Abstract Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF), yet the optimal timing of initiation in routine clinical practice remains uncertain. We investigated the impact of early initiation of SGLT2i within 30 days of HFrEF diagnosis on mortality and HF hospitalization. Methods Using Danish nationwide register data from July 2020 to August 2024, adults with incident HFrEF eligible for SGLT2i therapy were identified. A target trial comparing initiation of SGLT2i within 30 days of HFrEF diagnosis versus no SGLT2i initiation during this 30-day period was emulated. The analysis used a clone-censor-weight design with follow-up starting at HFrEF diagnosis. The primary outcome was one-year all-cause mortality, and HF hospitalization was assessed as a secondary outcome. Results Among 10,346 patients with incident HFrEF, 3268 (31.6%) initiated an SGLT2i within 30 days of HFrEF diagnosis and 7078 (68.4%) did not initiate the treatment during this 30-day window. About 226 deaths occurred among SGLT2i initiators and 637 deaths among non-initiators. Compared with non-initiation, initiation of SGLT2i within 30 days was associated with lower one-year risks of both death (RD −1.1 percentage points; 95% CI (−2.0 to −0.2)) and HF hospitalization (RD −3.4 percentage points; 95% CI (−3.9 to −2.9)). Conclusions Initiation of an SGLT2i within 30 days of HFrEF diagnosis was associated with lower one-year mortality and HF hospitalization compared with no initiation. These findings support prioritizing early SGLT2i initiation as part of foundational therapy for HFrEF in routine clinical practice.
Abstract Ischaemic limb necrosis and resulting symmetrical peripheral gangrene (SPG) are devastating complications of severe shock states, particularly septic shock, and are associated with major morbidity, limb loss, and mortality. These complications usually occur in patients requiring vasopressor support for cardiovascular resuscitation during profound circulatory collapse. In this setting, however, thromboinflammatory microvascular injury represents the principal mechanism underlying ischaemic tissue injury. Life-threatening shock is characterized by endothelial injury, glycocalyx disruption, disseminated intravascular coagulation (DIC), impaired fibrinolysis, and ischaemic hepatic injury (“shock liver”) with endogenous natural anticoagulant factor depletion (antithrombin, protein C, protein S) that promotes diffuse thromboinflammatory microvascular thrombosis and impaired tissue perfusion independent of vasopressor therapy. Importantly, most critically ill patients receiving prolonged or high-dose vasopressor therapy do not develop ischaemic limb necrosis in the absence of severe coagulopathy, DIC, or shock liver. In contrast, patients developing SPG typically exhibit DIC (severe thrombocytopenia, greatly elevated D-dimer levels), hepatic dysfunction, and multiorgan failure. Under these conditions, progressive microthrombosis in distal limbs produces acral ischaemia and tissue necrosis. This review examines SPG in severe shock states through the framework of thromboinflammatory microvascular dysfunction, hepatic dysfunction, dysregulated coagulation with natural anticoagulant depletion, and endothelial injury, culminating in acral microthrombosis; we evaluate key limitations and confounders in the literature on vasopressor-associated ischaemia; and discuss the clinical phenotype of SPG in septic shock and critical illness. Finally, we address some of the important clinical and treatment implications of ischaemic limb necrosis during vasopressor support in critically ill patients with shock.
Abstract Vericiguat, an oral soluble guanylate cyclase stimulator, provides a mechanistically distinct approach to reducing residual risk in heart failure with reduced ejection fraction (HFrEF). The VICTORIA trial demonstrated a reduction in cardiovascular death or heart failure hospitalisation among patients with recent worsening heart failure, whereas vericiguat did not significantly reduce the primary endpoint in the subsequent VICTOR trial in a more stable HFrEF population. Nevertheless, the prespecified pooled analysis of VICTORIA and VICTOR showed a significant reduction in cardiovascular death or first heart failure hospitalisation across the combined HFrEF population, without significant heterogeneity between the trials. Together, these findings shift the focus from efficacy alone to clinical prioritisation according to baseline risk and timing, while recognising that validated treatment-selection criteria and an optimal timing strategy remain undefined. Contemporary observational studies have identified associations between blood pressure, disease severity, prior heart failure hospitalisation, and clinical or biomarker outcomes during vericiguat treatment; however, these characteristics have not been validated as predictors of vericiguat-specific treatment benefit. This review integrates evidence from VICTORIA, VICTOR, pooled analyses, and contemporary real-world studies and proposes a hypothesis-generating, risk- and timing-based framework for vericiguat use. Clinically meaningful worsening heart failure may represent a period of increased absolute risk in which consideration of vericiguat may be particularly relevant after clinical stabilisation, but neither an optimal therapeutic window nor a validated responder phenotype has been established. Prospective studies specifically evaluating treatment-by-risk and treatment-by-timing interactions are required to validate this framework.
