Abstract Introduction Angiotensin receptor neprilysin inhibitors (ARNi) significantly improve cardiovascular outcomes in patients with heart failure (HF). Their effects on kidney function in this population remain incompletely characterized. A systematic review and meta-analysis were performed to explore the impact of ARNi on renal outcomes. Methods MEDLINE, Embase, and PubMed databases were searched for randomized trials comparing ARNi with renin–angiotensin–aldosterone system inhibitors (RAASi) alone. Outcomes included the incidence of worsening renal function, hyperkalaemia, hypotension, >50% decrease in eGFR, end-stage renal disease, rise in serum creatinine >2.5 mg/dl, and acute kidney injury. Risk of bias was assessed using the ROB 2.0 tool. Results Fifteen studies with 31 574 individuals were included. Mean age was 67 years and 33% were female. ARNi significantly reduced the incidence of worsening renal function events [relative risk (RR): 0.83, 95% confidence interval (CI): 0.71–0.96; P = .01], corresponding to 13 fewer events per 1000 patients. ARNi were also associated with a lower risk of >50% decline in eGFR (RR: 0.61, 95% CI: 0.47–0.78; P < .001) and acute kidney injury events (RR: 0.82, 95% CI: 0.69–0.97; P = .024) compared with RAASi alone. There was no significant difference in the incidence of hyperkalaemia >5.5 mmol/L between groups, while ARNi were associated with a higher incidence of symptomatic hypotension (RR: 1.54, CI 95%: 1.35–1.76; I2 = 69%; P < .001). Conclusions ARNi are associated with a lower risk of adverse renal outcomes compared with RAASi in patients with heart failure. However, this benefit should be interpreted alongside an increased risk of symptomatic hypotension.
Abstract Aims The actual European heart failure (HF) guidelines recommend the combination of four drugs as a standard therapy (angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI); beta-blocker (BB); mineralocorticoid receptor antagonist (MRA); sodium-glucose co-transporter 2 inhibitor (SGLT-2i)) in patients with heart failure and reduced ejection fraction (HFrEF). We investigated the current use of this combined treatment in comparison to partly using these drugs in routine data with respect to outcomes of mortality and readmission. Methods We included anonymized data from all patients who were insured with Germany’s largest health insurer and had a claims record for hospitalization (2021-2023, follow-up in 2024) with a primary hospital diagnosis of HF. The use of different combinations of the four drug classes and their association with mortality and readmission within 91-365 days following the index stay were analysed (n = 307,755). Data were adjusted for a large set of potential confounders including age, sex, and comorbidities. In addition, the frequency of different 2-, 3-, and 4-drug heart failure medications was assessed from 2019 to 2023. Results In 2019 the dominant combination of drugs was ACEI/ARB and BB in nearly 37.84% of all cases. By 2023, the dominating combination was ACEI/ARB/ARNI, BB and SGLT-2i with or without an additional MRA (40.85%). The complete four-pillar therapy was prescribed in 21.81% of cases, while the old combination of ACEI/ARB and BB declined to 21.07%. Outcomes were assessed in 307,755 cases. In total, 55,985 of 298,535 (18.8%) included HF patients died 91–365 days after hospital discharge. Multivariable Cox proportional hazards models indicated a significantly lower mortality risk when patients had a combined treatment of all four drugs compared to a two-drug therapy (HR 0.89, 95% CI 0.86–0.92). The four-drug therapy was more effective with respect to mortality compared to the three-drug combination with an MRA (0.85, 95% CI 0.82-0.89). The comparison with a three-drug combination including an SGLT-2i performed equally (0.99, CI 0.95-1.03). Female sex was an independent negative predictor of four-drug therapy prescription after multivariable adjustment (AOR 0.62, 95% CI 0.60-0.63). Conclusions Our study suggests that the comprehensive four-drug therapy for heart failure is increasingly implemented in routine care and is independently associated with lower mortality and readmission rates. A three-drug combination including an SGLT-2i may be equivalent in selected cases. Female sex is associated with a lower likelihood of four-drug therapy prescription. These hypothesis-generating results underscore the necessity of investigating sex-specific clinical phenotypes and prescribing patterns in heart failure populations.
Abstract Sex is one of the most consistent, yet clinically underexploited, determinants of heart failure phenotype, mechanism and outcome. Building on landmark reviews and the 2024 scientific statement of the Heart Failure Association, which documented well-recognized phenotypic differences but noted that their mechanisms remain only partially defined, this review examines how sex differences in heart failure arise and how firmly they should guide practice. Epidemiologically, female predominance in heart failure with preserved ejection fraction is age- and menopause-dependent rather than lifelong. Mechanistically, sex-divergent hormonal signalling, autonomic tone, coronary microvascular dysfunction and myocardial fibrosis often produce similar phenotypes through different mechanisms: microvascular dysfunction is similarly prevalent in both sexes but linked to fibrosis in women and to atherosclerotic risk factors in men, and oestradiol regulates collagen synthesis in opposite directions in female and male cardiac fibroblasts. Clinically, comorbidities carry divergent prognostic weight by sex. Graded against the strength of evidence, sodium-glucose cotransporter 2 inhibitors show established sex-neutral efficacy, whereas the greater benefit of angiotensin receptor-neprilysin inhibition and mineralocorticoid receptor antagonism in women rests on subgroup signals that await confirmation. Natriuretic peptide concentrations are substantially sex-dependent, yet diagnostic thresholds remain sex-neutral, although sex-specific calibration is methodologically achievable. Women remain underrepresented in heart failure trials and less often referred to specialized care. Heart failure is therefore best understood as a sex-differentiated syndrome whose frameworks were built largely around male-pattern disease. Sex-calibrated trial enrolment, sex-specific biomarker and ejection fraction thresholds, and stratification by menopausal stage are concrete next steps towards personalized care.
Abstract Background Interventricular septal (IVS) thickness is routinely measured by echocardiography, yet its prognostic significance in heart failure (HF), and whether it differs by sex, remains uncertain. Methods This retrospective study included patients with HF from the SHEBAHEART registry (2009-2025). IVS thickness was classified as normal (<1.1 cm), mildly thickened (≥1.1 to ≤1.3 cm), or severely thickened (>1.3 cm), using identical thresholds by sex. Associations with all-cause mortality were evaluated using Kaplan-Meier analysis and multivariable Cox models adjusted for age, body mass index, systolic blood pressure, comorbidities, and left ventricular ejection fraction, with formal testing for sex-by-IVS interaction. Results Among 20,836 patients (median age, 74 years; 39% women), 41% had mild and 18% had severe IVS thickening. During a median follow-up of 4 years, 11,930 patients (57%) died; 4-year Kaplan-Meier cumulative mortality increased across IVS categories (35%, 39%, and 42%; P < 0.001). In primary complete-case analysis (n = 13,902), the sex-by-IVS interaction was significant (P = 0.030). Adjusted hazard ratios (95% confidence intervals) for mild and severe thickening were 1.16 (1.07-1.26) and 1.19 (1.08-1.32) in women, compared with 1.02 (0.96-1.09) and 1.07 (0.99-1.16) in men. The sex-by-IVS interaction remained significant in multiple-imputation and time-varying Cox analyses, but not with sex-specific IVS reference partitions. Conclusions With common absolute IVS thresholds, increased septal thickness was more strongly associated with all-cause mortality in women than in men with HF. These findings support evaluation of IVS thickness as a potential component of sex-specific risk stratification in HF.
