Advanced heart failure (AHF) represents the terminal stage of heart failure (HF), characterized by persistent symptoms and functional limitations despite optimal guideline-directed medical therapy (GDMT). This review explores the clinical definition, pathophysiology, and therapeutic approaches for AHF. Characterized by severe symptoms, New York Heart Association (NYHA) class III-IV, significant cardiac dysfunction, and frequent hospitalizations, AHF presents substantial challenges in prognosis and management. Pathophysiological mechanisms include neurohormonal activation, ventricular remodeling, and systemic inflammation, leading to reduced cardiac output and organ dysfunction. Therapeutic strategies for AHF involve a multidisciplinary approach, including pharmacological treatments, device-based interventions like ventricular assisted devices, and advanced options such as heart transplantation. Despite progress, AHF management faces limitations, including disparities in access to care and the need for personalized approaches. Novel therapies, artificial intelligence, and remote monitoring technologies offer future opportunities to improve outcomes. Palliative care, which focuses on symptom relief and quality of life, remains crucial for patients ineligible for invasive interventions. Early identification and timely intervention are pivotal for enhancing survival and functional outcomes in this vulnerable population. This review underscores the necessity of integrating innovative technologies, personalized medicine, and robust palliative strategies into AHF management to address its high morbidity and mortality.

Background: Sotatercept, a first-in-class activin-signaling inhibitor, demonstrated efficacy in pulmonary arterial hypertension (PAH) in the pivotal PULSAR and STELLAR trials. However, whether these benefits and the drug’s distinct safety profile translate to routine clinical practice in the treatment of idiopathic PAH remains unclear. Methods: We conducted a retrospective study using the TriNetX global health research network. Adult patients with idiopathic PAH treated with standard-of-care (SoC) background therapies were identified. Those receiving add-on sotatercept were matched 1:1 with patients on background therapy alone using propensity score matching. Results: A total of 1378 matched patients (689 per arm) were included. The median follow-up was 13.8 months for the SoC group and 10.3 months for the sotatercept group; therefore, the analysis was limited to up to 12 months. Sotatercept was associated with a 49% reduction in the risk of all-cause mortality (HR = 0.51, p = 0.002). A significant reduction was observed in all-cause hospitalizations for the sotatercept arm (HR = 0.44; 12-month rate 6.3% vs. 11.5%, p = 0.010). Safety analysis revealed 2.5-fold increased odds of epistaxis (OR = 2.68, p < 0.001) and 4-fold increased odds of erythrocytosis (OR = 4.26, p < 0.001) with sotatercept, while thrombocytopenia rates were similar (OR = 0.98, p = 0.946). Sotatercept seems to be associated with a higher risk of hypertension compared to background therapy alone (OR = 1.85, p = 0.155). Conclusions: In this large real-world cohort, the addition of sotatercept to SoC background therapy significantly improved survival in idiopathic PAH. While bleeding events, erythrocytosis and elevated blood pressure seemed to be more frequent with sotatercept, the overall safety profile was acceptable, suggesting that the substantial survival and hospitalization benefits outweigh these risks in routine clinical practice.

Aims: Evidence on cardiovascular/renal outcomes associated with GLP‐1‐based therapies in type 1 diabetes (T1D) is limited. We examined the effects of GLP‐1‐based therapy on major clinical outcomes and safety, including diabetic ketoacidosis (DKA) and hypoglycemia risk, in adults with T1D in a large real‐world cohort. Materials and Methods: This retrospective cohort study utilised the TriNetX global health research network. Adults with T1D were classified by exposure to GLP‐1‐based therapies. Propensity score matching (1:1) balanced baseline characteristics for age, sex, demographic characteristics, cardiometabolic risk factors, comorbidities, medication use, and laboratory parameters including lipid profile and glycemic control. Outcomes included all‐cause mortality, myocardial infarction, cerebral infarction, heart failure (HF), adapted major adverse cardiovascular events (MACE—all CV clinical outcomes), chronic kidney disease (CKD), and all‐cause hospitalisation, plus safety outcomes (hypoglycemia and DKA). Event accrual began 6 months after therapy initiation. Results: After matching, 4088 individuals per group were included. GLP‐1‐based therapy was associated with lower risks of all‐cause mortality (HR 0.67, 95% CI 0.46–0.98), HF (HR 0.38, 95% CI 0.21–0.67), adapted‐MACE (HR 0.61, 95% CI 0.40–0.94) and all‐cause hospitalisation (HR 0.70, 95% CI 0.51–0.96). No significant differences were observed for myocardial infarction, ischemic stroke, or CKD. DKA incidence was not increased, while hypoglycemia risk was lower with GLP‐1 therapy (HR 0.72, 95% CI 0.55–0.95). Less than 10 (0.2%) events of pancreatitis were noted in both groups. Conclusions: In this propensity score‐matched real‐world cohort of adults with T1D, GLP‐1‐based therapy was associated with lower risks of all‐cause mortality, HF, adapted‐MACE, hospitalisation, and hypoglycemia without increased DKA risk. Randomised controlled trials are needed to confirm these findings.