The EMPEROR Program

[Posted 16/May/2025]

AUDIENCE: Cardiology, Emergency Medicine

KEY FINDINGS: The erythropoietin-erythroferrone-TfR1-hepcidin axis is activated in patients with heart failure as the disease advances and is further heightened by SGLT2 inhibitors, in parallel with their effect to enhance erythropoiesis and iron mobilization and use. These changes have important implications for understanding the mechanism of action of SGLT2 inhibitors and for monitoring the response to treatment.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors stimulate erythropoiesis, but the mechanisms and clinical relevance of the effect of SGLT2 inhibitors on systemic iron metabolism in patients with heart failure is not well understood. The authors sought to characterize a comprehensive suite of iron metabolism biomarkers—particularly the erythroblast signaling molecule, erythroferrone—in patients with heart failure before and after short- and long-term treatment with empagliflozin in patients with heart failure and a reduced or preserved ejection fraction.

DETAILS: Authors measured serum iron metabolism biomarkers at baseline, 12 weeks, and 52 weeks in 1,139 patients who were treated with placebo or empagliflozin in the EMPEROR (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure) program, and characterized the inter-relationships of these biomarkers with clinical status and with the effect of empagliflozin on erythropoiesis and heart failure outcomes. Correlations among iron biomarkers indicated the presence of a functional erythropoietin-erythroferrone-transferrin-receptor-protein-1 (TfR1)-hepcidin axis. As heart failure advanced, patients showed higher levels of erythropoietin, erythroferrone, and TfR1 (P trend <0.01), and levels of these proteins predicted a heightened risk of cardiovascular death or heart failure hospitalization (all P < 0.01). Compared with placebo, at 12 weeks, empagliflozin increased hemoglobin by 0.6 to 0.9 g/dL (P < 0.001), an effect that was accompanied by further activation of the erythropoietin-erythroferrone-TfR1 axis and increased iron use. Empagliflozin increased serum levels of erythroferrone by >40% (along with increases in erythropoietin and TfR1), while simultaneously decreasing hepcidin levels and reducing serum iron concentrations and transferrin saturation (all P < 0.01). When treated with empagliflozin, patients with evidence of iron deficiency at baseline showed attenuation of the erythrocytic response (P trend = 0.04) but no diminution of the heart failure benefits.

Copyright © American College of Cardiology Foundation. All rights reserved.

Source: Ferreira, J. P., Anker, S. D., Butler, J., et al. (20245). Effect of Empagliflozin on the Mechanisms Driving Erythropoiesis and Iron Mobilization in Patients With Heart Failure: The EMPEROR Program. J Am Coll Cardiol.. 2025; 85(18): 1757-1770. Published: May, 2025. DOI: 10.1016/j.jacc.2025.03.503.

A Cohort Study From the EINSTEIN-Jr Phase 3 Trial

[Posted 18/May/2025]

AUDIENCE: Hematology, Pediatric

KEY FINDINGS: Incidences of recurrent venous thromboembolism and bleeding during extended-phase anticoagulant treatment were low and similar to those observed during acute-phase treatment and adult studies on extended-phase anticoagulant treatment, providing valuable information for clinical practice on extended anticoagulation in children.

BACKGROUND: Extended-phase anticoagulation of venous thromboembolism in children is not well documented nor systematically reported. Previously, we reported on recurrent venous thromboembolism and bleeding during acute-phase anticoagulation in EINSTEIN-Jr, a randomised controlled study in 500 children with venous thromboembolism comparing rivaroxaban to standard anticoagulants. The aim of the present study was to evaluate the efficacy and safety of extended-phase anticoagulant therapy in children and to characterise factors associated with the decision to extend anticoagulation.

DETAILS: Children aged 17 years or younger, who were enrolled in the EINSTEIN-Jr trial (NCT02234843) from 107 paediatric hospitals in 28 countries, and who had previously completed a 3-month acute anticoagulation treatment phase (1-month in children <2 years with catheter-related venous thromboembolism) for acute venous thromboembolism within the trial were included in this cohort study. After completion of the preceding acute anticoagulation treatment phase, children could extend study treatment for up to 9 months (or up to 2 months for children <2 years with catheter-related venous thromboembolism). Study anticoagulants were bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20 mg equivalent dose or standard anticoagulants (heparin or vitamin K antagonist). The main outcomes were suspected recurrent venous thromboembolism (primary efficacy outcome) and clinically relevant bleeding (principal safety outcome), both confirmed or refuted by appropriate objective testing. Cumulative incidences of efficacy and safety outcomes are reported for children who received extended anticoagulation within the framework of the study. We also compared demographic and clinical characteristics of those administered any extended-phase anticoagulation (whether within or outside the framework of the study) with those not administered extended-phase anticoagulation, applying multivariable logistic regression. 248 (51%) children received extended-phase anticoagulation between Nov 14, 2014, and Jan 15, 2019, 214 within the study and 34 outside the framework of the study. During extended-phase anticoagulant treatment, recurrent venous thromboembolism occurred in three (1%) of the 214 children within the study (cumulative incidence 3.0%; 95% CI 0.9-9.8). Clinically relevant non-major bleeding occurred in four (2%) of 214 children (3.3%; 1.2-9.2). Fatal venous thromboembolism or major bleeding did not occur. Outcome rates were similar with rivaroxaban or standard anticoagulants. Symptomatic index venous thromboembolism (odds ratio 1.88; 95% CI 1.14-3.11), unprovoked venous thromboembolism or persistent risk factor (2.16; 1.46-3.19), and residual thrombosis on repeat imaging (3.79; 2.52-5.71) were associated with the decision to extend anticoagulation.

Copyright © Elsevier Ltd. All rights reserved.

Source: Male, C., Lensing, A. W. A., Chan, A. K. C., et al. Extended-Phase Anticoagulant Treatment of Acute Venous Thromboembolism in Children: A Cohort Study From the EINSTEIN-Jr Phase 3 Trial. The Lancet Haematology. 2025; 12(5):5, e357-e364. Published: April, 2025. DOI: PIIS2352-3026(25)00067-5.

A Systematic Review

[Posted 24/Apr/2025]

AUDIENCE: Family Medicine, Cardiology

KEY FINDINGS: The use of cPOCUS by non-expert physicians after a short training course appears to be an accurate complementary tool for LVEF assessment in daily practice. Its diffusion in primary care could optimize patient management, without replacing specialist assessment.

BACKGROUND: Heart failure (HF) is the most frequent cardiovascular pathology in primary care. Echocardiography is the gold standard for diagnosis, follow-up, and prognosis of HF. Point-of-care ultrasound (POCUS) is of growing interest in daily practice. This study aimed to systematically review the literature to evaluate left ventricular ejection fraction (LVEF) assessment of unselected patients in primary care by non-expert physicians with cardiac POCUS (cPOCUS).

DETAILS: Authors searched in Medline, Embase, and Pubmed up to January 2024 for interventional and non-interventional studies assessing LVEF with cPOCUS in unselected patients with suspected or diagnosed HF in hospital or outpatient settings, performed by non-expert physicians. Forty-two studies were included, involving 6598 patients, of whom 60.2% were outpatients. LVEF was assessed by 351 non-expert physicians after an initial ultrasound training course. The LVEF was mainly assessed by visual estimation (90.2%). The most frequent views were parasternal long/short axis, and apical 4-chamber. The median time of cPOCUS was 8 minutes. A strong agreement was found (κ = 0.72 [0.63; 0.83]) compared to experts when using different types of ultrasound devices (hand-held and standard), and agreement was excellent (κ = 0.84 [0.71; 0.89]) with the same device. Training course combined a median of 4.5 hours for theory and 25 cPOCUS for practice.

Copyright © Oxford University Press. All rights reserved.

Source: Allimant, P., Guillo, L., Fierling, T., et al. (20245). Point-of-Care Ultrasound to Assess Left Ventricular Ejection Fraction in Heart Failure in Unselected Patients in Primary Care: A Systematic Review. Family Practice. 2025; 42(2): cmae040. Published: April, 2025. DOI: 10.1093/fampra/cmae040.

National Cohort and Co-Sibling Study

[Posted 21/Apr/2025]

AUDIENCE: Cardiology, Ob/Gyn

KEY FINDINGS: In this large national cohort, women who experienced any of 5 major adverse pregnancy outcomes had increased risk for HF up to 46 years later. Women with adverse pregnancy outcomes need early preventive actions and long-term clinical care to reduce the risk of HF.

BACKGROUND: Adverse pregnancy outcomes, such as preterm delivery and hypertensive disorders of pregnancy, may be associated with higher future risks of heart failure (HF). However, the comparative effects of different adverse pregnancy outcomes on long-term risk of HF, and their potential causality, are unclear. The authors sought to examine 5 major adverse pregnancy outcomes in relation to long-term risk of HF in a large population-based cohort.

DETAILS: A national cohort study was conducted of all 2,201,638 women with a singleton delivery in Sweden in 1973-2015, followed up for HF identified from nationwide outpatient and inpatient diagnoses through 2018. Cox regression was used to compute HRs for HF associated with preterm delivery, small for gestational age, preeclampsia, other hypertensive disorders of pregnancy, and gestational diabetes, while adjusting for other adverse pregnancy outcomes and maternal factors. Co-sibling analyses assessed for potential confounding by shared familial (genetic or environmental) factors. In 48 million person-years of follow-up, 667,774 women (30%) experienced an adverse pregnancy outcome, and 19,922 women (0.9%) were diagnosed with HF (median age, 61 years). All 5 adverse pregnancy outcomes were independently associated with long-term increased risk of HF. With up to 46 years of follow-up after delivery, adjusted HRs for HF associated with specific adverse pregnancy outcomes were: gestational diabetes, 2.19 (95% CI: 1.95-2.45); preterm delivery, 1.68 (95% CI: 1.61-1.75); other hypertensive disorders, 1.68 (95% CI: 1.48-1.90); preeclampsia, 1.59 (95% CI: 1.53-1.66); and small for gestational age, 1.35 (95% CI: 1.31-1.40). All HRs remained significantly elevated (1.3- to 3.0-fold) even 30 to 46 years after delivery. These findings were only partially explained by shared familial factors. Women with multiple adverse pregnancy outcomes had further increases in risk (eg, up to 46 years after delivery, adjusted HRs associated with 1, 2, or ≥3 adverse pregnancy outcomes were 1.51 [95% CI: 1.47-1.56], 2.31 [95% CI: 2.19-2.45], and 3.18 [95% CI: 2.85-3.56], respectively).

Copyright © American College of Cardiology Foundation. All rights reserved.

Source: Crump, C., Crump, J., and Crump, K. (20245). Adverse Pregnancy Outcomes and Long-Term Risk of Heart Failure in Women: National Cohort and Co-Sibling Study. J Am Coll Cardiol HF.. 2025; 3(4): 589–598. Published: April, 2025. DOI: 10.1016/j.jchf.2024.11.004.

A Population-Based Cohort Study in Sweden

[Posted 3/Mar/2025]

AUDIENCE: Cardiology, Emergency Medicine, Rheumatology

KEY FINDINGS: In patients with gout and without CHD, long-term allopurinol use protects against first-ever ACS compared with non-users. In contrast, allopurinol initiators, possibly having more systemic inflammation, had a higher risk of first-ever ACS compared with long-term users.

BACKGROUND: Purpose of this study is to investigate the impact of allopurinol use on the risk of first-ever acute coronary syndrome (ACS) event in patients with gout.

DETAILS: Using national and regional register data, we included all patients with a gout diagnosis at primary or specialised care in Western Sweden in the period 2007-2017 (n=18,862; 67% male patients). Patients with a prior history of coronary heart disease (CHD) were excluded. Follow-up started at the first gout diagnosis and ended at the first-ever ACS event, death or study end. The main outcome was the risk of first-ever ACS in: (1) allopurinol users versus non-users, by defining three categories of allopurinol exposure: exposed to 100 mg, >100 mg and no exposure (reference) and (2) allopurinol initiators (within 125 days) versus long-term users (reference). Multivariable logistic regression analysis was used to calculate ORs and 95% CIs. In analysis 1 (n=18,862), 15.3% (n=2892) were exposed to 100 mg, 9.1% (n=1717) to >100 mg and 75.6% (n=14,253) were not exposed. Allopurinol users were older and had more comorbidities compared with non-users. Allopurinol exposure (100 mg and >100 mg) was associated with significantly lower odds of first-ever ACS (OR 0.77; 95% CI 0.63 to 0.94, and OR 0.61; 95% CI 0.47 to 0.81, respectively). In Analysis 2, allopurinol initiators (n=489) had significantly higher odds of first-ever ACS compared with long-term users (n=2916) (OR 1.68; 95% CI 1.03 to 2.75).

Copyright © BMJ Publishing Group Ltd.. All rights reserved.

Source: Drivelegka, P., Jacobsson, L., Sandstrom, T. Z., et al. (2025). Allopurinol Use and Risk of Acute Coronary Syndrome in Gout Patients: A Population-Based Cohort Study in Sweden. BMJ Open. 2025; 15(2): e092522. Published: February 27, 2025. DOI: 10.1136/bmjopen-2024-092522.

Primary Results of the PEERLESS Randomized Controlled Trial

[Posted 4/Feb/2025]

AUDIENCE: Cardiology, Emergency Medicine

KEY FINDINGS: PEERLESS met its primary end point in favor of LBMT compared with CDT in treatment of intermediate-risk pulmonary embolism. LBMT had lower rates of clinical deterioration and/or bailout and postprocedural intensive care unit use compared with CDT, with no difference in mortality or bleeding.

BACKGROUND: There are a lack of randomized controlled trial data comparing outcomes of different catheter-based interventions for intermediate-risk pulmonary embolism.

DETAILS: PEERLESS is a prospective, multicenter, randomized controlled trial that enrolled 550 patients with intermediate-risk pulmonary embolism with right ventricular dilatation and additional clinical risk factors randomized 1:1 to treatment with large-bore mechanical thrombectomy (LBMT) or catheter-directed thrombolysis (CDT). The primary end point was a hierarchal win ratio composite of the following (assessed at the sooner of hospital discharge or 7 days after the procedure): (1) all-cause mortality, (2) intracranial hemorrhage, (3) major bleeding, (4) clinical deterioration and/or escalation to bailout, and (5) postprocedural intensive care unit admission and length of stay. Assessments at the 24-hour visit included respiratory rate, modified Medical Research Council dyspnea score, New York Heart Association classification, right ventricle/left ventricle ratio reduction, and right ventricular function. End points through 30 days included total hospital stay, all-cause readmission, and all-cause mortality. The primary end point occurred significantly less frequently with LBMT compared with CDT (win ratio, 5.01 [95% CI, 3.68-6.97]; P<0.001). There were significantly fewer episodes of clinical deterioration and/or bailout (1.8% versus 5.4%; P=0.04) with LBMT compared with CDT and less postprocedural intensive care unit use (P<0.001), including admissions (41.6% versus 98.6%) and stays >24 hours (19.3% versus 64.5%). There were no significant differences in mortality, intracranial hemorrhage, or major bleeding between strategies or in a secondary win ratio end point including the first 4 components (win ratio, 1.34 [95% CI, 0.78-2.35]; P=0.30). At the 24-hour visit, respiratory rate was lower for patients treated with LBMT (18.3±3.3 versus 20.1±5.1; P<0.001), and fewer had moderate to severe modified Medical Research Council dyspnea scores (13.5% versus 26.4%; P<0.001), New York Heart Association classifications (16.3% versus 27.4%; P=0.002), and right ventricular dysfunction (42.1% versus 57.9%; P=0.004). Right ventricle/left ventricle ratio reduction was similar (0.32±0.24 versus 0.30±0.26; P=0.55). Patients treated with LBMT had shorter total hospital stays (4.5±2.8 overnights versus 5.3±3.9 overnights; P=0.002) and fewer all-cause readmissions (3.2% versus 7.9%; P=0.03), whereas 30-day mortality was similar (0.4% versus 0.8%; P=0.62).

Copyright © American Heart Association, Inc. All rights reserved.

Source: Jaber, W. A., Gonsalves, C. F., Stortecky, S., et al. (2024). Large-Bore Mechanical Thrombectomy Versus Catheter-Directed Thrombolysis in the Management of Intermediate-Risk Pulmonary Embolism: Primary Results of the PEERLESS Randomized Controlled Trial. Circulation. 2025; 151(5). Published: February 4, 2025. DOI: 10.1161/CIRCULATIONAHA.124.07236.