Faiez Zannad

Aims: To define the impact of diastolic dysfunction (DD) on the response to empagliflozin treatment in patients with heart failure with preserved ejection fraction. Methods and Results: Diastolic dysfunction was defined by left atrial volume index ≥34 ml/m2, the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular tissue velocity (E/e) ≥ 13 or left ventricular mass index >115 (males) or >95 (females). We created three categories of increasing DD (0, 1, or ≥2 DD criteria at baseline) to describe the effect of DD on response to empagliflozin therapy and adverse effects. Of 5988 patients in the EMPEROR-Preserved trial, 3766 (63%) had no documented baseline DD, 1619 (27%) had one, and 603 (10%) had two or more measures. Baseline DD was associated with sex, race, ethnicity, and region and was more common with lower heart rate, DBP, body weight, and eGFR. Despite baseline DD not being significantly associated with the primary endpoint of hospitalization for heart failure or cardiovascular death within the placebo group, a progressive treatment effect across the three DD categories was seen (trend test P-value .0014), with estimated hazard ratios of empagliflozin vs placebo of 0.91 (none present), 0.64 (1 present), and 0.49 (≥2). A significant treatment-by-subgroup trend test was also observed for the total number of hospitalizations for heart failure. Both Kansas City Cardiomyopathy Questionnaire Clinical Summary Score improvement at week 52 and safety profile were consistent across DD categories. Conclusion: Baseline detection of echocardiographic DD predicted improved clinical response to empagliflozin in a graded fashion, but the reasons cannot be reliably determined from this analysis.

Cardiometabolic diseases increasingly manifest as interconnected dysfunction across the heart, vasculature, kidneys, liver, and metabolic system. The global rise in obesity, insulin resistance, and diabetes, together with therapies benefiting multiple organs, has reshaped the epidemiology and understanding of cardiometabolic disease, exposing the limitations of organ-specific or single-stage approaches. The cardioVascular–kidney–liver–metabolic (CVKLM) framework is a multidimensional staging system in which cardiac, vascular, kidney, liver, and metabolic involvement are graded independently from absent to advanced. Analogous to tumour–node–metastasis staging, it provides a standardized language describing disease severity within each organ and its distribution across organs. Rather than replacing existing classifications, CVKLM integrates universal heart failure stages, validated vascular risk assessment, KDIGO chronic kidney disease stratification, contemporary metabolic dysfunction-associated steatotic liver disease (MASLD) and advanced liver disease criteria, and current definitions of diabetes and clinical obesity. Unlike hierarchical frameworks assigning a single overall stage, CVKLM preserves organ-specific information and records coexisting abnormalities across domains. Intended for clinical and research phenotyping and staging rather than as a validated global risk score, it may facilitate systematic recognition of concomitant organ disease, support existing organ-specific diagnostic, referral, and treatment pathways, and provide a standardized taxonomy for observational studies and clinical trials. The prognostic significance of CVKLM profiles, their incremental value beyond established risk tools, and their clinical utility remain to be established. By integrating these domains within a common architecture, CVKLM offers a pragmatic framework spanning the full spectrum of cardiometabolic disease, from preclinical involvement to advanced multiorgan failure.

Background: Kidney function decline in heart failure (HF) may accelerate during periods surrounding HF-related events, while sodium-glucose cotransporter 2 inhibitors slow kidney function decline. However, the temporal relationship between kidney function changes, HF-related events, and treatment effects has not been well characterized. Aims: We aimed to explore kidney function trajectories around HF-related events and to assess whether empagliflozin modifies these changes. Methods and results: In a pooled analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials, we examined longitudinal changes in estimated glomerular filtration rate (eGFR) before and after HF-related events, defined as HF hospitalization or HF-related death. In the EMPEROR-Pooled analysis, HF-related events occurred in 12.7% of 9554 patients during a median follow-up of 20.9 months (14.7–28.6). Patients who experienced HF-related events had a steeper eGFR decline during the 12 months before the event than those without HF-related events: average −5.01 ml/min/1.73 m2/year vs −1.93 ml/min/1.73 m2/year; P < .001. During the 12 months after HF-related events, eGFR decline persisted at an average rate of −4.73 ml/min/1.73 m2/year. These trajectories were not materially altered after adjustment for concurrent NYHA class or natriuretic peptide levels. Compared with placebo, empagliflozin slowed eGFR decline in patients without events (between-group difference, 0.94 ml/min/1.73 m2/year) and before events (1.09 ml/min/1.73 m2/year). The post-event difference was smaller (0.29 ml/min/1.73 m2/year), without significant heterogeneity across periods (P > .10). Findings were consistent across trials and irrespective of prior HF hospitalization. Conclusion: Across the LVEF spectrum, kidney function decline accelerated before HF-related events and remained rapid thereafter. Empagliflozin attenuated eGFR decline without evidence of heterogeneity across periods.

Background: Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are a cornerstone of treatment for chronic heart failure (CHF), a condition characterised by systemic inflammation and congestion. Objectives: We investigated the relationship between the neutrophil-to-lymphocyte ratio (NLR), which is thought to reflect both inflammation and congestion, and the clinical characteristics and outcomes of patients with CHF. Additionally, we sought to evaluate the effects of empagliflozin on NLR and across NLR quintiles. Methods: For this post-hoc analysis, we used the EMPEROR-Pooled database, which combines the EMPEROR-Reduced (NCT03057977) and EMPEROR-Preserved (NCT03057951) trials, in which 9706 patients with CHF were randomised to empagliflozin or placebo and had NLR available at baseline. The primary outcome was time to first heart failure hospitalisation or cardiovascular death; secondary endpoints included all-cause mortality and renal outcomes. Results: Compared with patients in the lowest NLR quintile, those in the highest quintile were older, more likely to be men, more symptomatic, had higher plasma NT-proBNP and more likely to be treated with loop diuretics. Compared to the lowest NLR quintile, patients in the highest quintile had a greater risk of the primary outcome (14.9% versus 27.3% events; adjusted hazard ratio 1.44 (1.16-1.80); p=0.001), mainly due to more heart failure hospitalisations. Baseline NLR did not modify the effect of empagliflozin on either primary and secondary endpoints. NLR increased during follow-up but this was not affected by empagliflozin. Conclusions: In patients with CHF, a higher NLR was associated with greater congestion and poorer prognosis. The efficacy of empagliflozin was consistent, regardless of baseline NLR.

Background: The VICTOR trial did not meet its primary composite endpoint of cardiovascular death or first hospitalization for heart failure (HF) but demonstrated a nominally significant reduction in the prespecified and powered endpoint of cardiovascular death with vericiguat in patients with HF and reduced ejection fraction (HFrEF). Bayesian and actuarial methods offer complementary frameworks to quantify the probability and lifetime implications of this mortality benefit. Methods: This post hoc analysis of the VICTOR trial applied Bayesian and actuarial analyses. Bayesian analysis estimated the probability that vericiguat reduces mortality, integrating trial data with prior evidence. Actuarial analysis used restricted mean survival time (RMST) to quantify event-free survival at 1 and 2 years, and age-based Cox proportional hazards modelling to project lifetime survival gains across ages 45–80. Results: Bayesian analyses showed a consistently high probability of mortality benefit with vericiguat, regardless of whether sceptical or optimistic prior evidence was weighted. For cardiovascular mortality, the sceptical prior yielded a 98.4% posterior probability of any benefit, a 77.6% probability of at least a 10% relative reduction, and a 20.4% probability of at least a 20% reduction. The VICTORIA-based optimistic prior yielded 99.1%, 60.7%, and 2.2%, respectively. Similar results were observed for all-cause mortality. Actuarial analyses demonstrated greater event-free survival with vericiguat over 1 and 2 years. Lifetime projections suggested that vericiguat may extend overall survival across a broad age range, with the largest gains observed of ∼1.6 to 1.9 years for those aged 55 to 60 at randomization. Conclusion: In this post hoc analysis, Bayesian and actuarial methods provided hypothesis-generating evidence of a cardiovascular mortality benefit with vericiguat in HFrEF, an endpoint for which the trial was prospectively powered, that warrants prospective confirmation.

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 randomized HF trials including 35 550 patients with HFrEF, 6484 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 left ventricular ejection fraction 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 ( 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 a 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 favoured 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. Conclusion: 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. Clinical Trial Registration: NCT05093933