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Pages 85-96 (April - June 2022)
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Vol. 57. Issue 2.
Pages 85-96 (April - June 2022)
Original article
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Risk of outcomes in a Spanish population with heart failure
Riesgo de eventos en una población española con insuficiencia cardiaca
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Nicolás Manitoa, Carlos Escobarb,
Corresponding author
, Beatriz Palaciosc, Luis Varelac, Unai Arandac, Margarita Capelc, Antoni Sicrasd, Aram Sicrasd, Antonio Hormigoe, Roberto Alcázarf, Manuel Botanag
a Servicio de Cardiología, Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
b Servicio de Cardiología, Hospital Universitario La Paz, Madrid, Spain
c AstraZeneca, Spain
d Investigación Sobre Economía y Resultados de la Salud, Atrys Health, Barcelona, Spain
e Centro de Salud Puerta Blanca, Málaga, Spain
f Servicio de Nefrología, Hospital Universitario Infanta Leonor, Madrid, Spain
g Servicio de Endocrinología, Hospital Universitario Lucus Augusti, Lugo, Spain
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Tables (5)
Table 1. Clinical characteristics and treatments in the prevalent HF population at index date.
Table 2. Risk of outcomes* between HF vs CKD and HF patients in the prevalent population after 3 years of follow-up.
Table 3. Clinical characteristics and treatments in the incident HF population at baseline.
Table 4. Percentage of patients who developed CKD within 24 months from HF diagnosis.
Table 5. Event rates per 100 patient-year for HF patients diagnosed in 2017 with or without CKD at baseline and followed for 24 months.
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Abstract
Introduction and objectives

To assess mortality, cardiovascular and renal outcomes among patients with heart failure (HF) (primary objective), with a particular focus on the risk of developing chronic kidney disease (CKD) (secondary).

Methods

Observational cohort study, comprising cross-sectional and longitudinal retrospective analyses using secondary data from electronic health records. For the primary objective, adults with prevalent HF, defined as at least one diagnosis of HF prior to the index date (1 January 2017) were included. For the secondary objective, adults with incident HF in 2017 were enrolled.

Results

A total of 21 575 patients had HF in the prevalent population (8391 with CKD at baseline), whereas 3045 patients were included in the incident population. In the prevalent population, the risk of all-cause death (HR, 1.227; 95%CI, 1.172–1.285), CKD hospitalization (HR, 1.427; 95%CI, 1.379–1.479) and acute kidney failure (HR, 1.377; 95%CI, 1.222–1.524) was greater in those patients with HF and CKD vs HF only after 3 years of follow-up. For the incident population, within 24 months from HF diagnosis, 5.9% of patients developed CKD. Overall, 23.4% were taking angiotensin-converting enzyme inhibitors, 26.3% angiotensin receptor blockers, 7.9% sacubitril/valsartan, 64.2% beta blockers, 11.5% aldosterone antagonists and 4.5% sodium-glucose Cotransporter-2 inhibitors.

Conclusions

In Spain, patients with HF have a high risk of developing cardiovascular and renal complications. Despite that, there is a substantial proportion of patients that are not taking guideline recommended drugs. A higher use of these drugs could reduce HF burden and complications in clinical practice.

Keywords:
Cardiovascular
Chronic kidney disease
Death
Heart failure
Sacubitril/valsartan
Renal
SGLT2 inhibitors
Resumen
Introducción y objetivos

Determinar la mortalidad y los eventos cardiovasculares y renales en pacientes con insuficiencia cardiaca (IC) (objetivo primario), en particular sobre el desarrollo de enfermedad renal crónica (ERC) (secundario).

Métodos

Estudio observacional, con análisis transversal y retrospectivo, empleando datos secundarios de registros electrónicos de salud. Para el objetivo primario se incluyeron adultos con IC prevalente, definida como al menos un diagnóstico de IC antes de la fecha índice (1 de enero de 2017). Para el secundario se incluyeron adultos con IC incidente en 2017.

Resultados

Se incluyeron 21.575 pacientes con IC en la población prevalente (8.391 con ERC basal) y 3.045 en la población incidente. En la población prevalente el riesgo de muerte (HR=1,227; IC95%, 1,172-1,285), hospitalización por ERC (HR=1,427; IC95%, 1,379-1,479) y fallo renal agudo (HR=1,377; IC95%, 1,222-1,524) fue mayor en los pacientes con IC y ERC frente a IC sola, tras 3años de seguimiento. En la población incidente, a los 24meses del diagnóstico el 5,9% desarrollaron ERC. Globalmente, el 23,4% tomaban inhibidores de la enzima convertidora de angiotensina, el 26,3% antagonistas de los receptores de angiotensinaII, el 7,9% sacubitrilo/valsartán, el 64,2% bloqueadores beta, el 11,5% antialdosterónicos y el 4,5% inhibidores del cotransportador sodio-glucosa tipo2.

Conclusiones

En España, los pacientes con IC tienen un riesgo elevado de desarrollar complicaciones cardiovasculares y renales. Sin embargo, existe una proporción importante de pacientes que no toman los fármacos recomendados por las guías. Un mayor uso podría reducir la carga de IC y las complicaciones en la práctica clínica.

Palabras clave:
Cardiovascular
Enfermedad renal crónica
Muerte
Insuficiencia cardiaca
Sacubitrilo/valsartán
Renal
Inhibidores SGLT-2
Full Text
Introduction

Heart failure (HF) is a common condition. It has been estimated that the current prevalence reaches 2% in developed countries, but will increase in the following years due to the ageing of the population, better management of acute cardiovascular conditions and new HF treatments.1–4 Despite traditional HF therapies, HF is associated with a poor prognosis and high cost burden.5,6 In fact, in 2013, the MAGGIC meta-analysis reported that around 40% of HF patients died after only 2.5 years of follow-up.7 Hospitalizations are the most common complication in patients with chronic HF, mainly due to acute HF decompensation, but also because other conditions, such as chronic kidney disease (CKD).4,8–10

The 2021 European HF guidelines recommend the use of angiotensin-converting enzyme inhibitors or sacubitril/valsartan, beta blockers, aldosterone antagonists, and sodium-glucose Cotransporter-2 (SGLT-2) inhibitors as first-line therapies in patients with reduced HF and should be early used in this population.1 However, according to the available evidence,11,12 the 2016 HF guidelines recommended a step by step approach, starting with the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta blockers as a first-line approach, adding aldosterone antagonists if symptoms persisted and then changing to sacubitril/valsartan from angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or adding ivabradine if patients remained symptomatic.13 Of note, although clinical trials performed in diabetic population had suggested a positive effect on HF incidence with the use of some SGLT-2 inhibitors,12 their beneficial effects in patients with reduced HF, regardless diabetes status, has recently been demonstrated.14,15 Unfortunately, data regarding the impact of these new therapies on morbidity and mortality in real-life patients are lacking. On the other hand, patients with reduced ejection fraction exhibit relevant disparities in the clinical profile, treatment and prognosis compared to patients with preserved ejection fraction.16–18 However, current data about differences in the management and outcomes of both entities are scarce.

The objectives of this study were to assess all-cause mortality, and cardiovascular and renal outcomes among patients with HF (primary objective), with a particular focus on the risk of developing CKD following diagnosis of HF (secondary objective).

Methods

Observational and cohort study, using secondary data collected from the electronic health records of 7 Spanish Autonomous Communities within the validated BIG PAC database.19 This study was approved by the Investigation Ethics Committee of Consorci Sanitari from Terrassa. No informed consent was provided, as this was a secondary data study and data were fully anonymized and dissociated from patients.

To assess the objectives of the study, cross-sectional and longitudinal retrospective analyses were performed. For the primary objective of the study, adults with prevalent HF, defined as at least one diagnosis of HF prior to the index date (1 January 2017) (prevalent population) were included. CKD was defined as an estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 by CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) or ≥60mL/min/1.73m2 with a urine albumin-to-creatinine ratio (UACR) ≥30mg/g at index date. For the secondary objective, adults with incident HF, defined as new diagnosis of HF in 2017 were included (incident population). Index date was the first HF diagnosis date in 2017. According to DAPA-HF and DELIVER trials,14,20 HF with reduced o preserved left ventricular ejection fraction was defined as those patients with HF and a left ventricular ejection fraction40% or >40%, respectively. In both populations, CKD stages were classified, as follows: CKD stage 1: eGFR90mL/min/1.73m2 and UACR30mg/g; CKD stage 2: eGFR 60–89mL/min/1.73m2 and UACR30mg/g; CKD stage 3a: eGFR 45–59mL/min/1.73m2; CKD stage 3b: eGFR 30–44mL/min/1.73m2; CKD stage 4: eGFR 15–29mL/min/1.73m2; CKD stage 5: eGFR<15mL/min/1.73m2; CKD unspecified: no eGFR data available.

In the prevalent population, at baseline (index date 1 January 2017), biodemographic data, physical examination, HF data, laboratory data, comorbidities and concomitant drugs were recorded. In the incident population, baseline clinical characteristics, including comorbidities, laboratory data and concomitant medications were reported in relation to the index date (the first HF diagnosis date in 2017). Data were presented according to the HF type and CKD stage.

Regarding the primary objective (prevalent population), for overall mortality, patient follow-up began at index date (1 January 2017) and continued until the death date or censored at the earliest of the end of enrolment for the latest available linked data or observational study period end date (31 December 2019, 3 years of follow-up). For other outcomes, patient follow-up began on the index date and continued until the specified cardiorenal event (hospitalization for HF, CKD, albuminuria transition from UACR<30 to 30–300mg/g and acute kidney failure) occurred or was censored at the earliest of the end of enrolment for the latest available linked data, death date or observational study period end date (31 December 2019, 3 years of follow-up). Within each event category, patients were censored after the first event for the category but not for events from other categories. For the secondary objective of the study, patients were followed from HF diagnosis in 2017, for 24 months.

Statistical analysis

Absolute and relative frequency distributions were used to describe the qualitative variables and mean and standard deviation for quantitative variables. Event rates were calculated as the number of new cases from index date in the 24 months of follow up divided by the total time at risk of the event. Event rates were presented as events and events per 100 patient-years for all-cause death, HF, CKD, and albuminuria. Time to first hospitalization due to event was analyzed descriptively. Follow-up was censored at observation period, or death end unless an event had occurred. The corresponding adjusted hazard ratios and 95% confidence intervals to estimate the risk of outcomes in the prevalent population after 3 years of follow-up were calculated. The pathway to develop CKD in patients with incident HF was evaluated for 24 months from index date. Categorical variables were compared using the chi-square test or the Fisher exact test when appropriate. When 2 means were compared, the t test or the Mann–Whitney test was used, as applicable. The data were analyzed using the statistical package SPSS v25.0 (SPSS Inc., Chicago, United States).

Results

Overall, 21 575 patients had HF in the prevalent population (13 184 without CKD at baseline and 8391 with CKD at baseline), whereas 3045 patients were included in the incident population (Fig. 1 of the supplementary data).

Among patients with HF but without CKD at baseline, mean age was 77.8±13.7 years, 52.7% were men, 31.9% type 2 diabetes, and 21.4% prior myocardial infarction. With regard to the type of HF, 51.7% had HF with reduced left ventricular ejection fraction and 48.3% HF with preserved left ventricular ejection fraction. With respect to treatments, 30.6%, 32.4% and 7.7% were taking angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and sacubitril/valsartan, respectively, and 4.3% SGLT-2 inhibitors. Compared with patients with HF without CKD, those with CKD were older, more commonly women, had higher levels of systolic blood pressure, body mass index, glycosylated hemoglobin (HbA1c), UACR and serum potassium levels. Comorbidities, including diabetes, atrial fibrillation, myocardial infarction, stroke, and peripheral artery disease were more common in those patients with CKD and HF (vs HF alone). In addition, more patients in the HF and CKD population (vs HF alone) were taking more angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and beta blockers, with a similar proportion of aldosterone antagonists and SGLT-2 inhibitors (Table 1).

Table 1.

Clinical characteristics and treatments in the prevalent HF population at index date.

  Only HF(n=13 184; 61.1%)  HF+CKD(n=8391; 38.9%)  PHF+CKDvsCKD 
Biodemographic data
Age, years  77.8±13.7  79.4±10.9  <.001 
Gender, male, (%)  6949 (52.7)  4237 (50.5)  <.001 
Physical examination
Systolic blood pressure, mmHg  130.7±21.3  133.9±20.5  <.001 
Diastolic blood pressure, mmHg  83.8±7.2  83.7±6.9  .312 
BMI, kg/m2  28.4±5.0  28.9±5.2  <.001 
BMI>30kg/m2, n (%)  2914 (22.1)  2013 (24.0)  <.001 
Laboratory data
HbA1c, %  7.3±1.8  7.7±2.0  <.001 
<7%, n (%)  6895 (52.3)  4256 (50.7)  <.001 
7 to <8%, n (%)  2278 (17.3)  1680 (20.0)  <.001 
8 to <9%, n (%)  1185 (9.0)  867 (10.3)  <.001 
≥9%, n (%)  936 (7.1)  769 (9.2)  <.001 
eGFR*  85.5±7.2  46.4±9.8  <.001 
UACR, mg/g  16.7±9.8  361.2±148.5  <.001 
Serum potassium levels, mmol/L  4.5±0.5  5.7±1.6  <.001 
Left ventricular ejection fraction, %  44.2±10.2  43.4±10.1  .235 
Comorbidities,n(%)
CVD  5415 (41.1)  5180 (61.7)  <.001 
Stroke  1364 (10.3)  1030 (12.3)  <.001 
Myocardial infarction  2824 (21.4)  2154 (25.7)  <.001 
PAD  681 (5.2)  564 (6.7)  <.001 
Atrial fibrillation  4379 (33.2)  2970 (35.4)  <.001 
HF  13 184 (100)  8391 (100)  – 
HF-reduced ejection fraction  6810 (51.7)  4465 (53.2)  <.001 
HF-preserved ejection fraction  6374 (48.3)  3926 (46.8)  <.001 
CKD  –  8391 (100)  – 
Stage 1  –  977 (11.6)  – 
Stage 2  –  1584 (18.9)  – 
Stage 3a  –  1753 (20.9)  – 
Stage 3b  –  1961 (23.4)  – 
Stage 4  –  1127 (13.4)  – 
Stage 5  –  296 (3.5)  – 
Type 2 diabetes  4200 (31.9)  5034 (60.0)  <.001 
Hyperkalemia  6 (0)  851 (10.1)  – 
Medications, n (%)
CVD risk treatment  13 184 (100)  8391 (100)  – 
Antihypertensives  12 230 (92.8)  7960 (94.9)  <.001 
ACEi  4034 (30.6)  2716 (32.4)  <.001 
ARBs  4269 (32.4)  3548 (42.3)  <.001 
ARNI  1017 (7.7)  743 (8.9)  .142 
Beta blockers  9107 (69.1)  5998 (71.5)  <.001 
Loop diuretics  9263 (70.3)  5978 (71.2)  .186 
Aldosterone antagonists  4258 (32.3)  2781 (33.1)  .130 
Calcium channel blockers  1234 (9.4)  658 (7.8)  <.001 
Thiazide diuretics  665 (5.0)  433 (5.2)  .747 
Antidiabetics  3823 (29.0)  3571 (42.6)  <.001 
Metformin  2739 (20.8)  2021 (24.1)  <.001 
Sulfonylurea  1571 (11.9)  969 (11.5)  .761 
DPP4 inhibitors  1371 (10.4)  962 (11.5)  .098 
SGLT-2 inhibitors  571 (4.3)  333 (4.0)  .933 
GLP-1 receptor agonists  141 (1.1)  221 (2.6)  <.001 
Metiglinides  190 (1.4)  375 (4.5)  <.001 
Thiazolidinediones  25 (0.2)  27 (0.3)  .977 
Acarbose  22 (0.2)  20 (0.2)  .849 
Insulin  950 (7.2)  1255 (15.0)  <.001 
Statins  7846 (59.5)  5327 (63.5)  <.001 
Digoxin  878 (6.7)  524 (6.2)  .891 
Nitrates  1442 (10.9)  1267 (15.1)  <.001 
Warfarin/acenocoumarol  2506 (19.0)  1887 (22.5)  <.001 
Low dose aspirin  2819 (21.4)  2518 (30.0)  <.001 
Receptor P2Y12antagonists  1041 (7.9)  880 (10.5)  <.001 

ACEi, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; ARNI, angiotensin receptor and neprilysin inhibition; BMI, body mass index; CVD, cardiovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; DPP4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; *, mL/min/1.73m2; GLP-1, glucagon-like peptide-1; HF, heart failure; PAD, peripheral artery disease; SGLT-2, sodium-glucose Cotransporter-2; UACR, Urine albumin-to-creatinine ratio; hyperkalemia: serum potassium>5.5mmol/L.

Regarding outcomes between HF vs HF and CKD patients in the prevalent population after 3 years of follow-up, the risk of all-cause death (HR, 1.227; 95%CI, 1.172–1.285; P<.001), hospitalization for CKD (HR, 1.427; 95%CI, 1.379–1.479; P<.001), and acute kidney failure (HR, 1.377; 95%CI, 1.222–1.524; P<.001) was greater in those patients with HF and CKD compared to HF only patients (Table 2, and Fig. 2 of the supplementary data).

Table 2.

Risk of outcomes* between HF vs CKD and HF patients in the prevalent population after 3 years of follow-up.

Group  Endpoint  Follow-up (median, days)  Events, N  HRCKDandHFvsHF  95%CI  P 
CKD and HF  All-cause death428  3132  37.3%  1.2271.172–1.285<.001
HF  552  4579  34.7% 
CKD and HF  HF447  3994  47.6%  1.0130.973–1.056.526
HF  458  5416  41.1% 
CKD and HF  CKD545  2097  25.0%  1.4271.379–1.479<.001
HF  538  3070  23.3% 
CKD and HF  UACR progression: <30 to 30–300mg/g504  43  0.5%  1.3090.956–1.770.094
HF  548  725  5.5% 
CKD and HF  Acute kidney failure (ICD N17)592  164  2.0%  1.3771.222–1.524<.001
HF  642  49  0.4% 

95%CI, confidence interval; CKD, chronic kidney disease; HF, heart failure; UACR, urine albumin-to-creatinine ratio.

* All-cause mortality and first hospitalization for cardiorenal events (HF, CKD, acute kidney failure) or albuminuria transitions during follow-up.

In the incident population, 3045 patients with HF (2435 [79.6%] without CKD at baseline) were included (Table 3). Overall, mean age was 65.4±23.2 years, 51.4% men, left ventricular ejection fraction 45.4±11%, eGFR 85.8±7.9mL/min/1.73m2 and UACR 96.5±44.4mg/g. One third of patients had diabetes, 20.0% CKD and 14.1% prior myocardial infarction. Patients without CKD at baseline were younger and suffered less from prior myocardial infarction, atrial fibrillation or stroke. Data according to the type of HF (reduced and preserved left ventricular ejection fraction) are shown in Tables 1 and 2 of the supplementary data. Despite patients with preserved HF were older than those with reduced HF, both had many comorbidities. With regard to HF treatments, in the overall incident HF population, 23.4% were taking angiotensin-converting enzyme inhibitors, 26.3% angiotensin receptor blockers, 7.9% sacubitril/valsartan (total 57.6%), 64.2% beta blockers, 11.5% aldosterone antagonists and 4.5% SGLT-2 inhibitors.

Table 3.

Clinical characteristics and treatments in the incident HF population at baseline.

  All HF (n=3045; 100%)  HF without CKD (n=2435; 79.6%)  PHFwithoutCKDvsHFCKD  HF+CKD at index dateTotal with CKD (n=610; 20.4%) 
        Stage 1 (n=19; 3.1%)  Stage 2 (n=115; 18.9%)  PStage2vs1  Stage 3a (n=201; 33.0%)  PStage3avs1  Stage 3b (n=148; 24.3%)  PStage3bvs1  Stage 4 (n=44; 7.2%)  PStage4vs1  Stage 5 (n=37; 6.1%)  PStage5vs1  Unspecified (n=46; 7.5%)  PUnspvs1   
Biodemographic data
Age, years  65.4±23.2  60.6±20.4  <.001  58.4±24.5  59.8±24.4  .817  61.1±23.6  .635  65.2±22.7  .225  68.7±21.4  .099  69.8±20.3  .069  59.1±20.8  .907  67.8±22.1 
Gender, male, n (%)  1565 (51.4)  1259 (51.7)  .116  5 (26.3)  58 (50.4)  <.001  103 (51.2)  <.001  74 (50.0)  <.001  23 (52.3)  <.001  19 (51.4)  <.001  24 (52.2)  <.001  306 (50.2) 
Physical examination
Systolic blood pressure, mmHg  129.8±19.8  129.6±20.4  .595  128.6±21.2  128.7±21.3  .798  129.2±20.5  .759  129.1±20.6  .845  129.8±20.8  .756  130.2±22.1  .845  128.7±19.7  .657  130.1±22.1 
Diastolic blood pressure, mmHg  83.5±6.9  83.4±7.1  <.001  82.9±7.0  82.8±6.8  .854  82.9±6.9  .985  83.2±7.0  .756  83.1±7.2  .654  84.1±7.1  .761  82.9±7.0  .758  82.2±6.9 
BMI, kg/m2  28.7±5.1  28.6±5.0  <.001  28.5±4.9  28.7±4.8  .867  28.6±4.9  .854  28.8±5.1  .654  28.9±5.0  .754  28.9±4.9  .752  28.7±5.1  .861  27.8±5.0 
HF data                                   
Left ventricular ejection fraction, %  45.4±11  45.8±<.001  45.7±10.6  45.5±9.9  .789  45.5±9.1  .845  45.4±10.6  .745  45.3±11  .845  44.9±10.5  .456  45.8±10.6  .769  43.3±9.4 
LVEF40%, n (%)  1542 (50.6)  1223 (50.2)  .155  10 (52.6)  58 (50.4)  .7  106 (52.7)  .997  79 (53.4)  .829  23 (52.3)  .974  19 (51.4)  .982  24 (52.2)  .8  319 (52.3) 
LVEF>40%, n (%)  1496 (49.1)  1205 (49.5)  .159  9 (47.4)  57 (49.6)  .936  95 (47.3)  .993  69 (46.6)  .762  21 (47.7)  .795  18 (48.6)  .804  22 (47.8)  .796  291 (47.7) 
NYHA functional class, n (%)
386 (12.7)  311 (12.8)  .829  3 (15.8)  15 (13.0)  .987  26 (12.9)  .715  17 (11.5)  .717  4 (9.1)  .63  3 (8.1)  .848  7 (15.2)  .933  75 (12.3) 
II  1391 (45.7)  1130 (46.4)  <.001  8 (42.1)  48 (41.7)  .996  87 (43.3)  .873  63 (42.6)  .982  19 (43.2)  .872  16 (43.2)  .765  20 (43.5)  .802  261 (42.8) 
III  1134 (37.2)  890 (36.6)  <.001  7 (36.8)  44 (38.3)  .797  80 (39.8)  .85  61 (41.2)  .862  19 (43.2)  .837  16 (43.2)  .79  17 (37.0)  .84  244 (40.0) 
IV  124 (4.1)  97 (4.0)  .798  1 (5.3)  4 (3.5)  .801  9 (4.5)  .912  7 (4.7)  .706  2 (4.5)  .777  2 (5.4)  .954  2 (4.3)  .842  27 (4.4) 
Laboratory data
eGFR*  85.8±7.9  96.2±4.9  <.001  94.3±3.7  74.7±8.6  <.001  52.1±10.8  <.001  36.8±10.6  <.001  21.9±10.5  <.001  8.8±7.4  <.001  –  –  43.4±8.8 
UACR, mg/g  96.5±44.4  14.8±6.8  <.001  105.8±43.4  128.1±64.1  <.001  249.8±122.4  <.001  261.3±109.7  <.001  1631.4±750.4  <.001  1651.3±726.6  <.001  122.3±51.4  <.001  384.2±180.6 
HbA1c. %  7.1±1.9  5.3±1.4  <.001  6.1±1.7  6.8±.152  6.9±1.9  <.001  7.1±.421  7.3±2.1  .345  7.5±.453  6.9±.453  6.7±1.9 
<7%, n (%)  1574 (51.7)  1256 (51.6)  .924  10 (52.6)  60 (52.2)  .949  105 (52.2)  .907  77 (52.0)  .986  23 (52.3)  .912  19 (51.4)  .703  24 (52.2)  .779  318 (52.1) 
7–<8%, n (%)  535 (17.6)  433 (17.8)  .627  19 (16.5)  –  35 (17.4)  –  26 (17.6)  –  7 (15.9)  .279  7 (18.9)  .075  8 (17.4)  .183  102 (16.7) 
8–<9%, n (%)  270 (8.9)  205 (8.4)  <.001  2 (10.5)  11 (9.6)  .893  20 (10.0)  .784  18 (12.2)  .815  5 (11.4)  .84  5 (13.5)  .844  4 (8.7)  .851  65 (10.7) 
≥9%, n (%)  231 (7.6)  174 (7.1)  .074  1 (5.3)  9 (7.8)  .82  19 (9.5)  .989  16 (10.8)  .566  5 (11.4)  .78  4 (10.8)  .946  3 (6.5)  .761  57 (9.3) 
Comorbidities,n(%)
CVD  2246 (73.8)  1801 (74.0)  .374  14 (73.7)  85 (73.9)  .927  148 (73.6)  .81  105 (70.9)  .890  32 (72.7)  .72  28 (75.7)  .907  33 (71.7)  .927  445 (73.0) 
Myocardial infarction  429 (14.1)  307 (12.6)  <.001  3 (15.8)  23 (20.0)  .98  41 (20.4)  .998  29 (19.6)  .959  9 (20.5)  .765  8 (21.6)  .818  9 (19.6)  .812  122 (20.0) 
Stroke  183 (6.0)  101 (4.1)  <.001  2 (10.5)  14 (12.2)  .988  27 (13.4)  .9  23 (15.5)  .488  6 (13.6)  .968  5 (13.5)  .769  5 (10.9)  .751  82 (13.4) 
Atrial fibrillation  836 (27.5)  626 (25.7)  <.001  7 (36.8)  39 (33.9)  .891  69 (34.3)  .961  52 (35.1)  .925  15 (34.1)  .995  13 (35.1)  .942  15 (32.6)  .871  210 (34.4) 
Peripheral artery disease  137 (4.5)  102 (4.2)  .243  1 (5.3)  6 (5.2)  .923  11 (5.5)  .729  10 (6.8)  .965  3 (6.8)  .94  2 (5.4)  .849  2 (4.3)  .916  35 (5.7) 
CKD  610 (20.0)  –  19 (100)  115 (100)  –  201 (100)  –  148 (100)  –  44 (100)  –  37 (100)  –  46 (100)  –  610 (100) 
Diabetes  1010 (33.2)  801 (32.9)  .241  7 (36.8)  38 (33.0)  .766  70 (34.8)  .953  51 (34.5)  .894  15 (34.1)  .754  13 (35.1)  .873  15 (32.6)  .898  209 (34.3) 
Medications,n(%)
HF medication  3001 (98.6)  2391 (98.2)  .206  19 (100)  115 (100)  –  201 (100)  –  148 (100)  –  44 (100)  –  37 (100)  –  46 (100)  –  610 (100) 
RAAS inhibitors  1493 (49.0)  1205 (49.5)  <.001  10 (52.6)  51 (44.3)  .205  93 (46.3)  .506  70 (47.3)  .492  21 (47.7)  .933  19 (51.4)  .98  24 (52.2)  .919  288 (47.2) 
ACEi  712 (23.4)  558 (22.9)  <.001  5 (26.3)  27 (23.5)  .986  50 (24.9)  .847  37 (25.0)  .892  12 (27.3)  .77  11 (29.7)  .986  12 (26.1)  .911  154 (25.2) 
ARBs  801 (26.3)  632 (26.0)  .128  6 (31.6)  30 (26.1)  .629  54 (26.9)  .729  42 (28.4)  .843  12 (27.3)  .785  11 (29.7)  .968  14 (30.4)  .74  169 (27.7) 
Beta blockers  1954 (64.2)  1531 (62.9)  <.001  13 (68.4)  80 (69.6)  .733  138 (68.7)  .74  103 (69.6)  .934  31 (70.5)  .894  26 (70.3)  .958  32 (69.6)  .767  423 (69.3) 
Loop-diuretics  2090 (68.6)  1655 (68.0)  <.001  13 (68.4)  83 (72.2)  .937  145 (72.1)  .885  105 (70.9)  .99  31 (70.5)  .774  27 (73.0)  .793  31 (67.4)  .923  435 (71.3) 
Aldosterone antagonists  349 (11.5)  273 (11.2)  .231  2 (10.5)  14 (12.2)  .823  25 (12.4)  .828  20 (13.5)  .97  5 (11.4)  .865  4 (10.8)  .891  6 (13.0)  .966  76 (12.5) 
ARNI  242 (7.9)  187 (7.7)  .275  1 (5.3)  10 (8.7)  .754  18 (9.0)  .833  15 (10.1)  .946  4 (9.1)  .956  3 (8.1)  .972  4 (8.7)  .791  55 (9.0) 
Digoxin  213 (7.0)  169 (6.9)  .866  1 (5.3)  8 (7.0)  .955  15 (7.5)  .909  11 (7.4)  .73  3 (6.8)  .947  3 (8.1)  .716  3 (6.5)  .722  44 (7.2) 
Antidiabetics  867 (28.5)  682 (28.0)  <.001  6 (31.6)  35 (30.4)  .808  60 (29.9)  .799  45 (30.4)  .962  14 (31.8)  .814  12 (32.4)  .954  13 (28.3)  .838  185 (30.3) 
Metformin  594 (19.5)  462 (19.0)  <.001  5 (26.3)  24 (20.9)  .542  43 (21.4)  .904  32 (21.6)  .865  9 (20.5)  .77  9 (24.3)  .738  10 (21.7)  .987  132 (21.6) 
Sulfonylurea  367 (12.1)  295 (12.1)  .774  2 (10.5)  15 (13.0)  .714  23 (11.4)  .833  17 (11.5)  .892  5 (11.4)  .746  4 (10.8)  .723  6 (13.0)  .746  72 (11.8) 
DPP4 inhibitors  339 (11.1)  273 (11.2)  .862  2 (10.5)  12 (10.4)  .703  22 (10.9)  .984  16 (10.8)  .932  5 (11.4)  .909  4 (10.8)  .981  5 (10.9)  .723  66 (10.8) 
SGLT-2 inhibitors  138 (4.5)  101 (4.1)  .236  1 (5.3)  6 (5.2)  .994  13 (6.5)  .967  10 (6.8)  .832  3 (6.8)  .967  2 (5.4)  .932  2 (4.3)  .87  37 (6.1) 
GLP-1 receptor agonists  29 (1.0)  23 (0.9)  .913  –  1 (0.5)  –  2 (1.4)  –  1 (2.3)  –  1 (2.7)  –  1 (2.2)  –  6 (1.0) 
Metiglinides  43 (1.4)  35 (1.4)  .963  1 (0.9)  –  2 (1.0)  –  2 (1.4)  –  1 (2.3)  –  1 (2.7)  –  1 (2.2)  –  8 (1.3) 
Thiazolidinedione  10 (0.3)  5 (0.2)  .714  –  1 (0.5)  –  2 (1.4)  –  1 (2.3)  –  1 (2.7)  –  –  5 (0.8) 
Acarbose  6 (0.2)  5 (0.2)  .973  –  –  1 (0.7)  –  –  –  –  1 (0.2) 
Insulin  222 (7.3)  176 (7.2)  .813  1 (5.3)  8 (7.0)  .763  15 (7.5)  .861  12 (8.1)  .881  4 (9.1)  .823  3 (8.1)  .839  3 (6.5)  .761  46 (7.5) 
Statins  1763 (57.9)  1396 (57.3)  <.001  11 (57.9)  68 (59.1)  .928  122 (60.7)  .848  90 (60.8)  .786  27 (61.4)  .962  23 (62.2)  .886  26 (56.5)  .735  367 (60.2) 
Antihypertensives  626 (20.6)  490 (20.1)  .212  4 (21.1)  24 (20.9)  .900  45 (22.4)  .91  34 (23.0)  .928  10 (22.7)  .848  9 (24.3)  .71  10 (21.7)  .853  136 (22.3) 
Dihydropyridine CCB  439 (14.4)  352 (14.5)  .91  2 (10.5)  17 (14.8)  .997  29 (14.4)  .805  21 (14.2)  .903  6 (13.6)  .898  5 (13.5)  .881  7 (15.2)  .998  87 (14.3) 
Thiazide diuretics  185 (6.1)  143 (5.9)  .421  1 (5.3)  7 (6.1)  .737  14 (7.0)  .8  11 (7.4)  .896  3 (6.8)  .922  3 (8.1)  .83  3 (6.5)  .747  42 (6.9) 
Non-dihydropyridine CCB  92 (3.0)  68 (2.8)  .606  1 (5.3)  4 (3.5)  .945  8 (4.0)  .749  6 (4.1)  .965  2 (4.5)  .763  2 (5.4)  .962  1 (2.2)  .873  24 (3.9) 
Nitrates  312 (10.2)  236 (9.7)  <.001  2 (10.5)  13 (11.3)  .917  25 (12.4)  .74  19 (12.8)  .968  6 (13.6)  .92  6 (16.2)  .802  5 (10.9)  .831  76 (12.5) 
Warfarin/acenocoumarol  618 (20.3)  496 (20.4)  .859  3 (15.8)  22 (19.1)  .902  41 (20.4)  .722  30 (20.3)  .794  9 (20.5)  .836  8 (21.6)  .949  9 (19.6)  .981  122 (20.0) 
Low dose aspirin  632 (20.8)  492 (20.2)  <.001  4 (21.1)  25 (21.7)  .740  47 (23.4)  .741  35 (23.6)  .831  10 (22.7)  .783  9 (24.3)  .909  10 (21.7)  .803  140 (23.0) 
Receptor P2Y12antagonists  232 (7.6)  176 (7.2)  .208  1 (5.3)  9 (7.8)  .813  19 (9.5)  .837  15 (10.1)  .964  4 (9.1)  .835  4 (10.8)  .808  4 (8.7)  .702  56 (9.2) 

ACEi, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; ARNI, angiotensin receptor and neprilysin inhibition; BMI, body mass index; CCB, calcium channel blockers; CVD, cardiovascular disease; CKD, chronic kidney disease; DPP4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; * mL/min/1.73m2; GLP-1: glucagon-like peptide-1; HF: heart failure; LVEF: left ventricular ejection fraction; RAAS: renin–angiotensin system; SBP: systolic blood pressure; SGLT-2: sodium-glucose cotransporter-2; UACR: urine albumin-to-creatinine ratio.

Within 24 months from HF diagnosis, eGFR progressively decreased from 85.8±7.5 to 75.9±7.3mL/min/1.73m2; P<.001 (from 96.2±3.2 to 85.9±7.8mL/min/1.73m2 among those patients without CKD at baseline), whereas UACR increased from 96.5±44.4 to 103.4±42.4mg/g; P<.001 (from 14.8±6.7 to 15.4±7.2mg/g; P=.003 among those patients without CKD at baseline). The same trend towards worsening was observed in all stages for patients with CKD at baseline (Table 3 of the supplementary data). Thus, during this period, 5.9% of patients developed CKD, regardless of left ventricular ejection fraction (Table 4). In the overall study population, all-cause death, and hospitalization for HF and CKD were 17.2, 20.6 and 9.4 per 100 patient-year, after 24 months of follow-up, respectively. These numbers were 16.1, 20.2 and 9.3 per 100 patient-year in those patients without CKD at baseline and 21.9, 23.8 and 11.0 per 100 patient-year, in those with CKD at baseline, respectively. In general, outcome rates increased and time to first event shortened as renal function worsened (Table 5). These figures were higher in those patients with HF and reduced left ventricular ejection fraction than in those with HF and preserved left ventricular ejection fraction, both in patients with or without CKD at index date, consistent with the slightly higher percentage of patients with reduced ejection fraction HF who developed CKD at the end of the 24-month follow up period (6.0% vs 5.8%, respectively) (Tables 4 and 5 of the supplementary data). In addition, in the overall study population, 6.4 per 100 patient-year developed type 2 diabetes during this period (Table 5), slightly more common in those patients with HF and reduced left ventricular ejection fraction than in those with HF and preserved left ventricular ejection fraction (Tables 4 and 5 of the supplementary data).

Table 4.

Percentage of patients who developed CKD within 24 months from HF diagnosis.

    3 months  6 months  12 months  24 months  Total 
All HF patients who develop CKD according to CKD grade, n (%)Stage 1  1 (20.0)  3 (10.7)  2 (6.3)  4 (5.1)  10 (7.0) 
Stage 2  4 (14.3)  4 (12.5)  14 (17.9)  22 (15.4) 
Stage 3a  2 (40.0)  8 (28.6)  10 (31.3)  22 (28.2)  42 (29.4) 
Stage 3b  2 (40.0)  5 (17.9)  8 (25.0)  18 (23.1)  33 (23.1) 
Stage 4  3 (10.7)  5 (15.6)  8 (10.3)  16 (11.2) 
Stage 5  3 (10.7)  4 (5.1)  7 (4.9) 
Unspecified  2 (7.1)  3 (9.4)  8 (10.3)  13 (9.1) 
Total CKD  5 (100)  28 (100)  32 (100)  78 (100)  143 (100) 
HF who stay without CKD, n (%)  Baseline           
All HF  2435  2430 (99.8)  2404 (98.7)  2375 (97.5)  2302 (94.5)  2292 (94.1) 
HF-rEF  1223  1221 (99.8)  1207 (87.7)  1193 (97.5)  1155 (94.4)  1150 (94.0) 
HF-pEF  1212  1209 (99.8)  1197 (98.7)  1182 (97.5)  1147 (94.6)  1142 (94.2) 

CKD: chronic kidney disease; HF: heart failure; HF-rEF: heart failure with reduced ejection fraction; HF-pEF: heart failure with preserved ejection fraction.

Table 5.

Event rates per 100 patient-year for HF patients diagnosed in 2017 with or without CKD at baseline and followed for 24 months.

  HF without CKD at index (n=2435)  HF+CKD at indexTotal HF (n=3045) 
    Stage 1 (n=19)  Stage 2 (n=115)  Stage 3a (n=201)  Stage 3b (n=148)  Stage 4 (n=44)  Stage 5 (n=37)  Unspecified (n=46)  Total CKD (n=610)  PHFwithoutCKDvsHF+CKD   
All-cause death, n (event rates)  382 (16.1)  2 (10.5)  16 (14.9)  35 (17.0)  32 (21.3)  11 (25.5)  9 (27.6)  6 (14.4)  111 (21.9)  <.001  493 (17.2) 
Time to first event, days  426.9  446.4  429.9  396.8  330.7  264.6  231.5  438.2  348.1  <.001  410.8 
HF, n (event rates)  480 (20.2)  2 (10.5)  18 (16.2)  37 (18.5)  35 (23.1)  12 (27.7)  10 (30.0)  7 (15.6)  121 (23.8)  <.001  601 (20.6) 
Time to first event, days  393.9  499.8  481.3  444.2  370.2  296.2  259.1  490.5  366.5  <.001  396.1 
CKD, n (event rates)  214 (9.3)  1 (5.3)  8 (7.8)  18 (9.0)  17 (11.2)  5 (13.4)  5 (14.6)  3 (7.6)  57 (11.0)  .203  271 (9.4) 
Time to first event, days  441.2  626.5  603.3  556.9  464.0  371.2  324.8  614.9  450.5  .359  447.5 
Albuminuria, n (event rates)  238 (10.3)  1 (5.3)  9 (8.8)  20 (10.1)  20 (12.6)  6 (15.1)  5 (16.4)  4 (8.5)  65 (12.1)  <.001  303 (10.6) 
Time to first event, days  424.1  532.9  513.2  473.7  394.7  315.8  276.3  523.0  372.4  <.001  421.8 
T2D development, n (event rates)  149 (6.4)  1 (5.3)  6 (6.0)  14 (6.9)  13 (8.6)  4 (10.3)  4 (11.1)  3 (5.8)  45 (8.4)  <.001  194 (6.4) 
Time to TD2 development, days  413.1  515.9  496.8  458.6  382.1  305.7  267.5  506.3  376.7  <.001  405.7 

CKD: chronic kidney disease; HF: heart failure; T2D: type 2 diabetes.

Discussion

Our study showed in a wide sample of patients representative of the Spanish population, that both prevalent and incident HF patients have many comorbidities and high risk of presenting cardiovascular and renal complications that could be partially related with an underuse of HF guidelines recommended therapies in a substantial proportion of patients.

At baseline, HF patients were old and had many comorbidities. Of note, the clinical profile of patients worsened with the presence of CKD. This is in line with previous studies performed in Spain and in other developed countries.21,22 In fact, our data were collected from the BIG-PAC database that comprised nearly 1.8 million persons daily attended in clinical practice and has been demonstrated its validity for observational studies and its representativeness of the Spanish population.19

On the other hand, approximately 52% of prevalent or incident patients had HF with reduced left ventricular ejection fraction and the remaining 48% preserved HF. First, it should be emphasized that in our study, in line with the DAPA-HF and DELIVER trials,14,20 preserved HF was defined as those patients with HF and a left ventricular ejection fraction>40%. However, current European guidelines define preserved HF with an ejection fraction50% and mildly reduced HF with an ejection fraction 41%–49%,1 and this could partially limit the interpretation of the data.

Previous studies have shown that HF with preserved ejection fraction accounts for at least half of the cases of HF, but reaches almost three-quarters of all HF patients among those subjects aged 65 years or older.17,18,23 Although previous studies have shown relevant differences in the clinical profile of patients with both entities, with more comorbidities in those patients with preserved HF,24,25 in our study baseline characteristics were quite similar. Although the definition of preserved HF was different in our study, these data suggest that the type of HF cannot be based solely on the presence of some particular conditions, but on an adequate diagnostic approach.1 In any case, although more evidences exist about treatments with reduced HF, overall, the management of HF patients is complex and requires a comprehensive approach.1

With regard to HF treatments, in the overall study population, around 30%–40% of patients were not taking angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or sacubitril/valsartan, 30%–35% beta blockers, 70%–90% aldosterone antagonists and 95% SGLT-2 inhibitors (85% among patients with type 2 diabetes). In those patients with HF and reduced left ventricular ejection fraction, these numbers were 19%, 35%, 88% and 95% (83%), respectively. Although the prevalence of renal dysfunction was important, partially explained by the elderly population, some with hyperkalemia, and this could have had an impact on the management of these patients, overall, there was a substantial proportion of patients that were not taking those drugs that have demonstrated clinical benefits on reduced HF patients. It is likely that the use of oral potassium-binding agents in some cases could increase the use of renin–angiotensin system inhibitors.26 On the other hand, in the case of SGLT-2 inhibitors this low use could be explained because the DAPA-HF and the EMPEROR-Reduced trials were published in 2019 and 2020, respectively.14,15 However, the use of other HF guideline-directed medical therapies was too low, despite the clear recommendations performed by 2016 European guidelines, the current recommendations at the moment of the study.13 Although data provided from specific HF units show better numbers, studies performed in other clinical settings report similar figures than those observed in our study.27–30 As a result, more efforts are necessary to reduce the gap between guidelines recommendations and clinical practice.31,32 Of note, the 2021 European guidelines recommend the use of angiotensin-converting enzyme inhibitors/sacubitril-valsartan, beta blockers, aldosterone antagonists and SGLT-2 inhibitors as first line-therapy in the treatment of reduced HF patients,1 as this approach has been shown to significantly reduce mortality and HF hospitalization compared to standard HF therapy.33

Our study showed that the risk of outcomes in patients with HF remains unacceptably high. Thus, after only two years, rate of overall mortality was 17.2/100 patient-year and rates of hospitalization for HF and CKD were 20.6 and 9.4/100 patient-year. In a meta-analysis of 60 studies with data from 1.5 million people with HF, although the 5-year survival rates have improved in the last years (from 29.1% between 1970–1979 to 59.7% in 2000–2009), these remain very high.34 A recent study showed in patients with HF that 3 out of every 5 patients had died within 5 years of follow-up, with a median survival of 3 years.35 However, the elevated risk of outcomes in this population, particularly as renal function worsens, many patients do not receive evidence-based medical therapies, what worsens the prognosis.36 These data emphasize the need of prescribing recommended drugs as soon as possible to get the maximum benefit, as HF is a progressive condition without the appropriate treatment.37

Our study showed that among HF patients, renal function progressively decreased and albuminuria increased (11.5% and 7.2%, respectively) and 5.9% of patients developed CKD after only 2 years of follow-up. In addition, the risk of outcomes was higher in those patients with HF and CKD and time to first event was shorter (vs only HF alone) and worsened as CKD stage increased. Remarkably, although patients with HF and CKD were taking more angiotensin-converting enzyme inhibitors and angiotensin receptor blockers than those without CKD at baseline, the proportion of SGLT-2 inhibitors was similar. The relationship between HF and CKD is bidirectional and one condition promotes the development of the other and vice versa.38 Traditionally, renin–angiotensin system inhibitors have been the drugs used for the prevention and treatment of both, cardiovascular and renal complications, and their prescription should be promoted.1,39 Remarkably, in the last years, different clinical trials have shown that some SGLT-2 inhibitors can reduce the risk of cardiovascular and renal complications in patients with CKD (dapagliflozin in DAPA-CKD and canagliflozin in CREDENCE) and also in patients with HF and reduced left ventricular ejection fraction (dapagliflozin in DAPA-HF and empagliflozin in EMPEROR-Reduced).14,15,40,41 In addition, in patients with HF, SGLT2-inhibitors reduce the rate of kidney function decline, regardless baseline renal function.9,10 Unfortunately, our data showed that the current use of SGLT-2 inhibitors in this population is marginal. However, these drugs should be used to a higher extent, as their use is associated with a reduction of morbidity and mortality in patients with HF and reduced left ventricular ejection fraction, regardless of the renal function.42

Finally, although rates of outcomes were also high in patients with HF and preserved left ventricular ejection fraction, these seemed somewhat lower than in patients with reduced HF. This is in line with previous studies that have shown a similar or lower risk of mortality and cardiovascular complications in this population when compared to patients with reduced HF.23,24,43,44 Unfortunately, although some studies have suggested that some drugs could provide some benefits in patients with preserved HF,45,46 the fact is that the best approach in this population is a comprehensive management, treating adequately all comorbidities and congestive symptoms.1 However, at this moment different studies are being developed to assess the impact of SGLT-2 inhibitors on this population.20

Limitations

This was an observational cohort study, with cross-sectional and longitudinal retrospective analyses that used secondary data from electronic health records. Therefore, only data that were recorded in the electronic clinical history could be collected, leading to a possible underdiagnosis of some comorbidities in some patients. In addition, data regarding the department where patients were managed (ie. HF unit, cardiology, internal medicine, intensive care unit, etc.) were not available in the database. However, although only indirect causality can be provided, this is the best design to actually represent clinical practice. In addition, the high number of patients included, as well as the robustness of the data, may reduce potential bias. On the other hand, no mildly reduced ejection fraction HF was considered as a separate entity in our study, as was included in the preserved HF cohort, what could limit the generalizability of the results.

In Spain, patients with HF are old, have many comorbidities and a high risk of developing cardiovascular and renal complications regardless of the ejection fraction group. Despite that, there is a substantial proportion of patients that are not taking guideline recommended drugs, partially due to the high prevalence of renal insufficiency. A higher use of these drugs could reduce HF burden in clinical practice.

What is known about the subject?

  • Current data about the management and cardiovascular and renal outcomes of patients with preserved and reduced HF are scarce.

Does it contribute anything new?

  • In Spain, patients with HF are old, have many comorbidities.

  • HF patients have a high risk of developing cardiovascular and renal complications regardless of the ejection fraction group.

  • Unfortunately, there is a substantial proportion of patients that are not taking guideline recommended drugs, partially due to the high prevalence of renal insufficiency.

Funding

This study was fully funded with an unrestricted grant of AstraZeneca.

Authors’ contributions

All authors have contributed to the study design, result review, manuscript preparation and final approval of the manuscript.

Conflicts of interest

None.

Appendix A
Supplementary data

The following are the supplementary data to this article:

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Abbreviations: CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; HF: heart failure; UACR: urine albumin-to-creatinine ratio; SGLT-2: sodium-glucose cotransporter-2.

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