardiac surgery (MICS), ischemia on electrocardiogram (ECG), and mortality is uncertain. In this study we aimed to determine whether potential ischemic ECG changes after cardiac surgery are associated with 30-day mortality. METHODS:In a cohort of adults who underwent cardiac surgery, experts interpreted ECGs preoperatively; on postoperative days 0, 1, 2, and 3; and on the last day before discharge (59,539 total ECGs reviewed) for new potential ischemic ECG changes. RESULTS:Among 12,594 patients, 9097 (72.2%) had potential ischemic ECG changes; 259 (2.1%) died within 30 days after surgery. Among patients with troponin elevation meeting MICS criteria, in models adjusting for EuroSCORE II, the hazard ratio (HR) for 30-day mortality was 0.57 (95% confidence interval [CI] 0.35-0.94, P = 0.03) for new Q waves, 2.17 (95% CI 1.14-4.13, P = 0.02) for ST depression ≥ 2 mm, and 0.58 (95% CI 0.39-0.87, P = 0.007) for T-wave inversion 1-1.9 mm. ST elevation was not significantly associated with 30-day mortality. The only ECG change for which coronary artery bypass grafting (CABG) was an effect modifier was new left bundle branch block (LBBB), with an HR of 2.78 (95% CI 1.69-4.60, P = 0.0001) with CABG and an HR of 1.10 (95% CI 0.54-2.21, P = 0.27) without CABG (P value for interaction = 0.03). CONCLUSIONS:After cardiac surgery, potential ischemic ECG changes are common and have divergent associations with mortality. ST depression was associated with a higher risk of death, whereas new Q waves and T-wave inversions were associated with a lower risk of death. A new LBBB was associated with a higher risk of death only among patients who underwent CABG. Potential ischemic ECG changes are common after cardiac surgery and lack specificity for the diagnosis of myocardial infarction.

New-onset postoperative atrial fibrillation (POAF) complicates 1 in 3 cardiac surgeries and is associated with morbidity, mortality and clinical AF in long-term follow-up. Clinical risk scores have modest performance for predicting POAF. Polygenic risk scores are derived from the summation of up to millions of genetic variants and have shown good predictive ability for incident AF in the community. The ability of polygenic risk scores to predict POAF and subsequent recurrence of clinical AF in cardiac surgery patients is unclear. We performed a prospective cohort study of patients from 4 regions (Canada, Hong Kong, Malaysia, United Kingdom) without a pre-operative history of atrial fibrillation (AF) who underwent cardiac surgery and were followed for 1 year. From pre-operative blood samples, we extracted DNA and calculated each participant’s polygenic risk score for AF using a penalized regression method (lassosum) to combine the effects of 5,000,621 genetic variants, weighted by their association with AF status from a previous genome-wide association study by Miyazawa (Nature Genetics, 2023). We estimated the association of this polygenic risk score for AF with the incidence of new-onset POAF using analyses adjusted for genetic ancestry. We assessed the ability of the polygenic risk score to predict POAF when added to common clinical risk scores. As a secondary objective, among patients who developed POAF, we estimated the association of the polygenic risk score with AF recurrence in follow-up beyond 30 post-operative days. Among 3031 patients (63.5% isolated coronary artery bypass grafting), 1282 patients (42.3%) developed new-onset POAF. The polygenic risk score for AF was strongly associated with the risk for POAF (odds ratio 1.3 per standard deviation increase in polygenic risk score [95% CI 1.2-1.4]). The 10% of participants with highest polygenic risk had a risk of POAF of 50.5% as compared to 41.4% for the bottom 90% (odds ratio 1.4 [95% CI 1.1-1.8]). When the polygenic risk score was added to the clinical risk scores, it improved the model fit for all scores, significantly improved the C-statistic for the CHA2DS2-VASc, POAF and HATCH Scores and improved measures of risk classification for all scores (Table). Follow-up data on AF status beyond 30 days were available for 902 patients; 71 patients (7.9%) had AF recurrence detected beyond 30 days post-operatively. The polygenic risk score was not significantly associated with a higher risk for AF recurrence (odds ratio, 1.1 per standard deviation increase in polygenic risk score [95% CI, 0.9-1.5]). A higher polygenic risk score for AF is associated with the development of new-onset POAF following cardiac surgery and improves risk classification compared with clinical risk scores alone. However, this study failed to demonstrate an association of the polygenic risk score with AF recurrence in patients who develop POAF.

Sternal surgical site infections after cardiac surgery can lead to significant morbidity, mortality, and cost. The effects of negative pressure wound management and adding vancomycin as perioperative antimicrobial prophylaxis are unknown. The PICS-PREVENA pilot/vanguard trial, a 2x2 factorial, open label, cluster-randomized crossover trial with 4 periods, was conducted at two major cardiac surgery hospitals in Ontario, Canada. Sites were randomized to one of eight sequences of the four study arms (Cefazolin or Cefazolin + Vancomycin (not analyzed) and standard wound dressing or a negative pressure 3M Prevena incision management system (Prevena). Only diabetic or obese patients were eligible for the latter comparison. This trial investigated feasability including adherence to protocol of each intervention (goal: > 90% each) and loss to follow-up (goal: < 10%). Among the 4107 included patients, 2230 were obese/diabetic (1208 standard wound dressing period, 1022 during Prevena period). Compliance to wound management and antimicrobial prophylaxis was 68.1% and 98.7%, respectively. Loss to follow-up was 3.6%. Deep/organ-space sternal surgical site infections occurred in 16 (1.6%) patients in the Prevena allocated periods and in 17 (1.4%) patients in the standard wound dressing allocated periods (OR= 1.11, 95% CI: 0.56-2.20). Other clinical outcomes did not suggest a difference and a post-hoc as-treated analysis showed similar results. This study showed challenges with introducing a novel technology as standard of care, with non-compliance mostly driven by one of the sites. No firm conclusions should be drawn regarding the effectiveness of Prevena, as this vanguard trial was not powered for clinical outcomes.