Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction.

BACKGROUND: Cardiovascular events frequently recur after acute myocardial infarction, and low cholesterol efflux - a process mediated by apolipoprotein A1, which is the main protein in high-density lipoprotein - has been associated with an increased risk of cardiovascular events. CSL112 is human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity. Whether infusions of CSL112 can reduce the risk of recurrent cardiovascular events after acute myocardial infarction is unclear. METHODS: We conducted an international, double-blind, placebo-controlled trial involving patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors. Patients were randomly assigned to receive either four weekly infusions of 6 g of CSL112 or matching placebo, with the first infusion administered within 5 days after the first medical contact for the acute myocardial infarction. The primary end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes from randomization through 90 days of follow-up. RESULTS: A total of 18,219 patients were included in the trial (9112 in the CSL112 group and 9107 in the placebo group). There was no significant difference between the groups in the risk of a primary end-point event at 90 days of follow-up (439 patients [4.8%] in the CSL112 group vs. 472 patients [5.2%] in the placebo group; hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.05; P = 0.24), at 180 days of follow-up (622 patients [6.9%] vs. 683 patients [7.6%]; hazard ratio, 0.91; 95% CI, 0.81 to 1.01), or at 365 days of follow-up (885 patients [9.8%] vs. 944 patients [10.5%]; hazard ratio, 0.93; 95% CI, 0.85 to 1.02). The percentage of patients with adverse events was similar in the two groups; a higher number of hypersensitivity events was reported in the CSL112 group. CONCLUSIONS: Among patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors, four weekly infusions of CSL112 did not result in a lower risk of myocardial infarction, stroke, or death from cardiovascular causes than placebo through 90 days. (Funded by CSL Behring; AEGIS-II ClinicalTrials.gov number, NCT03473223.).

Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

Graft Failure After Coronary Artery Bypass Grafting and Its Association With Patient Characteristics and Clinical Events: A Pooled Individual Patient Data Analysis of Clinical Trials With Imaging Follow-Up.

BACKGROUND: Graft patency is the postulated mechanism for the benefits of coronary artery bypass grafting (CABG). However, systematic graft imaging assessment after CABG is rare, and there is a lack of contemporary data on the factors associated with graft failure and on the association between graft failure and clinical events after CABG. METHODS: We pooled individual patient data from randomized clinical trials with systematic CABG graft imaging to assess the incidence of graft failure and its association with clinical risk factors. The primary outcome was the composite of myocardial infarction or repeat revascularization occurring after CABG and before imaging. A 2-stage meta-analytic approach was used to evaluate the association between graft failure and the primary outcome. We also assessed the association between graft failure and myocardial infarction, repeat revascularization, or all-cause death occurring after imaging. RESULTS: Seven trials were included comprising 4413 patients (mean age, 64.4±9.1 years; 777 [17.6%] women; 3636 [82.4%] men) and 13 163 grafts (8740 saphenous vein grafts and 4423 arterial grafts). The median time to imaging was 1.02 years (interquartile range [IQR], 1.00-1.03). Graft failure occurred in 1487 (33.7%) patients and in 2190 (16.6%) grafts. Age (adjusted odds ratio [aOR], 1.08 [per 10-year increment] [95% CI, 1.01-1.15]; P=0.03), female sex (aOR, 1.27 [95% CI, 1.08-1.50]; P=0.004), and smoking (aOR, 1.20 [95% CI, 1.04-1.38]; P=0.01) were independently associated with graft failure, whereas statins were associated with a protective effect (aOR, 0.74 [95% CI, 0.63-0.88]; P<0.001). Graft failure was associated with an increased risk of myocardial infarction or repeat revascularization occurring between CABG and imaging assessment (8.0% in patients with graft failure versus 1.7% in patients without graft failure; aOR, 3.98 [95% CI, 3.54-4.47]; P<0.001). Graft failure was also associated with an increased risk of myocardial infarction or repeat revascularization occurring after imaging (7.8% versus 2.0%; aOR, 2.59 [95% CI, 1.86-3.62]; P<0.001). All-cause death after imaging occurred more frequently in patients with graft failure compared with patients without graft failure (11.0% versus 2.1%; aOR, 2.79 [95% CI, 2.01-3.89]; P<0.001). CONCLUSIONS: In contemporary practice, graft failure remains common among patients undergoing CABG and is strongly associated with adverse cardiac events.

Prospective Study of Risk Factors for Postoperative Atrial Fibrillation After Cardiac Surgery.

INTRODUCTION: To examine risk factors for new-onset postoperative atrial fibrillation (POAF) after cardiac surgery. METHODS: Patients enrolled in the Cardiothoracic Surgical Trials Network multicenter, randomized trial of rate control versus rhythm control for POAF were included. Predictors of POAF were determined using multivariable logistic regression. RESULTS: Among the 2104 patients who were enrolled preoperatively, 695 developed POAF (33.0%). Rates of POAF were 28.1% after isolated coronary artery bypass grafting (CABG), 33.7% after isolated valve repair or replacement, and 47.3% after CABG plus valve repair or replacement. Baseline characteristics associated with an increased risk of POAF identified on multivariable analysis included older age (odds ratio [OR] 1.57; 95% confidence interval [CI] 1.42-1.73, per 10 y), White race or non-Hispanic ethnicity (OR 1.52; CI: 1.11-2.07), history of heart failure (OR 1.55; CI: 1.16-2.08), and history of hypothyroidism (OR 1.42; CI 1.04-1.94). The type of cardiac procedure was associated with an increased risk of POAF with both isolated valve repair or replacement (OR 1.33, CI 1.08-1.64) and combined CABG plus valve repair or replacement (OR 1.64, CI 1.24-2.17) having increased risk of POAF compared to isolated CABG. No preoperative cardiac medication was associated with POAF. CONCLUSIONS: In this prospective cohort of patients, older age, a history of hypothyroidism, a history of heart failure, and valve repair or replacement, with or without CABG, and White non-Hispanic race were associated with an increased risk of POAF.

Predictors of bleeding and thrombotic events among patients admitted to the hospital with COVID-19 and elevated D-dimer: insights from the ACTION randomized clinical trial.

Therapeutic anticoagulation showed inconsistent results in hospitalized patients with COVID-19 and selection of the best patients to use this strategy still a challenge balancing the risk of thrombotic and hemorrhagic outcomes. The present post-hoc analysis of the ACTION trial evaluated the variables independently associated with both bleeding events (major bleeding or clinically relevant non-major bleeding) and the composite outcomes thrombotic events (venous thromboembolism, myocardial infarction, stroke, systemic embolism, or major adverse limb events). Variables were assessed one by one with independent logistic regressions and final models were chosen based on Akaike information criteria. The model for bleeding events showed an area under the curve of 0.63 (95% confidence interval [CI] 0.53 to 0.73), while the model for thrombotic events had an area under the curve of 0.72 (95% CI 0.65 to 0.79). Non-invasive respiratory support was associated with thrombotic but not bleeding events, while invasive ventilation was associated with both outcomes (Odds Ratio of 7.03 [95 CI% 1.95 to 25.18] for thrombotic and 3.14 [95% CI 1.11 to 8.84] for bleeding events). Beyond respiratory support, creatinine level (Odds Ratio [OR] 1.01 95% CI 1.00 to 1.02 for every 1.0 mg/dL) and history of coronary disease (OR 3.67; 95% CI 1.32 to 10.29) were also independently associated to the risk of thrombotic events. Non-invasive respiratory support, history of coronary disease, and creatinine level may help to identify hospitalized COVID-19 patients at higher risk of thrombotic complications.ClinicalTrials.gov: NCT04394377.

Bone morphogenetic protein 10: a novel risk marker of ischaemic stroke in patients with atrial fibrillation.

AIMS: Biomarkers specifically related to atrial tissue may increase the understanding of the pathophysiology of atrial fibrillation (AF) and further improve risk prediction in this setting. Bone morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. We evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with and without oral anticoagulation (OAC). METHODS AND RESULTS: BMP10 was measured in plasma samples collected at randomisation in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). BMP10 was analysed with a prototype Elecsys immunoassay. Associations with outcomes were evaluated by Cox-regression models adjusted for clinical characteristics, kidney function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median concentrations of BMP10 were 2.47 and 2.44 ng/mL, in the non-OAC and OAC cohort, respectively. Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death. CONCLUSION: The novel atrial biomarker BMP10 was independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke in AF. ONE-SENTENCE SUMMARY: In this study, BMP10 may be a novel specific biomarker of ischaemic stroke in patients with atrial fibrillation, irrespective of oral anticoagulation.

A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction.

BACKGROUND: Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without substantially increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI). METHODS: We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6 to 12 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on FXIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo. RESULTS: The median age was 68 years, 23% of participants were women, 51% had ST-segment-elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity, with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian versus placebo: hazard ratio, 0.98 [90% CI, 0.71-1.35]). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian 20 and 50 mg versus placebo: hazard ratio, 1.05 [90% CI, 0.69-1.61]). CONCLUSIONS: In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients who experienced acute MI. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04304534; URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2019-003244-79.

Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex.

BACKGROUND: Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation. Meta-analyses using individual patient data offer substantial advantages over study-level data. METHODS: We used individual patient data from the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database, which includes all patients randomized in the 4 pivotal trials of DOACs versus warfarin in atrial fibrillation (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48]), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (HRs [95% CIs]) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex. RESULTS: A total of 71 683 patients were included (29 362 on standard-dose DOAC, 13 049 on lower-dose DOAC, and 29 272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke or systemic embolism (883/29 312 [3.01%] versus 1080/29 229 [3.69%]; HR, 0.81 [95% CI, 0.74-0.89]), death (2276/29 312 [7.76%] versus 2460/29 229 [8.42%]; HR, 0.92 [95% CI, 0.87-0.97]), and intracranial bleeding (184/29 270 [0.63%] versus 409/29 187 [1.40%]; HR, 0.45 [95% CI, 0.37-0.56]), but no statistically different hazard of major bleeding (1479/29 270 [5.05%] versus 1733/29 187 [5.94%]; HR, 0.86 [95% CI, 0.74-1.01]), whereas lower-dose DOACs were associated with no statistically different hazard of stroke or systemic embolism (531/13 049 [3.96%] versus 1080/29 229 [3.69%]; HR, 1.06 [95% CI, 0.95-1.19]) but a lower hazard of intracranial bleeding (55/12 985 [0.42%] versus 409/29 187 [1.40%]; HR, 0.28 [95% CI, 0.21-0.37]), death (1082/13 049 [8.29%] versus 2460/29 229 [8.42%]; HR, 0.90 [95% CI, 0.83-0.97]), and major bleeding (564/12 985 [4.34%] versus 1733/29 187 [5.94%]; HR, 0.63 [95% CI, 0.45-0.88]). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke or systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (P=0.01) and lower creatinine clearance (P=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (P=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction P=0.02) and lower-dose DOACs (interaction P=0.01) versus warfarin. CONCLUSIONS: Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with atrial fibrillation.

Rivaroxaban in Patients with Atrial Fibrillation and a Bioprosthetic Mitral Valve.

BACKGROUND: The effects of rivaroxaban in patients with atrial fibrillation and a bioprosthetic mitral valve remain uncertain. METHODS: In this randomized trial, we compared rivaroxaban (20 mg once daily) with dose-adjusted warfarin (target international normalized ratio, 2.0 to 3.0) in patients with atrial fibrillation and a bioprosthetic mitral valve. The primary outcome was a composite of death, major cardiovascular events (stroke, transient ischemic attack, systemic embolism, valve thrombosis, or hospitalization for heart failure), or major bleeding at 12 months. RESULTS: A total of 1005 patients were enrolled at 49 sites in Brazil. A primary-outcome event occurred at a mean of 347.5 days in the rivaroxaban group and 340.1 days in the warfarin group (difference calculated as restricted mean survival time, 7.4 days; 95% confidence interval [CI], -1.4 to 16.3; P<0.001 for noninferiority). Death from cardiovascular causes or thromboembolic events occurred in 17 patients (3.4%) in the rivaroxaban group and in 26 (5.1%) in the warfarin group (hazard ratio, 0.65; 95% CI, 0.35 to 1.20). The incidence of stroke was 0.6% in the rivaroxaban group and 2.4% in the warfarin group (hazard ratio, 0.25; 95% CI, 0.07 to 0.88). Major bleeding occurred in 7 patients (1.4%) in the rivaroxaban group and in 13 (2.6%) in the warfarin group (hazard ratio, 0.54; 95% CI, 0.21 to 1.35). The frequency of other serious adverse events was similar in the two groups. CONCLUSIONS: In patients with atrial fibrillation and a bioprosthetic mitral valve, rivaroxaban was noninferior to warfarin with respect to the mean time until the primary outcome of death, major cardiovascular events, or major bleeding at 12 months. (Funded by PROADI-SUS and Bayer; RIVER ClinicalTrials.gov number, NCT02303795.).

Individual net clinical outcome with oral anticoagulation in atrial fibrillation using the ABC-AF risk scores.

BACKGROUND: Decisions on stroke prevention strategies in patients with atrial fibrillation (AF) depend on the perceived risks of stroke and bleeding with different antithrombotic treatment strategies. The study objectives were to evaluate net clinical outcome with oral anticoagulation (OAC) for the individual patient with AF and to identify clinically relevant thresholds for OAC treatment. METHODS: Patients with AF receiving OAC treatment in the randomized ARISTOTLE and RE-LY trials, with available biomarkers for calculation of ABC-AF scores at baseline, were included (n = 23,121). Observed 1-year risk on OAC was compared with predicted 1-year risk if the same patients would not have received OAC using the ABC-AF scores calibrated for aspirin. Net clinical outcome was defined as the sum of stroke and major bleeding risks. RESULTS: The ratio between the 1-year incidence of major bleeding and stroke/systemic embolism events ranged from 1.4 to 10.6 according to different ABC-AF risk profiles. Net clinical outcome analyses showed that in patients with an ABC-AF-stroke risk >1% per year on OAC (>3% without OAC), treatment with OAC consistently provides larger net clinical benefit than no-OAC treatment. In patients with an ABC-AF-stroke risk <1.0% per year on OAC (<3% without OAC) an individualized balancing of risks regarding OAC or no-OAC treatment is needed. CONCLUSIONS: In patients with AF, the ABC-AF risk scores allow an individual and continuous estimate of the balance between benefits and risks with OAC treatment. This precision medicine tool therefore seems useful as decision support and visualizes the net clinical benefit or harm with OAC treatment (http://www.abc-score.com/abcaf/). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00412984 (ARISTOTLE) and NCT00262600 (RE-LY).

Postoperative pericardial effusion, pericardiotomy, and atrial fibrillation: An explanatory analysis of the PALACS trial.

BACKGROUND: In the Posterior left pericardiotomy for the prevention of atrial fibrillation after cardiac surgery (PALACS) trial, posterior pericardiotomy was associated with a significant reduction in postoperative atrial fibrillation (POAF) after cardiac surgery. We aimed to investigate the mechanisms underlying this effect. METHODS: We included PALACS patients with available echocardiographic data (n = 387/420, 92%). We tested the hypotheses that the reduction in POAF with the intervention was associated with 1) a reduction in postoperative pericardial effusion and/or 2) an effect on left atrial size and function. Spline and multivariable logistic regression analyses were used. RESULTS: Most patients (n = 307, 79%) had postoperative pericardial effusions (anterior 68%, postero-lateral 51.9%). The incidence of postero-lateral effusion was significantly lower in patients undergoing pericardiotomy (37% vs 67%; P < .001). The median size of anterior effusion was comparable between patients with and without POAF (5.0 [IQR 3.0-7.0] vs 5.0 [IQR 3.0-7.5] mm; P = .42), but there was a nonsignificant trend towards larger postero-lateral effusion in the POAF group (5.0 [IQR 3.0-9.0] vs 4.0 [IQR 3.0-6.4] mm; P = .06). There was a non-linear association between postero-lateral effusion and POAF at a cut-off at 10 mm (OR 2.70; 95% CI 1.13, 6.47; P = .03) that was confirmed in multivariable analysis (OR 3.5, 95% CI 1.17, 10.58; P = 0.02). Left atrial dimension and function did not change significantly after posterior pericardiotomy. CONCLUSIONS: Reduction in postero-lateral pericardial effusion is a plausible mechanism for the effect of posterior pericardiotomy in reducing POAF. Measures to reduce postoperative pericardial effusion are a promising approach to prevent POAF.

Heart rate and death and hospitalization for heart failure in patients with persistent or permanent atrial fibrillation: Insights from the ARISTOTLE trial.

Rate control is fundamental in the treatment of patients with atrial fibrillation (AF). The independent association of heart rate with outcomes and range of heart rate associated with best outcomes remains uncertain. We assessed the relationship between heart rate and clinical outcomes in patients with persistent or permanent AF enrolled in the randomized, double-blind ARISTOTLE trial. In patients with persistent or permanent AF, a faster heart rate is associated with a modest, but statistically significant increase in death and heart failure hospitalizations. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00412984).

Rationale and design for the myocardial ischemia and transfusion (MINT) randomized clinical trial.

BACKGROUND: Accumulating evidence from clinical trials suggests that a lower (restrictive) hemoglobin threshold (<8 g/dL) for red blood cell (RBC) transfusion, compared with a higher (liberal) threshold (≥10 g/dL) is safe. However, in anemic patients with acute myocardial infarction (MI), maintaining a higher hemoglobin level may increase oxygen delivery to vulnerable myocardium resulting in improved clinical outcomes. Conversely, RBC transfusion may result in increased blood viscosity, vascular inflammation, and reduction in available nitric oxide resulting in worse clinical outcomes. We hypothesize that a liberal transfusion strategy would improve clinical outcomes as compared to a more restrictive strategy. METHODS: We will enroll 3500 patients with acute MI (type 1, 2, 4b or 4c) as defined by the Third Universal Definition of MI and a hemoglobin <10 g/dL at 144 centers in the United States, Canada, France, Brazil, New Zealand, and Australia. We randomly assign trial participants to a liberal or restrictive transfusion strategy. Participants assigned to the liberal strategy receive transfusion of RBCs sufficient to raise their hemoglobin to at least 10 g/dL. Participants assigned to the restrictive strategy are permitted to receive transfusion of RBCs if the hemoglobin falls below 8 g/dL or for persistent angina despite medical therapy. We will contact each participant at 30 days to assess clinical outcomes and at 180 days to ascertain vital status. The primary end point is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary end points include all-cause mortality at 30 days, recurrent adjudicated MI, and the composite outcome of all-cause mortality, nonfatal recurrent MI, ischemia driven unscheduled coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or readmission to the hospital for ischemic cardiac diagnosis within 30 days. The trial will assess multiple tertiary end points. CONCLUSIONS: The MINT trial will inform RBC transfusion practice in patients with acute MI.

Morbidity and Mortality Associated With Heart Failure in Acute Coronary Syndrome: A Pooled Analysis of 4 Clinical Trials.

BACKGROUND: Heart failure (HF) may complicate acute coronary syndrome (ACS) and is associated with a high burden of short- and long-term morbidity and mortality. Only limited data regarding future ischemic events and rehospitalization are available for patients who suffer HF before or during ACS. METHODS: A secondary analysis of 4 large ACS trials (PLATO, APPRAISE-2, TRACER, and TRILOGY ACS) using Cox proportional hazards models was performed to investigate the association of HF status (no HF, chronic HF, de novo HF) at presentation for ACS with all-cause and cardiovascular death, major adverse cardiovascular event (MACE ), myocardial infarction, stroke, and hospitalization for heart failure (HHF) by 1 year. Cumulative incidence plots are presented at 30 days and 1 year. RESULTS: A total of 11.1% of the 47,474 patients presenting with ACS presented with evidence of acute HF, 55.0% of whom presented with de novo HF. Patients with chronic HF presented with evidence of acute HF at a higher rate than those with no previous HF (40.3% vs 6.9%). Compared to those without HF, those with chronic and de novo HF had higher rates of all-cause mortality (adjusted hazard ratio [aHR] 2.01, 95% confidence interval [CI] 1.72-2.34 and aHR 1.47, 95% CI1.15-1.88, respectively), MACE (aHR 1.47, 95% CI1.31-1-.66 and aHR 1.38, 95% CI1.12-1.69), and HHF (aHR 2.29, 95% CI2.02-2.61 and aHR 1.48, 95% CI 1.20-1.82) at 1 year. CONCLUSION: In this large cohort of patients with ACS, both prior and de novo HF complicating ACS were associated with significantly higher risk-adjusted rates of death, ischemic events and HHF at 30 days and 1 year. Further studies examining the association between HF and outcomes in this high-risk population are warranted, especially given the advent of more contemporary HF therapies.

Plasma angiopoietin-2 and its association with heart failure in patients with atrial fibrillation.

AIMS: Several biomarkers are associated with clinical outcomes in patients with atrial fibrillation (AF), but a causal relationship has not been established. This study aimed to evaluate angiopoietin-2, a novel candidate biomarker of endothelial inflammation and vascular remodelling, in patients with AF. METHODS AND RESULTS: Angiopoietin-2 was measured in plasma obtained from patients with AF treated with aspirin monotherapy (exploration cohort, n = 2987) or with oral anticoagulation (validation cohort, n = 13 079). Regression models were built to assess the associations between angiopoietin-2, clinical characteristics, and outcomes. In both cohorts, plasma angiopoietin-2 was independently associated with AF on the baseline electrocardiogram and persistent/permanent AF, age, history of heart failure, female sex, tobacco use/smoking, body mass index, renal dysfunction, diabetes, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Angiopoietin-2 was independently associated with subsequent hospitalization for heart failure after adjusting for age, creatinine, and clinical characteristics in the exploration cohort [c-index 0.79, 95% confidence interval (CI) 0.75-0.82; third vs. first quartile, hazard ratio (HR) 1.74, 95% CI 1.26-2.41] and in the validation cohort (c-index 0.76, 95% CI 0.74-0.78; HR 1.58, 95% CI 1.37-1.82). In both cohorts, the association persisted when also adjusting for NT-proBNP (P ≤ 0.001). In full multivariable models also adjusted for NT-proBNP, angiopoietin-2 did not show statistically significant associations with ischaemic stroke, cardiovascular and all-cause death, or major bleeding that were consistent across the two cohorts. CONCLUSIONS: In patients with AF, plasma levels of angiopoietin-2 were independently associated with subsequent hospitalization for heart failure and provided incremental prognostic value to clinical risk factors and NT-proBNP.

Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial.

BACKGROUND: The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains controversial. METHODS: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (composite of death, myocardial infarction, or stroke) through 12 months. RESULTS: Because of slower-than-projected enrollment and fewer-than-projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From May 3, 2016, to April 16, 2020, a total of 545 patients from 113 sites across 12 countries were randomly selected. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease, and 20.4% had metastatic disease. A major adverse cardiovascular event occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) patients assigned to leuprolide (hazard ratio, 1.28 [95% CI, 0.59-2.79]; P=0.53). CONCLUSIONS: PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02663908.

Apixaban or Vitamin K Antagonists and Aspirin or Placebo According to Kidney Function in Patients With Atrial Fibrillation After Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From the AUGUSTUS Trial.

BACKGROUND: In the AUGUSTUS trial (An Open-Label, 2×2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban Versus Vitamin K Antagonist and Aspirin Versus Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention), apixaban resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, and aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention treated with a P2Y12 inhibitor. We evaluated the risk-benefit balance of antithrombotic therapy according to kidney function. METHODS: In 4456 patients, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was used to calculate baseline estimated glomerular filtration rate (eGFR). The effect of apixaban versus vitamin K antagonists and aspirin versus placebo was assessed across kidney function categories by using Cox models. The primary outcome was International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and ischemic events (death, stroke, myocardial infarction, stent thrombosis [definite or probable], or urgent revascularization). Creatinine clearance <30 mL/min was an exclusion criterion in the AUGUSTUS trial. RESULTS: Overall, 30%, 52%, and 19% had an eGFR of >80, >50 to 80, and 30 to 50 mL·min-1·1.73 m-2, respectively. At the 6-month follow-up, a total of 543 primary outcomes of bleeding, 1125 death or hospitalizations, and 282 ischemic events occurred. Compared with vitamin K antagonists, patients assigned apixaban had lower rates for all 3 outcomes across most eGFR categories without significant interaction. The absolute risk reduction with apixaban was most pronounced in those with an eGFR of 30 to 50 mL·min-1·1.73 m-2 for bleeding events with rates of 13.1% versus 21.3% (hazard ratio, 0.59; 95% CI, 0.41-0.84). Patients assigned aspirin had a higher risk of bleeding in all eGFR categories with an even greater increase among those with eGFR >80 mL·min-1·1.73 m-2: 16.6% versus 5.6% (hazard ratio, 3.22; 95% CI, 2.19-4.74; P for interaction=0.007). The risk of death or hospitalization and ischemic events were comparable to aspirin and placebo across eGFR categories with hazard ratios ranging from 0.97 (95% CI, 0.76-1.23) to 1.28 (95% CI, 1.02-1.59) and from 0.75 (95% CI, 0.48-1.17) to 1.34 (95% CI, 0.81-2.22), respectively. CONCLUSIONS: The safety and efficacy of apixaban was consistent irrespective of kidney function, compared with warfarin, and in accordance with the overall trial results. The risk of bleeding with aspirin was consistently higher across all kidney function categories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02415400.

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. FUNDING: Coalition COVID-19 Brazil, Bayer SA.

Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation.

BACKGROUND: Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear. METHODS: In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events. RESULTS: Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = 0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group. CONCLUSIONS: In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both. (Funded by Bristol-Myers Squibb and Pfizer; AUGUSTUS ClinicalTrials.gov number, NCT02415400.).

Associated factors and clinical outcomes in mechanical circulatory support use in patients undergoing high risk on-pump cardiac surgery: Insights from the LEVO-CTS trial.

BACKGROUND: We describe variables and outcomes associated with peri-operative mechanical circulatory support (MCS) utilization among patients enrolled in the Levosimendan in patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial. METHODS: In the LEVO-CTS trial, MCS utilization (defined as intra-aortic balloon pump, extracorporeal membrane oxygenation, or surgical ventricular assist device) within 5 days of surgery was examined. The association between MCS use and outcomes including 90-day mortality, 30-day renal-replacement therapy, and hospital and critical stay length of stay were determined. RESULTS: Among the 849 patients from 70 centers randomized to levosimendan or placebo, 85 (10.0%) patients were treated with MCS (71 intra-aortic balloon pump, 7 extracorporeal membrane oxygenation, 7 ventricular assist device); with 89.4% started on post-operative day 0. Inter-institutional use ranged from 0% to 100%. Variables independently associated with MCS utilization included combined coronary artery bypass grafting and valve surgery (adjusted odds ratio [OR] 2.73, 95% confidence interval [CI] 1.70-4.37, P < .001), history of lung disease (OR 1.70, 95% CI 1.06-2.70, P = .029), and history of heart failure (OR 2.44, 95% CI 1.10-5.45, P = .027). Adjusted 90-day mortality (22.4% vs 4.1%, hazard ratio 6.11, 95% CI 3.95-9.44, P < .001) was higher, and median critical care length of stay (8.0 vs 4.0 days, P < .001) was longer in patients managed with MCS. CONCLUSIONS: In a randomized controlled trial of high-risk cardiac surgical patients in North America, we observed patient, and surgical variables associated with MCS utilization. MCS use was associated with a higher risk of post-operative mortality.