We performed an ambispective, longitudinal, single-centre observational study in the Cardiorenal Unit (CRU) of the Hospital Universitario Virgen de las Nieves in Granada between 10/1/2021 and 9/30/2023. In the absence of an independent control group, we used an adapted interrupted time-series design. We selected this design for ethical reasons, as delaying access to the CRU could not be justified. No sample size was calculated beforehand, as the study was designed as a real clinical practice analysis. Criteria for referral to the CRU at our centre included: 1) patients with HF and reduced (LVEF < 40%) or mildly reduced (40–49%) left ventricular ejection fraction (LVEF) and advanced CKD (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73 m2 using the CKD-EPIcr formula); 2) patients with HF and refractory congestion with eGFR < 60 ml/min/1.73 m2; and 3) patients with cardiorenal disease on RRT and HF with reduced LVEF requiring cardiological optimization for inclusion on the waiting list for renal, cardiac, or combined transplantation. To standardize the sample, patients meeting the first criterion were included, as they represent those with a clear indication for GDMT for HF. These patients are underrepresented in clinical trials due to their eGFR. Those under RRT at the start of follow-up were excluded. The follow-up time in the CRU defined for each patient was one year.

Demographic, clinical, analytical, and therapeutic data were collected at baseline, 3-month intervals, and 1 year. Triple therapy was defined as treatment with beta-blockers (BB), renin-angiotensin-aldosterone system inhibitors (RAASIs), or angiotensin-receptor/neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs), in line with the 20169 and 202110 ESC Guidelines. Quadruple therapy, according to the 202110 ESC Guidelines, consisted of triple therapy with the additional use of sodium-glucose cotransporter type 2 (SGLT2) inhibitors. Clinical events of interest included all-cause mortality during follow-up, as well as emergency department visits and hospitalizations for cardiovascular causes. A prospective follow-up of 12 months from inclusion in the CRU was planned, and for the control period, care data for the previous 12 months were collected retrospectively. Cardiovascular causes were defined as decompensated HF, coronary artery disease, cerebrovascular disease, arrhythmias, peripheral vascular disease, and renal events secondary to cardiovascular causes. All clinical events recorded in the cohort were included, regardless of their course during follow-up. CKD progression was assessed using the eGFR progression slope, following the definition of the Spanish Society of Nephrology consensus document.11 This study complied with the principles of the Declaration of Helsinki, and was approved by the ethics committee of the participating centre (SICEIA-2024-000589). We obtained informed consent from all included patients.

For each patient, we estimated the total economic cost based on health care resources consumed during hospital care, including emergency department (ED) visits and hospitalizations, in the two periods analysed. Both ED and hospitalization costs were obtained from the Analytical Management Accounting System of our centre. The average cost of an emergency department visit at our hospital in 2023 was 193.4 €. For hospitalization costs, we considered the average daily cost per hospital stay, which varied by the Clinical Management Unit (CMU) responsible for the admission. These costs included both direct costs (medical care, diagnostic tests, treatments, and room accommodation) and indirect costs (hospital infrastructure, administrative management, and maintenance). To calculate the total cost in each of the periods analysed, we multiplied the total number of days of hospitalization charged to each CMU by the corresponding average daily cost, and the total cost for emergency department visits, calculated similarly, was then added.

A descriptive statistical analysis was performed, using measures of central tendency and dispersion for quantitative variables, and absolute and relative frequencies for qualitative variables. To study the evolution of analytical data, we fitted a linear mixed-effects model, with time as the fixed-effects component. Pairwise comparisons of the estimated marginal mean for the time variable were conducted. We used Cochran’s test to compare the proportions of treatment variables over follow-up. Finally, we compared ED visits and hospitalizations using the Wilcoxon test for dependent samples. Calculations were performed using Stata, version 16.

A total of 55 patients were included (mean age 73.9 ± 8.6 years; 78% male). The general characteristics of the study population at the time of inclusion in the CRU are available in Table 1. 56.4% were aged ≥75 years. Baseline mean LVEF was 40.1 ± 9.3%, and it was ≤40% in 70.9% of patients. Baseline mean eGFR was 22.3 ± 7.61 ml/min/1.73 m2.

The percentage of patients prescribes RAASi/ARNI, MRA, SGLT2 inhibitors, and BB prior to inclusion in the CRU were 75.7%, 51.3%, 59.5% and 94.6%, respectively. The proportion of patients with triple and quadruple therapy was 45.95% and 27.03%. There was a significant increase in the prescription of MRA and SGLT2 from the ninth month (p = 0.025) and the third month (p = 0.028), respectively. Accordingly, we observed a significant increase in the number of patients receiving both triple (+10.81%, p = 0.049) and quadruple therapy (+24.32%, p = 0.001) (Fig. 1A). No patients discontinued MRA due to hyperkalaemia, and there was an increase in the prescription of potassium chelators. We observed no significant changes from baseline to the first year in eGFR (coefficient −1.4; CI 95%: −3.5 to 0.64; p = 0.17) or creatinine values (coefficient 0.1; CI 95%: −0.07 to 0.28; p = 0.24), suggesting a slowing of the CKD progression curve. There were also no statistically significant differences in serum potassium concentration between patients who received triple or quadruple therapy at different times of the study (Table 2).

Figure 1.

A) Percentage of patients with evidence-based treatment for heart failure with reduced ejection fraction (HF-REF) prior to inclusion in CRU (pre-CRU) as at baseline visit (0 m), at 3 month intervals, and at 1 year. B) Comparison of the total number of emergency department visits and hospitalizations for cardiovascular causes in the year prior to CRU and during the follow-up year broken down according to quadruple therapy. Significant statistical differences are shown with their corresponding p values.

ARB: angiotensin II receptor blockers; MRA: mineralocorticoid receptor antagonist; ARNI: angiotensin receptor/neprilysin inhibitor; BB: beta-blocker; quadrupleT: quadruple therapy; ACEI: angiotensin-converting enzyme inhibitor; SGLT2: sodium-glucose cotransporter type 2 inhibitor; ns: not statistically significant; p: p-value; CRU: cardiorenal unit.

During the year of follow-up, nine patients died (seven due to cardiovascular causes, one due to an oncologic cause, and 1 due to a digestive cause), and three started RRT: one opted for HD, while two started PD, although one later required transfer to HD due to catheter-related complications. In all cases, refractory congestion was the reason for initiating RRT.

In terms of care, there was a 65% decrease in the total number of emergency department visits for cardiovascular causes (63 in the annual period prior to inclusion in the CRU vs. 22 in the follow-up year; p = 0.0001), a 60.5% decrease in the total number of hospitalizations for cardiovascular causes (43 vs. 17; p = 0.0015), and a 33% decrease in the total number of days of hospitalization (464 vs. 311). The use of quadruple therapy was associated with a significant decrease in both emergency department visits (35 vs. 15; p = 0.02) and hospitalizations (27 vs. 9; p = 0.011), an effect not observed in patients who were not on quadruple therapy, in whom only emergency department visits were significantly reduced (28 vs. 7; p = 0.001) (Fig. 1B).

In economic terms, the comparison of the total cost of hospital care activity, broken down by the total number of days of stay in both periods analysed and by CMU, is shown in Table 3, which shows a reduction in total hospital expenditure of 699,647.40 €. This represents a reduction of 68.83% in the total annual cost of hospital care (1,016,381.2 € in the year prior to inclusion in the CRU compared to 316,733.8 € in the follow-up year). The average cost per patient for emergency care and hospital stays prior to the CRU was 18,479.66 €, which fell to 5,758.8 € in the year after, representing an average reduction of 12,720.86 € per patient per year. This decrease in expenditure is mainly due to the decrease in hospitalizations, especially stays in the intensive care unit, which is the CMU with the highest resource use: 8,222.03 € per stay.