Letter to ‘Therapy gaps in heart failure with reduced ejection fraction and chronic kidney disease: time to close the loopholes’

We thank Ma and colleagues for their timely prospective cohort highlighting how often patients with heart failure (HF) and chronic kidney disease (CKD) still miss guideline-directed medical therapy.1 Yet three methodological gaps deserve attention before the findings are translated into routine care. First, CKD was used as a cross-sectional label, so we do not know whether renal dysfunction antedated or followed the cardiac insult. Separating Type 1 [acute HF → acute kidney injury (AKI)] from Type 4 (CKD → cardiac deterioration) cardiorenal syndrome matters for mechanistic insight and trial design. Kobayashi et al. recently showed that an estimated Glomerular Filtration Rate (eGFR) slope that steepens at least 12 months before the first HF hospitalization more than doubles the risk of subsequent admission [Hazard Ratio (HR) ≈ 2.3], confirming that the direction of injury can—and should—be quantified.2 Second, female sex was dropped from the multivariable model (univariate P ≈ .12) despite women accounting for only 26% of hyperkalaemia events. Removing sex folds any inherent female susceptibility into the eGFR coefficient and risks overestimating the hazard attributed to advanced CKD. The 2025 ADQI consensus explicitly warns that failure to perform sex-stratified analyses masks biological interaction and inflates renal risk.3 Future analyses should retain sex and test sex ×eGFR interaction terms. Third, although Ma et al. report 3.9-year mortality and hospitalization rates, events were extracted from administrative databases without central adjudication and without patient-reported outcome measures (PROMs). The 2022 JAMA guidance reminds us that hard end points alone cannot capture symptoms, function, or quality of life.4 Centrally adjudicated cardiovascular death, serial echocardiography, and longitudinal PROMs, such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) or EuroQol 5-Dimension Questionnaire (EQ-5D), should be co-primary end points to keep evidence generation aligned with contemporary, patient-centred standards. Embedding temporal sequencing, mandatory sex stratification, and PROM-based adjudication will turn observational gaps into actionable, equitable, and patient-relevant therapeutic strategies. All authors declare that they have no conflict of interest. Not applicable. This work was supported by the Project of Hospital-level Key Discipline of Ningbo No. 2 Hospital (no. 2023-Y06).