Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. METHODS: Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction. RESULTS: Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m2 and 63.8±14.0 g/m2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1 to 1.5 g/m2; P=0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20-105 pg/mL) and 55 pg/mL (21-132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mm Hg (-5.2 to 2.6 mm Hg; P=0.52), 0.69 mm Hg (-1.9 to 3.3 mm Hg; P=0.60), and -6.1 pg/mL (-37.0 to 24.8 pg/mL; P=0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups. CONCLUSIONS: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04461041.

Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke.

BACKGROUND: Surgical occlusion of the left atrial appendage has been hypothesized to prevent ischemic stroke in patients with atrial fibrillation, but this has not been proved. The procedure can be performed during cardiac surgery undertaken for other reasons. METHODS: We conducted a multicenter, randomized trial involving participants with atrial fibrillation and a CHA2DS2-VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating greater risk of stroke) who were scheduled to undergo cardiac surgery for another indication. The participants were randomly assigned to undergo or not undergo occlusion of the left atrial appendage during surgery; all the participants were expected to receive usual care, including oral anticoagulation, during follow-up. The primary outcome was the occurrence of ischemic stroke (including transient ischemic attack with positive neuroimaging) or systemic embolism. The participants, research personnel, and primary care physicians (other than the surgeons) were unaware of the trial-group assignments. RESULTS: The primary analysis population included 2379 participants in the occlusion group and 2391 in the no-occlusion group, with a mean age of 71 years and a mean CHA2DS2-VASc score of 4.2. The participants were followed for a mean of 3.8 years. A total of 92.1% of the participants received the assigned procedure, and at 3 years, 76.8% of the participants continued to receive oral anticoagulation. Stroke or systemic embolism occurred in 114 participants (4.8%) in the occlusion group and in 168 (7.0%) in the no-occlusion group (hazard ratio, 0.67; 95% confidence interval, 0.53 to 0.85; P = 0.001). The incidence of perioperative bleeding, heart failure, or death did not differ significantly between the trial groups. CONCLUSIONS: Among participants with atrial fibrillation who had undergone cardiac surgery, most of whom continued to receive ongoing antithrombotic therapy, the risk of ischemic stroke or systemic embolism was lower with concomitant left atrial appendage occlusion performed during the surgery than without it. (Funded by the Canadian Institutes of Health Research and others; LAAOS III ClinicalTrials.gov number, NCT01561651.).

Aldosterone and aldosterone synthase inhibitors in cardiorenal disease.

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.

Acute Infarcts on Brain MRI Following Aortic Arch Repair With Circulatory Arrest: Insights From the ACE CardioLink-3 Randomized Trial.

BACKGROUND: to investigate the frequency and distribution of new ischemic brain lesions detected by diffusion-weighted imaging on brain magnetic resonance imaging after aortic arch surgery. METHODS: This preplanned secondary analysis of the randomized, controlled ACE (Aortic Surgery Cerebral Protection Evaluation) CardioLink-3 trial compared the safety and efficacy of innominate versus axillary artery cannulation during elective proximal aortic arch surgery. Participants underwent pre and postoperative magnetic resonance imaging. New ischemic lesions were defined as lesions visible on postoperative, but not preoperative diffusion weighted imaging. RESULTS: Of the 111 trial participants, 102 had complete magnetic resonance imaging data. A total of 391 new ischemic lesions were observed on diffusion-weighted imaging in 71 (70%) patients. The average number of lesions in patients with ischemic lesion were 5.5±4.9 with comparable numbers in the right (2.9±2.0) and left (3.0±2.3) hemispheres (P=0.49). Half the new lesions were in the middle cerebral artery territory; 63% of the cohort had ischemic lesions in the anterior circulation, 49% in the posterior circulation, 42% in both, and 20% in watershed areas. A probability mask of all diffusion-weighted imaging lesions revealed that the cerebellum was commonly involved. More severe white matter hyperintensity on preoperative magnetic resonance imaging (odds ratio, 1.80 [95% CI, 1.10-2.95]; P=0.02) and lower nadir nasopharyngeal temperature during surgery (odds ratio per 1°C decrease, 1.15 [95% CI, 1.00-1.32]; P=0.05) were associated with the presentation of new ischemic lesion; older age (risk ratio per 1-year increase, 1.02 [95% CI, 1.00-1.04]; P=0.03) and lower nadir temperature (risk ratio per 1°C decrease, 1.06 [95% CI, 1.00-1.14]; P=0.06) were associated with greater number of lesions. CONCLUSIONS: In patients who underwent elective proximal aortic arch surgery, new ischemic brain lesions were common, and predominantly involved the middle cerebral artery territory or cerebellum. Underlying small vessel disease, lower temperature nadir during surgery, and advanced age were risk factors for perioperative ischemic lesions. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02554032.

Empagliflozin improves circulating vascular regenerative cell content in people without diabetes with risk factors for adverse cardiac remodeling.

Sodium glucose-cotransporter 2 (SGLT2) inhibitors have been reported to reduce cardiovascular events and heart failure in people with and without diabetes. These medications have been shown to counter regenerative cell exhaustion in the context of prevalent diabetes. This study sought to determine if empagliflozin attenuates regenerative cell exhaustion in people without diabetes. Peripheral blood mononuclear cells were collected at the baseline and 6-mo visits from individuals randomized to receive empagliflozin (10 mg/day) or placebo who were participating in the EMPA-HEART 2 CardioLink-7 trial. Precursor cell phenotypes were characterized by flow cytometry for cell-surface markers combined with high aldehyde dehydrogenase activity to identify precursor cell subsets with progenitor (ALDHhi) versus mature effector (ALDHlow) cell attributes. Samples from individuals assigned to empagliflozin (n = 25) and placebo (n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDHhiSSClow), monocyte (ALDHhiSSCmid), and granulocyte (ALDHhiSSChi) precursor cells in both groups were similar. At 6 mo, participants randomized to empagliflozin demonstrated increased ALDHhiSSClowCD133+CD34+ proangiogenic cells (P = 0.048), elevated ALDHhiSSCmidCD163+ regenerative monocyte precursors (P = 0.012), and decreased ALDHhiSSCmidCD86 + CD163- proinflammatory monocyte (P = 0.011) polarization compared with placebo. Empagliflozin promoted the recovery of multiple circulating provascular cell subsets in people without diabetes suggesting that the cardiovascular benefits of SGLT2 inhibitors may be attributed in part to the attenuation of vascular regenerative cell exhaustion that is independent of diabetes status.NEW & NOTEWORTHY Using an aldehyde dehydrogenase (ALDH) activity-based flow cytometry assay, we found that empagliflozin treatment for 6 mo was associated with parallel increases in circulating vascular regenerative ALDHhi-CD34/CD133-coexpressing progenitors and decreased proinflammatory ALDHhi-CD14/CD86-coexpressing monocyte precursors in individuals without diabetes but with cardiovascular risk factors. The rejuvenation of the vascular regenerative cell reservoir may represent a mechanism via which sodium glucose-cotransporter 2 (SGLT2) inhibitors limit maladaptive repair and delay the development and progression of cardiovascular diseases.

Left ventricular mass predicts cardiac reverse remodelling in patients treated with empagliflozin.

BACKGROUND: The cardiovascular (CV) benefits of sodium-glucose transport protein 2 inhibitors have been attributed, in part, to cardiac reverse remodelling. The EMPA-HEART CardioLink-6 study reported that sodium-glucose cotransporter-2 inhibition for 6 months with empagliflozin was associated with a significant reduction in left ventricular mass indexed to body surface area (LVMi). In this sub-analysis, we evaluated whether baseline LVMi may influence how empagliflozin affects cardiac reverse remodelling. METHODS: A total of 97 patients with type 2 diabetes and coronary artery disease were randomized to empagliflozin (10 mg/d) or matching placebo for 6 months. The study cohort was divided into those whose baseline LVMi was ≤ 60 g/m2 and those who had a baseline LVMi > 60 g/m2. Subgroup comparisons were conducted using a linear regression model adjusted for baseline values (ANCOVA) that included an interaction term between LVMi subgroup and treatment. RESULTS: Baseline LVMi was 53.3 g/m2 (49.2-57.2) and 69.7 g/m2 (64.2-76.1) for those with baseline ≤ 60 g/m2 (n = 54) and LVMi > 60 g/m2 (n = 43) respectively. The adjusted difference of LVMi regression between those randomized to empagliflozin and placebo were - 0.46 g/m2 (95% CI: -3.44, 2.52, p = 0.76) in the baseline LVMi ≤ 60 g/m2 subgroup and - 7.26 g/m2 (95% CI: -11.40, -3.12, p = 0.0011) in the baseline LVMi > 60 g/m2 subgroup (p-for-interaction = 0.007). No significant associations were found between baseline LVMi and 6-month change in LV end systolic volume-indexed (p-for-interaction = 0.086), LV end diastolic volume-indexed (p-for-interaction = 0.34), or LV ejection fraction (p-for-interaction = 0.15). CONCLUSIONS: Patients with higher LVMi at baseline experienced greater LVM regression with empagliflozin.

Chronic heart failure management in adult patients with congenital heart disease.

PURPOSE OF REVIEW: A growing number of adult patients with congenital heart disease (ACHD) are entering the healthcare system as a result of advances in the diagnosis and management of congenital heart defects. Heart failure is a common final pathway for this diverse patient population, representing the leading cause of mortality in ACHD patients. Herein, we review present guideline-directed management of heart failure in ACHD patients. RECENT FINDINGS: There exists a dearth of data to guide management of ACHD-related heart failure. Given this gap, recent guidelines have been limited in the recommendations they can provide for this patient population, with practitioners being consequently forced to generalize findings from studies of acquired heart disease patients based on mechanistic plausibility. The small number of studies directly assessing ACHD patients have been largely limited in their clinical relevance through being negative, small, observational, limited to specific subsets of ACHD patients or assessing nonvalidated outcomes. SUMMARY: Despite the prevalence and impact of ACHD-related heart failure, there are limited evidence-based therapies for its management. Given the rising burden of this clinical problem, definitive trials assessing newer therapies are required to establish their potential role in heart failure amongst ACHD patients.

Transfusion thresholds in acute coronary syndromes.

PURPOSE OF REVIEW: Anemia is prevalent in patients with acute coronary syndromes. In this setting, there is uncertainty and controversy surrounding the optimal transfusion strategy for managing anemia. The goal of this review is to summarize the current clinical evidence, guidelines, and future directions for managing transfusion in acute coronary syndromes. RECENT FINDINGS: There is limited evidence from randomized trials evaluating restrictive versus liberal transfusion in patients hospitalized with and/or for acute coronary syndromes. The results from these studies suggest clinical equipoise between transfusion strategies for short term outcomes, and a trend toward favoring a liberal strategy for long term major adverse cardiac events. There is inconsistency across clinical practice guidelines with respect to the optimal strategy for managing anemia and transfusion in acute coronary syndromes due to insufficient evidence. SUMMARY: More evidence is urgently needed to conclusively establish the optimal strategy for transfusion management in the setting of acute coronary syndromes. These data will directly inform harmonization of clinical practice guidelines. Future investigations should explore alternative strategies to hemoglobin for quantifying the degree of anemic stress for personalizing transfusion therapy, the effects on functional outcomes, and managing anemia following hospital discharge.

Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: a systematic review and meta-analysis of randomised controlled trials and observational studies.

BACKGROUND: Benzodiazepine use is associated with delirium, and guidelines recommend avoiding them in older and critically ill patients. Their perioperative use remains common because of perceived benefits. METHODS: We searched CENTRAL, MEDLINE, CINAHL, PsycInfo, and Web of Science from inception to June 2021. Pairs of reviewers identified randomised controlled trials and prospective observational studies comparing perioperative use of benzodiazepines with other agents or placebo in patients undergoing surgery. Two reviewers independently abstracted data, which we combined using a random-effects model. Our primary outcomes were delirium, intraoperative awareness, and mortality. RESULTS: We included 34 randomised controlled trials (n=4354) and nine observational studies (n=3309). Observational studies were considered separately. Perioperative benzodiazepines did not increase the risk of delirium (n=1352; risk ratio [RR] 1.43; 95% confidence interval [CI]: 0.9-2.27; I2=72%; P=0.13; very low-quality evidence). Use of benzodiazepines instead of dexmedetomidine did, however, increase the risk of delirium (five studies; n=429; RR 1.83; 95% CI: 1.24-2.72; I2=13%; P=0.002). Perioperative benzodiazepine use decreased the risk of intraoperative awareness (n=2245; RR 0.26; 95% CI: 0.12-0.58; I2=35%; P=0.001; very low-quality evidence). When considering non-events, perioperative benzodiazepine use increased the probability of not having intraoperative awareness (RR 1.07; 95% CI: 1.01-1.13; I2=98%; P=0.03; very low-quality evidence). Mortality was reported by one randomised controlled trial (n=800; RR 0.90; 95% CI: 0.20-3.1; P=0.80; very low quality). CONCLUSIONS: In this systematic review and meta-analysis, perioperative benzodiazepine use did not increase postoperative delirium and decreased intraoperative awareness. Previously observed relationships of benzodiazepine use with delirium could be explained by comparisons with dexmedetomidine. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42019128144.

Effect of empagliflozin on cardiac remodelling in South Asian and non-South Asian individuals: insights from the EMPA-HEART CardioLink-6 randomised clinical trial.

BACKGROUND: This exploratory sub-analysis of the EMPA-HEART CardioLink-6 trial examined whether the previously reported benefit of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin on left ventricular (LV) mass (LVM) regression differs between individuals of South Asian and non-South Asian ethnicity. METHODS: EMPA-HEART CardioLink-6 was a double-blind, placebo-controlled clinical trial that randomised 97 individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) to either empagliflozin 10 mg daily or placebo for 6 months. LV parameters and function were assessed using cardiac magnetic resonance imaging. The 6-month changes in LVM and LV volumes, all indexed to baseline body surface area, for South Asian participants were compared to those for non-South Asian individuals. RESULTS: Compared to the non-South Asian group, the South Asian sub-cohort comprised more males, was younger and had a lower median body mass index. The adjusted difference for LVMi change over 6 months was -4.3 g/m2 (95% confidence interval [CI], -7.5, -1.0; P = 0.042) for the South Asian group and -2.3 g/m2 (95% CI, -6.4, 1.9; P = 0.28) for the non-South Asian group (Pinteraction = 0.45). There was no between-group difference for the adjusted differences in baseline body surface area-indexed LV volumes and LV ejection fraction. CONCLUSIONS: There was no meaningful difference in empagliflozin-associated LVM regression between South Asian and non-South Asian individuals living with T2DM and CAD in the EMPA-HEART CardioLink-6 trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02998970 (First posted on 21/12/ 2016).

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.

Understanding potential barriers and enablers to a perioperative early phase cell therapy trial.

BACKGROUND AIMS: Early-phase cell therapy clinical trials depend on patient and physician involvement, yet barriers can impede their participation. METHODS: To optimize engagement for a planned cell therapy trial to prevent perioperative cardiac complications, the authors conducted semi-structured interviews with at-risk patients and physicians who could potentially be involved in the study. The authors used the theoretical domains framework to systematically identify potential barriers and enablers. RESULTS: Forty-one interviews were conducted to reach data saturation, and four overall potential barriers to participation (themes) were identified. Theme 1 emphasizes that patients and physicians need accessible information to better understand the benefits and risks of the novel therapy and trial procedures and to address misconceptions. Theme 2 underscores the need for clarity on whether the trial's primary purpose is safety or efficacy, as this may influence patient and physician decisions. Theme 3 recognizes the resource and logistic realities for patients (e.g., convenient follow-up appointments) and physicians (e.g., personnel to assist in trial procedures, competing priorities). Theme 4 describes the importance of social influences (e.g., physicians and family, peers/colleagues) that may affect decisions to participate and the importance of patient preferences (e.g., availability of physicians to discuss the trial, including caregivers in discussions). CONCLUSIONS: Prospectively addressing these issues may help optimize feasibility prior to conducting an expensive, resource-intensive trial.

Cardiovascular efficacy of liraglutide and semaglutide in individuals with diabetes and peripheral artery disease.

AIM: To evaluate the cardiovascular (CV) efficacy of liraglutide and semaglutide in patients with type 2 diabetes (T2D) and peripheral artery disease (PAD). MATERIALS AND METHODS: LEADER and SUSTAIN 6 trials investigated subcutaneous liraglutide (≤1.8 mg/day) and semaglutide (0.5 or 1.0 mg/week), respectively, versus placebo in patients with T2D and high CV risk (median follow-up: 3.8 and 2.1 years, respectively). The primary outcome was a composite of CV death, non-fatal myocardial infarction or non-fatal stroke (major adverse CV event [MACE]) according to the presence of PAD at baseline. RESULTS: Overall, 1184/9340 (12.7%) patients in LEADER and 460/3297 (14.0%) in SUSTAIN 6 had PAD at baseline. Patients with PAD were at an ~35% increased risk of MACE versus those without (LEADER: hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.17-1.58; SUSTAIN 6: HR 1.33, 95% CI 0.94-1.83). The effects of both therapies on MACE were consistently beneficial in patients with PAD (liraglutide: HR 0.77, 95% CI 0.58-1.01; semaglutide: 0.61, 0.33-1.13) and without (liraglutide: HR 0.89, 95% CI 0.79-1.00; semaglutide: HR 0.77, 95% CI 0.58-1.01; Pinteraction  = .34 for liraglutide and .49 for semaglutide). Absolute risk reductions for MACE were higher in patients with PAD (liraglutide: 4.13%-point, 95% CI -0.15-8.42; semaglutide: 4.63%-point, 95% CI -0.58-9.84) versus without (liraglutide:1.42%-point, 95% CI -0.03-2.87; semaglutide: 1.90%-point, 95% CI 0.00-3.80). CONCLUSION: Both liraglutide and semaglutide reduce MACE with consistent CV efficacy regardless of PAD status.

Restrictive versus liberal transfusion in patients with diabetes undergoing cardiac surgery: An open-label, randomized, blinded outcome evaluation trial.

AIM: To characterize the association between diabetes and transfusion and clinical outcomes in cardiac surgery, and to evaluate whether restrictive transfusion thresholds are harmful in these patients. MATERIALS AND METHODS: The multinational, open-label, randomized controlled TRICS-III trial assessed a restrictive transfusion strategy (haemoglobin [Hb] transfusion threshold <75 g/L) compared with a liberal strategy (Hb <95 g/L for operating room or intensive care unit; or <85 g/L for ward) in patients undergoing cardiac surgery on cardiopulmonary bypass with a moderate-to-high risk of death (EuroSCORE ≥6). Diabetes status was collected preoperatively. The primary composite outcome was all-cause death, stroke, myocardial infarction, and new-onset renal failure requiring dialysis at 6 months. Secondary outcomes included components of the composite outcome at 6 months, and transfusion and clinical outcomes at 28 days. RESULTS: Of the 5092 patients analysed, 1396 (27.4%) had diabetes (restrictive, n = 679; liberal, n = 717). Patients with diabetes had more cardiovascular disease than patients without diabetes. Neither the presence of diabetes (OR [95% CI] 1.10 [0.93-1.31]) nor the restrictive strategy increased the risk for the primary composite outcome (diabetes OR [95% CI] 1.04 [0.68-1.59] vs. no diabetes OR 1.02 [0.85-1.22]; Pinteraction  = .92). In patients with versus without diabetes, a restrictive transfusion strategy was more effective at reducing red blood cell transfusion (diabetes OR [95% CI] 0.28 [0.21-0.36]; no diabetes OR [95% CI] 0.40 [0.35-0.47]; Pinteraction  = .04). CONCLUSIONS: The presence of diabetes did not modify the effect of a restrictive transfusion strategy on the primary composite outcome, but improved its efficacy on red cell transfusion. Restrictive transfusion triggers are safe and effective in patients with diabetes undergoing cardiac surgery.

ONTraC: A 20-Year History of a Successfully Coordinated Provincewide Patient Blood Management Program: Lessons Learned and Goals Achieved.

Our understanding of the risks associated with perioperative anemia and transfusion, in terms of increased morbidity and mortality, has evolved over the past 2 decades. By contrast, our understanding of the potential mechanisms of injury and optimal treatment strategies remains incomplete. As such, the important role of effective patient blood management (PBM) programs, which address both the effective treatment of anemia and minimizes the need for red blood cell (RBC) transfusion, is of central importance to optimizing patient care and improving patient outcomes. We report on important clinical outcomes of the Ontario Transfusion Coordinator (ONTraC Program), a network of 25 hospital sites, working in coordination over the past 20 years. Transfusion nurse coordinators were assigned to apply multimodal best practice in PBM (including recommended changes in surgical approach; diagnosis, assessment, and treatment of anemia; and adherence to more restrictive RBC transfusion thresholds). Data were collected on various clinical parameters. We further described lessons learned and difficulties encountered in this multisite PBM initiative. A significant reduction in RBC transfusions was observed for numerous indexed surgeries. For example, RBC transfusion rates for knee arthroplasty decreased from 25% in 2002 to 0.4% in 2020. For coronary artery bypass graft (CABG) surgery, transfusion rates decreased from 60% in 2002 to 27% in 2020. We also observed a decrease in RBC units utilized per transfused patient for knee (2.1 ± 0.5 [2002] vs 1.0 ± 0.6 [2020] units per patient) and CABG surgery (3.3 ± 0.6 [2002] vs 2.3 ± 1.9 [2020] units per patient). These reductions were associated with favorable clinical outcomes, including reduced length of hospital stay (P = .00003) and a reduced rate of perioperative infections (P < .001) for nontransfused versus transfused patients. These advances have been achieved with estimated savings in the tens of millions of dollars annually. Our experience and data support the hypothesis that instituting an integrated network of transfusion nurse coordinators can provide an effective provincewide PBM program, reduce RBC transfusions, improve some patient outcomes, and reduce health care costs, as an example of a "win-win-win" medical program.

Update on Applications and Limitations of Perioperative Tranexamic Acid.

Tranexamic acid (TXA) is a potent antifibrinolytic with documented efficacy in reducing blood loss and allogeneic red blood cell transfusion in several clinical settings. With a growing emphasis on patient blood management, TXA has become an integral aspect of perioperative blood conservation strategies. While clinical applications of TXA in the perioperative period are expanding, routine use in select clinical scenarios should be supported by evidence for efficacy. Furthermore, questions regarding optimal dosing without increased risk of adverse events such as thrombosis or seizures should be answered. Therefore, ongoing investigations into TXA utilization in cardiac surgery, obstetrics, acute trauma, orthopedic surgery, neurosurgery, pediatric surgery, and other perioperative settings continue. The aim of this review is to provide an update on the current applications and limitations of TXA use in the perioperative period.

Prolonged mechanical ventilation after cardiac surgery: substudy of the Transfusion Requirements in Cardiac Surgery III trial.

PURPOSE: Prolonged mechanical ventilation (MV) is a major complication following cardiac surgery. We conducted a secondary analysis of the Transfusion Requirements in Cardiac Surgery (TRICTS) III trial to describe MV duration, identify factors associated with prolonged MV, and examine associations of prolonged MV with mortality and complications. METHODS: Four thousand, eight hundred and nine participants undergoing cardiac surgery at 71 hospitals worldwide were included. Prolonged MV was defined based on the Society of Thoracic Surgeons definition as MV lasting 24 hr or longer. Adjusted associations of patient and surgical factors with prolonged MV were examined using multivariable logistic regression. Associations of prolonged MV with complications were assessed using odds ratios, and adjusted associations between prolonged MV and mortality were evaluated using multinomial regression. Associations of shorter durations of MV with survival and complications were explored. RESULTS: Prolonged MV occurred in 15% (725/4,809) of participants. Prolonged MV was associated with surgical factors indicative of complexity, such as previous cardiac surgery, cardiopulmonary bypass duration, and separation attempts; and patient factors such as critical preoperative state, left ventricular impairment, renal failure, and pulmonary hypertension. Prolonged MV was associated with perioperative but not long-term complications. After risk adjustment, prolonged MV was associated with perioperative mortality; its association with long-term mortality among survivors was weaker. Shorter durations of MV were not associated with increased risk of mortality or complications. CONCLUSION: In this substudy of the TRICS III trial, prolonged MV was common after cardiac surgery and was associated with patient and surgical risk factors. Although prolonged MV showed strong associations with perioperative complications and mortality, it was not associated with long-term complications and had weaker association with long-term mortality among survivors. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT02042898); registered 23 January 2014. This is a substudy of the Transfusion Requirements in Cardiac Surgery (TRICS) III trial.

RéSUMé: OBJET: La ventilation mécanique (VM) prolongée est une complication majeure après chirurgie cardiaque. Nous avons effectué une analyze secondaire de l'étude TRICS III sur les besoins de transfusion au cours de la chirurgie cardiaque pour décrire la durée de la VM, identifier les facteurs associés à une VM prolongée et examiner les associations de la VM prolongée avec la mortalité et les complications. MéTHODES: Quatre mille huit cent neuf participants subissant une chirurgie cardiaque dans 71 hôpitaux à travers le monde ont été inclus. La VM prolongée a été définie à partir de la définition de la Society of Thoracic Surgeons comme un événement durant 24 heures ou plus. Des associations ajustées de facteurs liés aux patients et à la chirurgie avec la VM prolongée ont été examinées en utilisant une régression logistique multifactorielle. Des associations de la VM prolongée avec des complications ont été évaluées en utilisant des rapports de cotes; les associations ajustées entre VM prolongée et mortalité ont été évaluées au moyen d'une régression multinominale. Les associations d'une VM de plus courte durée avec la survie et des complications ont été explorées. RéSULTATS: La VM prolongée est survenue chez 15 % (725/4 809) des participants. Une VM prolongée a été associée à des facteurs chirurgicaux indicateurs de complexité (comme une chirurgie cardiaque antérieure, la durée de la circulation extracorporelle et les tentatives de débranchement) et à des facteurs liés au patient (comme un état préopératoire critique, une défaillance ventriculaire gauche, une insuffisance rénale et une hypertension pulmonaire). La VM prolongée a été associée à des complications périopératoires, mais pas à des complications à long terme. Après ajustement pour le risque, la VM prolongée a été associée à la mortalité périopératoire; son association avec la mortalité à long terme des survivants a été plus faible. Les durées plus courtes de VM n'ont pas été associées à une augmentation du risque de mortalité ou à des complications. CONCLUSION: Dans cette étude auxiliaire de l'essai TRICS III, la VM prolongée a été fréquente après chirurgie cardiaque et a été associée à des facteurs de risque liés au patient et à la chirurgie. Bien que la VM prolongée ait présenté de fortes associations avec les complications périopératoires et la mortalité, elle n'a pas été associée avec des complications à long terme et était plus faiblement associée à la mortalité à long terme parmi les survivants. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT02042898); enregistrée le 23 janvier 2014. Il s'agit d'une étude auxiliaire de l'étude TRICS III sur les besoins de transfusion en chirurgie cardiaque.

Randomized, Controlled Trial Comparing Mitral Valve Repair With Leaflet Resection Versus Leaflet Preservation on Functional Mitral Stenosis: The CAMRA CardioLink-2 Study.

BACKGROUND: Equipoise exists between the use of leaflet resection and preservation for surgical repair of mitral regurgitation caused by prolapse. We therefore performed a randomized, controlled trial comparing these 2 techniques, particularly in regard to functional mitral stenosis. METHODS: One hundred four patients with degenerative mitral regurgitation surgically amenable to either leaflet resection or preservation were randomized at 7 specialized cardiac surgical centers. Exclusion criteria included anterior leaflet or commissural prolapse, as well as a mixed cause for mitral valve disease. Using previous data, we determined that a sample size of 88 subjects would provide 90% power to detect a 5-mm Hg difference in mean mitral valve gradient at peak exercise, assuming an SD of 6.7 mm with a 2-sided test with α=5% and 10% patient attrition. The primary end point was the mean mitral gradient at peak exercise 12 months after repair. RESULTS: Patient age, proportion who were female, and Society of Thoracic Surgeons risk score were 63.9±10.4 years, 19%, and 1.4±2.8% for those who were assigned to leaflet resection (n=54), and 66.3±10.8 years, 16%, and 1.9±2.6% for those who underwent leaflet preservation (n=50). There were no perioperative deaths or conversions to replacement. At 12 months, moderate mitral regurgitation was observed in 3 subjects in the leaflet resection group and 2 in the leaflet preservation group. The mean transmitral gradient at 12 months during peak exercise was 9.1±5.2 mm Hg after leaflet resection and 8.3±3.3 mm Hg after leaflet preservation (P=0.43). The participants had similar resting peak (8.3±4.4 mm Hg versus 8.4±2.6 mm Hg; P=0.96) and mean resting (3.2±1.9 mm Hg versus 3.1±1.1 mm Hg; P=0.67) mitral gradients after leaflet resection and leaflet preservation, respectively. The 6-minute walking distance was 451±147 m for those in the leaflet resection versus 481±95 m for the leaflet preservation group (P=0.27). CONCLUSIONS: In this adequately powered randomized trial, repair of mitral prolapse with either leaflet resection or leaflet preservation was associated with similar transmitral gradients at peak exercise at 12 months postoperatively. These data do not support the hypothesis that a strategy of leaflet resection (versus preservation) is associated with a risk of functional mitral stenosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier NCT02552771.

Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery.

BACKGROUND: We reported previously that, in patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive transfusion strategy was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or 28 days after surgery, whichever came first. We now report the clinical outcomes at 6 months after surgery. METHODS: We randomly assigned 5243 adults undergoing cardiac surgery to a restrictive red-cell transfusion strategy (transfusion if the hemoglobin concentration was <7.5 g per deciliter intraoperatively or postoperatively) or a liberal red-cell transfusion strategy (transfusion if the hemoglobin concentration was <9.5 g per deciliter intraoperatively or postoperatively when the patient was in the intensive care unit [ICU] or was <8.5 g per deciliter when the patient was in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis occurring within 6 months after the initial surgery. An expanded secondary composite outcome included all the components of the primary outcome as well as emergency department visit, hospital readmission, or coronary revascularization occurring within 6 months after the index surgery. The secondary outcomes included the individual components of the two composite outcomes. RESULTS: At 6 months after surgery, the primary composite outcome had occurred in 402 of 2317 patients (17.4%) in the restrictive-threshold group and in 402 of 2347 patients (17.1%) in the liberal-threshold group (absolute risk difference before rounding, 0.22 percentage points; 95% confidence interval [CI], -1.95 to 2.39; odds ratio, 1.02; 95% CI, 0.87 to 1.18; P=0.006 for noninferiority). Mortality was 6.2% in the restrictive-threshold group and 6.4% in the liberal-threshold group (odds ratio, 0.95; 95% CI, 0.75 to 1.21). There were no significant between-group differences in the secondary outcomes. CONCLUSIONS: In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy for red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis at 6 months after surgery. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).

Generalizability of Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial in patients with a history of coronary artery bypass graft surgery.

PURPOSE OF REVIEW: Following coronary artery bypass grafting (CABG), there remains persistent risk of ischemic events despite secondary prevention strategies, including low-density lipoprotein cholesterol lowering. Although REDUCE-IT recently demonstrated the benefits of icosapent ethyl (IPE) on reducing ischemic events in a broad population of primary and secondary prevention patients, its generalizability to a contemporary CABG population is not known. This article aims to ascertain the proportion of patients with a history of CABG that would be eligible for IPE treatment. RECENT FINDINGS: A review of recent literature highlights the presence of residual ischemic following CABG. Using the Québec Heart Database, a repository of contemporary Canadian cardiac patient information, was searched between 1 January 2006 and 31 December 2016, to ascertain generalizability of IPE. SUMMARY: In a large (N = 12 641), contemporary, Canadian cohort of patients with a history of CABG and currently on statin therapy, 21.9, 33.6 and 26.4% would be eligible for IPE, according to REDUCE-IT, Health Canada, and Food and Drug Administration criteria, respectively. These analyses would support IPE as an adjunct to secondary prevention therapies post-CABG.