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.
Concomitant transthyretin cardiac amyloidosis (ATTR-CA) is increasingly recognized among elderly patients with severe aortic stenosis (AS) referred to transcatheter aortic valve implantation (TAVI), yet its impact on early and late outcomes remains incompletely defined. We conducted a systematic review of studies comparing TAVI outcomes in patients with isolated AS and those with AS+ATTR-CA. Eleven observational studies were included, comprising 644,107 patients with isolated AS and 1,637 with AS+ATTR-CA. AS+ATTR-CA patients were older, more frequently male, and showed more atrial fibrillation, mildly reduced left ventricular ejection fraction, and markedly elevated cardiac biomarkers. Thirty-day mortality was low and similar between groups, with no consistent differences in stroke or major bleeding, whereas acute kidney injury and permanent pacemaker implantation were more frequent in AS+ATTR-CA. During follow-up, AS+ATTR-CA patients experienced higher heart failure readmissions and late all-cause mortality. ATTR-CA should not preclude TAVI but should inform risk stratification, peri-procedural management, and post-TAVI follow-up.
AIMS:Recent randomized controlled trials (RCTs) showed improved decongestive response with intensified treatment during hospitalization for acute decompensated heart failure (ADHF). Nevertheless, none demonstrated long-term benefit, possibly due to lack of statistical power. We therefore pooled individual data from three recent RCTs to assess the clinical impact of intensified decongestive therapy. METHODS:Individual patient data from three RCTs evaluating decongestive strategies in ADHF-acetazolamide (ADVOR), hydrochlorothiazide (CLOROTIC), and natriuresis-guided therapy (PUSH-AHF)-were pooled. The primary endpoint was 90-day heart failure (HF) re-hospitalization and/or all-cause mortality (adjusted for sex and trial). Secondary endpoints included 24- and 48-h diuresis, natriuresis, in-hospital mortality, and length of stay (LOS). RESULTS:A total of 1059 patients (mean age 79, 42% female) hospitalized for ADHF were included. Baseline characteristics were similar, except for a higher proportion of men in the intensified treatment arm (63% vs 54%, P = .004). Intensified treatment did not reduce 90-day all-cause mortality and/or HF readmissions (adjusted hazard ratio [HR] 1.03; 95% confidence interval [CI] 0.81-1.30); however, it was associated with lower in-hospital mortality (adjusted odds ratio [OR] 0.55; 95% CI 0.31-0.96; P = .038). Cumulative diuresis and natriuresis was significantly higher in patients with intensified treatment at 24 and 48 h (adjusted P < .001). There was no difference in doubling of serum creatinine at 3 days between the groups (adjusted P = .123). LOS was significantly shorter in patients in the intensified treatment arm (geometric mean of 9 [95% CI 8-9] days vs 10 [95% CI 9-10] days in the placebo group, adjusted P = .002). CONCLUSION:While intensified decongestive strategies in patients hospitalized for ADHF improve diuresis, natriuresis, and reduce LOS, no benefit was observed for post-discharge clinical outcomes. Although a potential reduction in in-hospital mortality was observed, this finding should be considered exploratory and hypothesis-generating.
AIMS:The interactions between heart failure (HF), chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and relative drug use remain poorly studied. METHODS:Patients enrolled in the Swedish HF registry 2017-2023 were divided according to CKD and T2DM. HF medication use and all-cause death, cardiovascular death, first HF hospitalization (HHF), their composite, and end-stage renal disease (ESRD) were assessed. RESULTS:Among 54 341 patients (34% females, mean age 73 years), 51% had no CKD/no T2DM, 24% CKD only, 14% T2DM only, and 11% both CKD/T2DM. CKD only and CKD/T2DM prevalences were higher in HF with preserved ejection fraction (HFpEF; 29% and 15%, respectively) than with mildly reduced EF (HFmrEF; 23% and 11%) and reduced EF (HFrEF 22% and 10%). HF medication use, especially of mineralocorticoid receptor antagonists, was generally lower in groups with CKD. Event rates for all outcomes were progressively higher going from no CKD/no T2DM, T2DM only, CKD only, and both CKD/T2DM in all EF categories. Independent risks of mortality and HF outcomes were significantly increased in the presence of CKD/T2DM, whereas for ESRD, T2DM alone did not significantly increase risk, CKD alone increased it threefold, and both CKD and T2DM increased it six-fold. CKD added more to the risk of events in HFrEF than in HFpEF. CONCLUSION:CKD was more common in HFpEF and a strong independent risk factor for all outcomes. T2DM was a moderate independent risk factor for all outcomes. These findings inform drug implementation and future aldosterone-targeting drug trials.
BACKGROUND:Growing evidence implicates gut dysbiosis in heart failure (HF) pathogenesis. This systematic review and meta-analysis synthesises prognostic associations of microbial metabolites in HF. METHODS:Electronic databases were searched through February 2026 for studies investigating associations between gut microbial metabolites and HF outcomes. Study characteristics, baseline covariates and outcomes were extracted in duplicate. The prespecified primary outcome was all-cause mortality; the secondary outcome was major adverse cardiac events (MACE). Random-effects models were applied to pool hazard ratios. Subgroup analyses stratified cohorts by HF phenotype and aetiology; meta-regression explored potential effect modifiers. This study was preregistered on PROSPERO (CRD42025631114). RESULTS:Twenty studies comprising 17,715 patients were included in meta-analysis; six studies were synthesised narratively. Median follow-up was 31.7 months. Elevated trimethylamine-N-oxide (TMAO) was associated with all-cause mortality in the overall population (HR 1.72, 95%CI 1.42-2.08, p=0.0002, I2 37.3%) and across HF phenotypes (HRHFrEF 2.17, 95%CI 1.68-2.81, I2 0%; HRHFpEF 1.55, 95%CI 0.92-2.61, I2 0%). Higher TMAO was also associated with MACE (HR 1.60, 95%CI 1.44-1.78, p<0.0001, I2 0%), consistent across HF phenotypes (HRHFrEF 1.43, 95%CI 1.15-1.78, I2 0%; HRHFpEF 1.76, 95%CI 1.21-2.55, I2 31.6%). Elevated phenylacetylglutamine (PAGln) was associated with mortality (HR 1.60, 95%CI 1.33-1.94, p<0.0001, I2 0%) and MACE (HR 1.65, 95%CI 1.37-1.99, p<0.0001, I2 2.1%) in the overall population. Meta-regression demonstrated no significant effect modification by baseline age, NT-proBNP, renal function or BMI. CONCLUSION:Elevated TMAO and PAGln are consistently associated with adverse outcomes across diverse HF cohorts, highlighting their potential relevance as indicators of residual risk in HF.
AIMS:Circadian patterns influence cardiovascular physiology, yet have not been characterized in intracardiac pressures of ambulatory chronic heart failure patients. We aimed to assess diurnal variation via a novel remote intracardiac left atrial pressure sensor. METHODS AND RESULTS:Daily ambulatory left atrial pressure (LAP) measurements were obtained with an implantable intracardiac sensor. Patients performed morning and evening measurements during longitudinal follow-up. We compared diurnal variability in morning and evening LAP, examined its potential association with diuretic regimen, presence of atrial fibrillation and acute decompensated heart failure (ADHF) events.Across >15,500 measurement days with an average follow up time of 25.5±18.6 months in 73 heart failure patients, median left atrial pressure was higher in the evening than in the morning (12.4 [6.8, 18.3] vs.10.7 [5.5, 17.3] mmHg; p < 0.01). Neither higher diuretic dose, twice-daily dosing, nor atrial fibrillation modified this diurnal variation (p =0.98, p=0.50).Patients who suffered ADHF events demonstrated higher left atrial pressures (14.3 [9.5, 19.9] vs 10.4 [5.4, 17.3] mmHg, p < 0.01). Higher LAP was also independently associated with increased risk of ADHF events (OR 1.40, 95% CI 1.10-1.78; p < 0.01). Diurnal variation was present irrespective of acute decompensated heart failure status (p = 0.79). CONCLUSIONS:Using direct ambulatory intracardiac LAP monitoring, we observed consistent diurnal variation with higher evening pressures, largely unchanged by diuretic dose or dosing schedule, atrial fibrillation, or association with ADHF events.
AIMS:Blood pressure (BP) control is a Class I recommendation for the management of heart failure with preserved ejection fraction (HFpEF); however, evidence supporting systolic BP (SBP) targets remains limited. We investigated associations between BP control and subsequent outcomes in patients with HF with mildly reduced EF (HFmrEF)/HFpEF. METHODS:We pooled TOPCAT (Americas), PARAGON-HF, DELIVER, and FINEARTS-HF, which tested spironolactone, sacubitril/valsartan, dapagliflozin, and finerenone, respectively, versus placebo or active control in patients with HF and an LVEF >40% (DELIVER), ≥40% (FINEARTS-HF), or ≥45% (TOPCAT-Americas, PARAGON-HF). Daily BPs were estimated by interpolation from standardized office measurements obtained at randomization and prespecified visits. Time in target range (TIR) was the percentage of the first year after randomization during which SBP was 110-<130 mmHg. Continuous associations between TIR and subsequent risk of HF hospitalization or cardiovascular death, its individual components, and all-cause death was assessed using landmark Cox proportional hazards models with linear splines, adjusted for baseline cardiovascular risk factors. RESULTS:Among 17,788 patients (mean age 72±9 years; 47% women; mean baseline SBP 129±15 mmHg), the median TIR was 38% (≈139 days). Randomization to active therapies increased TIR by 2% (95% CI: -2 to 6) with spironolactone, 7% (5 to 9) with sacubitril/valsartan, 2% (0 to 4) with dapagliflozin, and 3% (1 to 5) with finerenone. Higher TIR was associated with lower subsequent risk of the composite outcome (P=0.021), primarily driven by lower HF hospitalization risk (P=0.007); associations with cardiovascular death and all-cause death were not significant. Sensitivity analyses using stricter (120-<130 mmHg) or more liberal ranges (100-<130 and 120-<140 mmHg) yielded qualitatively similar findings. CONCLUSIONS:In patients with HFmrEF/HFpEF, BP control during the first year was associated with a lower subsequent risk of HF hospitalization. CLINICAL TRIALS REGISTRATION:ClinicalTrials.gov ID NCT00094302 (TOPCAT), NCT01920711 (PARAGON-HF), NCT03619213 (DELIVER), NCT04435626 (FINEARTS-HF).
AIMS:Digitoxin reduced the composite of death or worsening heart failure in DIGIT-HF, but whether these benefits translate into economic value remains unknown. We assessed its cost-effectiveness as add-on therapy for heart failure with reduced ejection fraction (HFrEF) across all 27 European Union Member States (EU-27) and the United States (US). METHODS:We developed a DIGIT-HF-informed, multi-jurisdictional three-state Markov cost-utility model projecting 10-year and lifetime outcomes. Clinical risks and intention-to-treat effects were held constant; hospitalization costs, EQ-5D-5L utilities, digitoxin costs, discounting, and willingness-to-pay (WTP) thresholds varied by jurisdiction. Uncertainty was assessed using 10 000 probabilistic simulations. RESULTS:Across the EU-27, digitoxin was cost-effective at 10 years, with incremental costs of -€338 to +€25 per patient, incremental quality-adjusted life-years (QALYs) of 0.188-0.231, and a maximum incremental cost-effectiveness ratio (ICER) of €120/QALY. Over lifetime, corresponding ranges were -€79 to +€72, 0.373-0.453 QALYs, and a maximum ICER of €174/QALY. At €50 000/QALY, cost-effectiveness probability was 92%. Digitoxin was cost-saving in 24 of 27 Member States at 10 years and 10 of 27 over lifetime. In the USA, it was cost-saving (lifetime savings US$405 per patient; 0.43 QALYs; 93.4% probability of cost-effectiveness). CONCLUSION:Digitoxin generated clinically meaningful health benefits at negligible incremental cost and remained cost-effective across every evaluated EU-27 healthcare system and the USA. Economic value emerged earliest within the first decade and in higher-cost hospital systems, while lifetime analysis captured larger cumulative gains in quality-adjusted survival.
