Abstract Background Cardio-renal-metabolic (CRM) syndrome describes the pathophysiological interconnection among diabetes mellitus (DM), atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF), and chronic kidney disease (CKD). Limited studies simultaneously examine progression trajectories across all three conditions at the population level. We aimed to quantify the coexistence of CRM components, with a specific focus on patients with HF, and analyse survival and disease progression in a real-world setting. Methods CaReMap, an observational cohort study, analysed data from an Italian Regional Epidemiological Repository. The selection period spanned from 2017 to 2022. Incident patients had a first diagnosis of DM, HF, or CKD after January 1, 2017. Prevalent patients were classified based on their baseline morbidity status on January 1, 2017. Descriptive statistics, Kaplan-Meier survival estimates, and cumulative incidence curves for cause-specific events were reported. The CRM stage was further defined according to disease coexistence and severity. Results CaReMap included 71,694 adults with established CRM-related conditions (31.8% incident; 68.2% prevalent). Among incident patients, HF was associated with the highest probability of developing an additional diagnosis (60.4% at 6 years), while CKD showed the highest probability of death before a new diagnosis (43.3% at 6 years). In prevalent patients, the DM&HF group showed the highest cumulative incidence of further diagnoses (47.1% at 6 years). Across both incident and prevalent cohorts, HF and CKD patients experienced the steepest decline in overall survival. Conclusion In this population-based Italian cohort, DM, HF, and CKD define distinct diagnostic trajectories with substantial competing risk of death. These findings provide real-world estimates of transition patterns and absolute risks that may inform risk stratification and integrated care pathways.
Abstract Aims Loop diuretics (LD) are the cornerstone of congestion management in heart failure (HF), but whether their requirement can be reduced by optimizing disease-modifying therapy is unknown. Methods In this post-hoc analysis of STRONG-HF (n=1,075 with post-randomization LD data), we assessed whether up-titration of guideline-directed medical therapy (GDMT) lowers LD demand, and whether LD dose reflects HF severity, predicts outcome, or modifies the benefit of high-intensity care. Patients were grouped by furosemide-equivalent dose; change at day 90 was compared by achievement of 100% target GDMT doses. Results Higher LD doses marked more severe HF. Achieving 100% of target doses of all GDMT classes (RASi, beta-blocker, MRA) translated into a substantially lower diuretic requirement: furosemide-equivalent dose at day 90 fell by −21.94 (SD 52.46) mg versus −1.55 (SD 49.886) mg in those not reaching targets (p<0.001); beta-blockers showed the largest effect of any single class −18.42 (SD 49.61) mg, (p<0.001). LD dose category was not independently associated with the primary endpoint (all-cause death or HF rehospitalization at 180 days) or its components; only LD dose doubling was associated with higher all-cause mortality (adjusted HR 1.47, 95% CI 1.04–2.09), without association with the primary endpoint or rehospitalization (both p>0.05). The benefit of high-intensity care was consistent across LD dose groups (no treatment-by-dose interaction). Conclusions GDMT optimization acted as diuretic-sparing therapy: reaching target doses, particularly of all three classes, was associated with markedly lower LD requirement. LD dose mirrored HF severity but neither consistently predicted outcome nor modified the benefit of up-titration.
Abstract Aims The prognostic significance of pulse pressure (PP) differs across HF phenotypes, but its relevance in HFmrEF remains uncertain. We evaluated associations between PP and clinical outcomes across HF phenotypes and assessed whether PP provides prognostic information beyond SBP. Methods and results We performed a patient-level pooled analysis of 13 randomised HF trials including 35,550 patients with HFrEF, 6,484 with HFmrEF, and 19,173 with HFpEF. PP–outcome associations were assessed using Cox models for quartiles and Poisson regression with restricted cubic splines for continuous PP. Across HF phenotypes, patients with higher PP were older, more frequently female, and had higher LVEF and greater adiposity. In HFrEF, PP was inversely associated with first HF hospitalization or cardiovascular death, with the lowest event rate in the highest PP quartile (>56 mmHg; 13.3 per 100 person-years [95% CI, 12.8–13.8]) and the highest event rate in the lowest quartile (<40 mmHg; 18.2 [17.5–18.9]). In contrast, HFpEF demonstrated a J-shaped relationship, with the lowest event rate in the second quartile (48–56 mmHg; 6.8 [6.4–7.3]) and the highest in the fourth quartile (> 66 mmHg; 9.7 [9.1–10.3]). HFmrEF exhibited a similar J-shaped association, closely paralleling HFpEF. PP improved model fit beyond SBP, but the incremental improvement in discrimination was small and largely limited to HF hospitalization-related outcomes in HFpEF. Conclusions PP has phenotype-specific prognostic implications in HF. Low PP identifies higher risk in HFrEF, whereas high PP identifies higher risk in HFpEF and HFmrEF. PP may support phenotype-specific risk stratification.
BACKGROUND AND AIMS:It is uncertain whether the effect of vericiguat varies across levels of background guideline-directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF). METHODS:We conducted an exploratory analysis of VICTOR, which enrolled 6105 ambulatory patients with HFrEF without recent worsening. GDMT exposure was classified as basic adherence (on vs. off), indication-corrected adherence (accounting for eligibility and contraindications), and dose-corrected adherence (≥50% target dose). A GDMT intensity score was computed from class-specific dose levels. The primary endpoint was the composite of cardiovascular death or first HF hospitalization. Stratified Cox proportional hazards regression models estimated adjusted hazard ratios for vericiguat versus placebo within GDMT strata, with treatment-by-GDMT interaction test. RESULTS:Baseline contemporary GDMT use was high (any ARNI/ACE/ARB 93.9%, ARNI 56%, SGLT2i 59%, MRA 78%, beta-blocker 94%). Basic adherence: adjusted HRs for the primary endpoint were similar whether or not patients were on ACEi/ARB, ARNI, any RAS inhibitor, beta-blocker, or SGLT2i. Dose-corrected adherence: adjusted HRs favored vericiguat in ARNI target-dose users (0.73; 0.57-0.93) and in any RAS target-dose users (0.77; 0.64-0.93), with lower risk on vericiguat in patients not meeting MRA target dose (0.67; 0.48-0.95); interaction P-values were nominally significant. The GDMT intensity score showed no significant interaction with treatment. Patterns for cardiovascular death and all-cause death paralleled the primary endpoint. CONCLUSIONS:In ambulatory patients with HFrEF receiving contemporary GDMT, we did not find convincing evidence that the neutral effect of vericiguat on cardiovascular death or first HF hospitalization was modified by GDMT class, dose attainment, or overall intensity, in a cohort with very high background GDMT use and limited power for interaction testing. These exploratory, hypothesis-generating findings do not establish independent efficacy or pathway additivity for vericiguat and should not be used to guide clinical recommendations regarding GDMT sequencing.
