John Hunter Alexander

BACKGROUND: Oral anticoagulation (OAC) remains underused in patients with atrial fibrillation or flutter at high risk of ischemic stroke. We aimed to characterize documented OAC prescribing at diagnosis and during 1-year follow-up and identify factors associated with baseline OAC prescribing. METHODS: Using electronic health records from 7 US health systems participating in the National Patient-Centered Clinical Research Network between 2015 and 2019, we identified patients with newly diagnosed atrial fibrillation at high risk of ischemic stroke (CHA ₂ DS ₂ -VASc score ≥2 for men or ≥3 for women). The primary outcomes were documented OAC prescription at baseline and during 1-year follow-up. Exposures included demographic, clinical, and health-system characteristics. Multivariable logistic regression was used to identify factors associated with baseline OAC prescribing and loss of documented OAC prescribing during follow-up. RESULTS: Among 161 295 patients (median age, 76 years [interquartile range, 68–82]; 70 327 [43.6%] women), 92 518 (57.4%) had a documented OAC prescription at baseline, increasing from 56.6% in 2015 to 62.6% in 2019. Among those with a documented baseline OAC prescription, 45.6% had no documented OAC prescription during 1-year follow-up. Among 68 777 patients without a documented baseline OAC prescription, 12.5% had an OAC prescription documented during follow-up. Dementia (odds ratio, 0.58 [95% CI, 0.56–0.61]), prior major bleeding (odds ratio, 0.69 [95% CI, 0.63–0.75]), and renal disease (odds ratio, 0.84 [95% CI, 0.81–0.88]) were associated with lower odds of baseline OAC prescribing, whereas heart failure was associated with higher odds (odds ratio, 1.40 [95% CI, 1.37–1.43]). CONCLUSIONS: Among patients with newly diagnosed atrial fibrillation at high risk for ischemic stroke, OAC prescribing at diagnosis was suboptimal, and loss of documented OAC prescribing was common during the first year. Baseline OAC use was more strongly associated with bleeding risk, frailty, and comorbidity burden, and less consistently aligned with ischemic stroke risk.

Background: Atrial fibrillation is associated with heart failure (HF) through a complex cause‐and‐effect relationship. We performed multiplex screening of plasma proteins in patients with atrial fibrillation to identify biomarkers and pathways associated with hospitalization for HF. Additionally, we aimed to identify potential pathophysiological differences between HF with reduced ejection fraction and HF with preserved ejection fraction at baseline in patients with atrial fibrillation. Methods: Using a case–cohort design of patients with atrial fibrillation from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, 596 cases with HF hospitalizations during follow‐up and 4029 randomly selected controls without HF hospitalization. Plasma obtained at randomization was analyzed with conventional immunoassays and proximity extension assay panels. Biomarker associations with HF hospitalization were evaluated using random survival forest, Boruta, and Cox‐regression analyses. Associations between biomarkers and HF subtype were evaluated with Wilcoxon−Mann–Whitney test with Bonferroni–Holm adjustment for multiplicity. Results: The biomarkers most strongly and significantly associated with increased risk of HF hospitalization after adjustment for clinical characteristics, renal function, and cardiac biomarkers, and after correction for multiplicity ( P ≤0.00027), were NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), BNP (B‐type natriuretic peptide), hs‐cTnT (high‐sensitivity cardiac troponin T), fibroblast growth factor 23, spondin 1, insulin‐like growth factor binding protein 7, urokinase‐type plasminogen activator receptor, osteopontin, pentraxin‐related protein 3, and transferrin receptor protein 1R. Among patients with prevalent HF, 9 biomarkers remained significant after adjustment for multiplicity; NT‐proBNP, BNP, hs‐cTnT, renin, angiotensin‐converting enzyme 2, growth differentiation factor 15, and interleukin‐6 levels were higher in HF with reduced ejection fraction, whereas levels of stem cell factor and leptin were higher in HF with preserved ejection fraction (all P <0.05). Conclusions: Of 268 evaluated biomarkers, this study identified biomarkers representing mechanisms strongly associated with subsequent HF hospitalization. HF with reduced ejection fraction was more strongly associated with cardiorenal dysfunction and inflammation markers, while HF with preserved ejection fraction was associated with adipose metabolism and tissue repair proteins.

A recent Perspective in Blood suggested that previous evidence from over a decade ago established that a liberal rather than a restrictive blood transfusion strategy results in better outcomes in patients with anemia and either acute myocardial infarction or stable cardiovascular disease. Their premise was that physiological evidence, and a different interpretation of the Transfusion Requirements in Critical Care (TRICC) trial should have been sufficient to establish clinical practice. They also suggest that a more personalized approach to the administration of transfusions would have been made possible by including a usual-care arm in all transfusion trials. In this counterpoint Perspective, we describe how and why 2 discrete and common blood transfusion thresholds were selected in the TRICC, FOCUS, REALITY, and MINT trials. We explain why a usual-care arm would have been uninformative. We also propose that we still do not have evidence to provide firm transfusion recommendations in several specific subpopulations of patients, including those with stable atherosclerotic coronary artery disease. Finally, we provide our perspective on the state of existing evidence and on the clinical recommendations that should be adopted in practice.

Obtaining informed consent for clinical trial participation in acute myocardial infarction presents unique ethical and logistical challenges because of the patient distress, sedation, and the urgency of treatment. Traditional consent procedures often conflict with the narrow enrollment windows, prompting the use of legally authorized representatives and short- and long-form consent models. Although these approaches enable faster trial enrollment, they may compromise patient autonomy, introduce selection bias, or create postenrollment ethical dilemmas. This review explores the complexities of informed consent in acute myocardial infarction research, evaluating the advantages and limitations of existing strategies, including legally authorized representative consent, 2-step consent processes, and alternatives such as deferred and verbal consent. It also examines international variations in regulatory oversight and presents emerging solutions, such as preemptive consent, opt-out models, electronic platforms, and registry-based trials, to streamline the enrollment without delaying care. Ultimately, consent regulations should be re-evaluated and potentially relaxed to better support timely research. A thoughtful reassessment of consent frameworks is essential to ethically and effectively advance acute myocardial infarction research in time-sensitive settings.

Importance: In patients with atrial fibrillation (AF), oral anticoagulants (OACs) reduce the risk of stroke.Objective: To investigate if patients with less prior OAC exposure respond differently to a new OAC than patients with more OAC exposure.Design, Setting, and Participants: In this prespecified exploratory subgroup analysis of the Oral Factor 11a Inhibitor Asundexian as Novel Antithrombotic–Atrial Fibrillation (OCEANIC-AF) randomized clinical trial, patients enrolled in the OCEANIC-AF trial were categorized as OAC naive or OAC experienced based on whether they had 6 or fewer weeks or more than 6 weeks of prior OAC use. The effect of asundexian vs apixaban was then compared on outcomes among patients who were OAC naive and OAC experienced. The study setting included 1035 sites in 38 countries, and participants were those enrolled in the OCEANIC-AF trial. Data were analyzed from June to July 2024.Interventions: Asundexian, a novel factor XIa inhibitor, was compared with apixaban in patients with AF.Main Outcomes and Measures: The primary efficacy outcome was stroke or systemic embolism. The main safety outcome was major bleeding.Results: Of patients in the OCEANIC-AF trial, 2493 (17%) were OAC naive (mean [SD] age, 72.6 [8.6] years; 1464 male [59%]) and 12 317 (83%) were OAC experienced (mean [SD] age, 74.2 [7.5] years; 8132 male [66%]). In the asundexian arm, patients who were OAC naive had a stroke or systemic embolism rate of 0.8% (10 of 1238) compared with 1.4% (88 of 6177) in those who were OAC experienced. In the apixaban arm, patients who were OAC naive had a stroke or systemic embolism rate of 0.6% (7 of 1255) compared with 0.3% (19 of 6140) in those who were OAC experienced. Thus, patients who were OAC naive had a smaller increase in stroke or systemic embolism with asundexian compared with apixaban (hazard ratio [HR], 1.42; 95% CI, 0.54-3.73) than patients who were OAC experienced (HR, 4.66; 95% CI, 2.84-7.65; P for interaction =.03). Bleeding rates were lower among both OAC-naive patients (0.2% [2 of 1228]) and OAC-experienced patients (0.2% [15 of 6145]) assigned asundexian than among OAC-naive patients (1.0% [13 of 1249]) and OAC-experienced patients (0.7% [40 of 6115]) assigned apixaban.Conclusions and Relevance: In the OCEANIC-AF randomized clinical trial, patients with AF who were OAC naive had a smaller increase in stroke or systemic embolism and a similar lower rate of bleeding with asundexian compared with apixaban than patients who were OAC experienced. The mechanism of these findings is unknown and deserves further research.Trial Registration: ClinicalTrials.gov Identifier: NCT05643573

Background and Aims: Oral anticoagulation reduces stroke risk in patients with atrial fibrillation (AF) but increases bleeding. Longer fibrin clot lysis time has been shown to predict adverse cardiovascular outcomes in acute coronary syndromes. This study explored relationships between fibrin clot lysis time at randomization and clinical outcomes in patients with AF enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF (ARISTOTLE) trial. Methods: Plasma samples were obtained from anticoagulation-naïve participants, before initiation of study medication (n = 1841). Fibrin clot turbidimetry was performed, and lysis time determined. Associations between lysis time and characteristics, biomarkers, and on-treatment bleeding and cardiovascular events were assessed by lysis time quartile (Q1-4, shortest to longest). Results: A shorter lysis time was associated with being older, male, permanent AF, lower body mass index, estimated glomerular filtration rate and C-reactive protein, and higher N-terminal pro-B-type natriuretic peptide. Major and clinically relevant non-major bleeding was significantly more frequent in lysis time Q1 vs. Q4 [6.3%/yr vs. 2.1%/yr; HR, 2.99 (95% CI, 1.75–5.12); P = .001], including after multifactorial adjustment [HR, 2.61 (1.45–4.69); P = .016]. Those in Q2 and Q3 had intermediate bleeding risk vs. Q4 [HR, 2.21 (1.27–3.87); 2.08 (1.18–3.66) respectively], suggesting a graduated effect. Treatment allocation to apixaban vs. warfarin did not affect the relationship between lysis time and bleeding (interaction-P = .80). There was no significant association between lysis time and a composite of cardiovascular death, stroke, systemic embolism or myocardial infarction. Conclusions: Shorter pre-treatment fibrin clot lysis time independently predicted higher bleeding risk in patients receiving oral anticoagulation for AF.

BACKGROUND: Blood transfusion may precipitate adverse outcomes, including heart failure (HF), among patients with acute myocardial infarction (MI). This study characterizes the effects of a restrictive or liberal transfusion strategy on outcomes in patients with MI and anemia with and without baseline HF. METHODS: In the MINT trial (Myocardial Ischemia and Transfusion), 3504 patients with MI and anemia (hemoglobin P _interaction =0.18) in patients with than in those without baseline HF. Among secondary outcomes, death or recurrent MI and death were more frequent among those with baseline HF. Restrictive transfusion resulted in numerically higher rates of death or MI and death in patients with than in those without baseline HF. Rates of HF were similar between restrictive and liberal transfusion in patients with baseline HF but lower with restrictive transfusion (rate ratio, 0.51 [95% CI, 0.29–0.92]; P _interaction =0.02) in patients without baseline HF. CONCLUSIONS: A liberal transfusion strategy is safe for patients with MI and anemia, including those with baseline HF. Restrictive transfusion tended to result in worse outcomes, particularly in patients with baseline HF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02981407.

Key Points: This Myocardial Ischemia and Transfusion (MINT) trial analysis evaluated the optimal transfusion strategy for patients with CKD and anemia experiencing acute myocardial infarction. In patients with CKD, a liberal transfusion strategy overall did not demonstrate benefit over a restrictive strategy. Background: CKD is associated with higher risk of myocardial infarction and anemia. Among patients with anemia and CKD who experience myocardial infarction, it remains uncertain whether a liberal red blood cell transfusion threshold strategy (hemoglobin cutoff N =1279), CKD with eGFR 30–60 ml/min per 1.73 m ² ( N =999), CKD with eGFR 2 ( N =802), and CKD requiring dialysis ( N =415) by assigned transfusion strategy. Results: No statistically significant interactions were observed between CKD stage and assigned transfusion strategy. Among non–dialysis-dependent patients with an eGFR 2 , a restrictive transfusion strategy was associated with a higher risk of 30-day death or recurrent myocardial infarction (risk difference [RD], 5.8%; 95% confidence interval [CI], 0.4% to 11.2%) compared with a liberal transfusion strategy. Among patients with an eGFR 30–60 ml/min per 1.73 m ² , a restrictive strategy was associated with a similar risk of 30-day death or recurrent myocardial infarction (RD, 3.7%; 95% CI, −0.9% to 8.2%) compared with a liberal transfusion strategy. Among patients with CKD requiring dialysis, a restrictive strategy was also associated with a similar risk of 30-day death or recurrent myocardial infarction (RD, −2.6%; 95% CI, −10.0% to 4.8%) compared with a liberal transfusion strategy. Conclusions: In patients with CKD included in this MINT subgroup analysis, a liberal transfusion strategy was not worse than a restrictive transfusion strategy and was associated with less harm in subgroups not receiving dialysis. Clinical Trial registry name and registration number: Myocardial Ischemia and Transfusion (MINT), NCT02981407.