Sodium-glucose cotransporter 2 inhibitors have demonstrated positive effects in heart failure (HF) patients. However, the effects of dapagliflozin in patients with decompensated HF remain unclear. This study aimed to compare the efficacy and safety of early and late dapagliflozin administration for decompensated HF. Data regarding dapagliflozin administration from 70 patients diagnosed with HF between December 2020 and November 2021 at a Japanese heart centre were analysed retrospectively. Propensity score matching was performed to compare the clinical outcomes of early and late dapagliflozin administration for decompensated HF. The primary end point was HF admission one year after dapagliflozin administration. The secondary end points were evaluated based on 24-hour urine volume, cardiac death, changes in ejection fraction (EF), blood pressure, glomerular filtration rate (GFR), haemoglobin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and side effects within one year of treatment. Fifteen matched pairs of patients were analysed. Admission rate within one year was significantly lower in the early administration group than in the late administration group (0 vs. 20%, p=0.03). Secondary end points were not significantly different between the two groups. In conclusion, early dapagliflozin administration significantly reduced HF admission within one year of treatment, although no differences were observed in 24-hour urine volume, cardiac death, EF, GFR, haemoglobin and NT-proBNP levels, and side effects.
Introduction
Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was first used as a type 2 diabetes drug. However, in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, dapagliflozin effectively reduced both hospitalisations due to heart failure (HF) and death in patients with HF with reduced ejection fraction (HFrEF).1 Therefore, the European Society of Cardiology (ESC) and Japanese Circulation Society (JCS) guidelines recommended the administration of SGLT2 inhibitors to patients with HFrEF.2,3 Moreover, dapagliflozin suppressed both renal failure exacerbation and all-cause death in patients with chronic renal failure.4 A recent study revealed that dapagliflozin administration reduced HF hospitalisation in patients with HF with preserved ejection fraction (HFpEF).5 In these studies, dapagliflozin was administered to patients with chronic HF; however, none have reported the safety or efficacy of its administration in the acute phase. A recent study reported that the administration of SGLT2 inhibitors in patients with HF reduced the use of diuretics and increased urine output.4 SGLT2 inhibitors are used for patients with chronic-phase HF; however, considering their diuretic effect, they may be administered to patients with decompensated HF. A recent study reported that empagliflozin administration could benefit patients with decompensated HF.5 However, no studies have examined the effects of dapagliflozin administration in patients with decompensated HF. Therefore, this study aimed to investigate the safety and efficacy of dapagliflozin administration in patients with decompensated HF.
Materials and method
Study design and patients
The records of hospitalised patients who were administered dapagliflozin treatment for decompensated HF at Nagoya Heart Center between December 2020 and November 2021 were retrospectively analysed. Seventy consecutive patients with decompensated HF were included in the analysis. All patients received 10 mg dapagliflozin. A 1:1 propensity score matching (PSM) of populations divided into early and late dapagliflozin administration groups was performed.
Follow-up clinical evaluations were performed at one, six, and 12 months using clinical symptoms, cardiac death, vital signs, laboratory data, ejection fraction (EF), HF admission, and side effects. Follow-up data were obtained from hospital charts or by contacting the patients, family members, or referring physicians. The study protocol was approved by the ethics committee of Nagoya Heart Center and was conducted in accordance with the tenets of the Declaration of Helsinki. Owing to the retrospective enrolment, the requirement for obtaining written informed consent from the patients was waived.
End points
The primary end point was HF admission one year after dapagliflozin administration. The secondary end points were evaluated based on 24-hour urine volume, cardiac death, the changes in EF, glomerular filtration rate (GFR), haemoglobin level, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) level within one year after treatment. The secondary end points included drug side effects, including hypoglycaemia, fracture, amputation, dehydration, urinary tract infection, allergy, and diabetic ketoacidosis (DKA), within one year of treatment.
Definitions
HF was defined as a clinical syndrome consisting of cardinal symptoms (such as breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (such as elevated jugular venous pressure, pulmonary crackles, and peripheral oedema), due to a structural and/or functional abnormality of the heart that induces elevated intracardiac pressure and/or inadequate cardiac output at rest and/or during exercise.6,7 HFrEF was defined as an ejection fraction of <40%.6 Early dapagliflozin administration was defined as administration within one week of HF diagnosis. The classification of chronic kidney disease (CKD) was defined according to the Kidney Disease Improving Global Outcomes CKD classification system.8
Statistical analysis
All statistical analyses were performed using the JMP version 14.0.2 software (SAS Institute Inc., Cary, NC, USA). To eliminate the potential influence of the non-randomised study design, PSM was performed using a multi-variate logistic-regression model with the dapagliflozin administration method (early vs. late administration of dapagliflozin) as the dependent variable. All baseline characteristics (age, sex, body mass index, hypertension, diabetes mellitus, dyslipidaemia, CKD, atrial fibrillation, ischaemic heart failure, current smoking status, de novo, New York Heart Association [NYHA] classification, EF, angiotensin-converting enzyme [ACE] inhibitor/angiotensin-receptor blocker [ARB]/angiotensin-receptor/neprilysin inhibitor [ARNI], beta blocker, mineralocorticoid-receptor antagonist [MRA], loop diuretic, tolvaptan, baseline blood pressure, estimated glomerular filtration rate [eGFR], haemoglobin level, and NT-proBNP level) were set as covariates. According to the recommendation by Austin, a caliper cutoff of 0.20 was used to obtain a satisfactory balance.9 Data are presented as numbers, percentages, means ± standard deviations (SD), or medians (interquartile ranges, IQR). Categorical variables were compared between the groups using the χ2 or Fisher’s exact test, as appropriate. Continuous variables were compared between the groups using the Mann–Whitney U test. A probability (p) value of <0.05 was considered statistically significant.
Results
Patients
A flowchart of the study is shown in figure 1. Of the 70 patients included for analysis, 15 and 55 received early and late dapagliflozin administration, respectively. The complete baseline clinical data and patient characteristics are shown in table 1. After PSM, 15 matched pairs of patients were included for analysis. In the matched populations, no significant differences were observed in baseline characteristics and clinical data between the two groups. The mean age of the patients was 73 years, 53% were male, 27% had ischaemic heart failure, mean left ventricular EF was 45%, and median NT-proBNP level was 4,481 pg/ml. The average length of dapagliflozin administration was 1.7 ± 0.8 versus 33.5 ± 17.8 days in the early and late groups (p<0.01).
Table 1. Baseline characteristics and clinical data of the study population before and after propensity score matching
| Character | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| Early group | Late group | p value | Early group | Late group | p value | |
| Number | 15 | 55 | 15 | 15 | ||
| Mean age ± SD, years | 74.4 ± 11.6 | 71.0 ± 11.9 | 0.42 | 74.4 ± 11.6 | 71.1 ± 13.2 | 0.46 |
| Male, n (%) | 42 (76.4) | 8 (53.3) | 0.09 | 8 (53.3) | 8 (53.3) | 1.0 |
| Mean BMI ± SD, kg/m2 | 23.2 ± 3.8 | 24.9 ± 4.8 | 0.19 | 23.2 ± 3.8 | 24.1 ± 4.8 | 0.58 |
| Hypertension, n (%) | 13 (86.7) | 50 (90.9) | 0.64 | 13 (86.7) | 14 (93.3) | 0.54 |
| Diabetes mellitus, n (%) | 8 (53.3) | 46 (83.6) | 0.02 | 8 (53.3) | 12 (80.0) | 0.12 |
| Dyslipidaemia, n (%) | 10 (66.7) | 46 (83.6) | 0.16 | 10 (66.7) | 14 (93.3) | 0.07 |
| Atrial fibrillation, n (%) | 6 (40.0) | 8 (14.6) | 0.04 | 6 (40.0) | 2 (20.0) | 0.22 |
| Ischaemic heart failure, n (%) | 2 (13.3) | 22 (40.0) | 0.04 | 2 (13.3) | 6 (40.0) | 0.09 |
| Current smoking, n (%) | 5 (33.3) | 25 (45.5) | 0.40 | 5 (33.3) | 5 (33.3) | 1.0 |
| Mean ejection fraction ± SD, % | 42.5 ± 20.2 | 43.9 ± 16.7 | 0.79 | 42.5 ± 20.2 | 47.3 ± 19.2 | 0.53 |
| HFrEF, n (%) | 9 (60.0) | 23 (41.8) | 0.21 | 9 (60.0) | 7 (46.7) | 0.46 |
| Mean baseline eGFR ± SD, ml/min/1.73 m2 | 52.5 ± 23.9 | 56.9 ± 23.0 | 0.52 | 52.5 ± 23.9 | 57.8 ± 19.5 | 0.51 |
| Mean haemoglobin ± SD, g/dL | 13.2 ± 2.6 | 13.2 ± 2.5 | 0.90 | 13.2 ± 2.6 | 13.7 ± 2.7 | 0.60 |
| Mean NT-proBNP ± SD, pg/ml | 5,172 ± 2,320 | 4,014 ± 1,964 | 0.48 | 5,172 ± 2,320 | 3,790 ± 1,710 | 0.29 |
| Chronic kidney disease, n (%) | ||||||
| Stage 3a | 1 (6.7) | 7 (12.7) | 0.50 | 1 (6.7) | 1 (6.7) | 0.83 |
| Stage 3b | 2 (13.3) | 11 (20.0) | 2 (13.3) | 1 (6.7) | ||
| Stage 4 | 3 (20.0) | 6 (10.9) | 3 (20.0) | 1 (6.7) | ||
| NYHA classification, n (%) | ||||||
| II | 6 (40.0) | 28 (50.9) | 0.27 | 6 (40.0) | 8 (53.3) | 0.20 |
| III | 6 (40.0) | 25 (45.5) | 6 (40.0) | 7 (46.7) | ||
| IV | 3 (20.0) | 2 (3.6) | 3 (20.0) | 0 (0) | ||
| Medication, n (%) | ||||||
| ACEi/ARB/ARNI | 10 (66.7) | 37 (67.3) | 0.96 | 10 (66.7) | 11 (73.3) | 0.69 |
| Beta blocker | 13 (86.7) | 42 (76.4) | 0.37 | 13 (86.7) | 10 (66.7) | 0.19 |
| MRA | 5 (33.3) | 21 (38.2) | 0.73 | 5 (33.3) | 3 (20.0) | 0.41 |
| Loop diuretic | 9 (41.8) | 23 (41.8) | 0.21 | 9 (60.0) | 4 (26.7) | |
| Tolvaptan | 1 (6.7) | 9 (16.4) | 0.31 | 1 (6.7) | 1 (6.7) | 1.0 |
| Mean blood pressure ± SD, mmHg | ||||||
| Systolic | 129.5 ± 23.2 | 125.7 ± 19.3 | 0.43 | 129.5 ± 23.2 | 127.4 ± 18.0 | 0.78 |
| Diastolic | 78.6 ± 19.1 | 71.2 ± 10.7 | 0.06 | 78.6 ± 19.1 | 70.8 ± 18.3 | 0.16 |
| Key: ACE = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; ARNI = angiotensin-receptor/neprilysin inhibitor; BMI = body mass index; eGFR = estimated glomerular filtration rate; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid-receptor antagonist; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; SD = standard deviation | ||||||
Primary and secondary outcomes
The primary and secondary outcomes are shown in table 2. The HF admission rate was significantly lower with early dapagliflozin administration than with late dapagliflozin administration (0 vs. 20%, p<0.03). However, no significant differences were observed regarding 24-hour urine volume, cardiac death, the changes in EF, GFR, haemoglobin level, and NT-proBNP level within one year between the two groups. The incidence of side effects was similar for patients in both groups, and only one instance of dehydration was observed in the late-administration group.
Table 2. Primary and secondary clinical outcomes
| Early group N=15 |
Late group N=15 |
p value | |
|---|---|---|---|
| Acute phase | |||
| Mean admission days ± SD | 14.4 ± 8.9 | 22.7 ± 9.8 | 0.35 |
| Mean bed-rest days ± SD | 2.0 ± 1.8 | 5.7 ± 6.3 | 0.18 |
| Mean BUN/Cr at discharge ± SD | 17.6 ± 4.4 | 21.6 ± 6.3 | 0.06 |
| Chronic phase | |||
| HF admission within 1 year, n (%) | 0 (0) | 3 (20.0) | 0.03 |
| Mean loop diuretic dose ± SD, mg | 18.0 ± 6.3 | 21.7 ± 9.8 | 0.38 |
| Mean ejection fraction ± SD, % | 53.8 ± 10.7 | 54.2 ± 17.0 | 0.95 |
| Mean eGFR ± SD, ml/min/1.73 m2 | 56.4 ± 19.7 | 59.1 ± 18.2 | 0.74 |
| Mean haemoglobin ± SD, g/dL | 13.6 ± 1.5 | 14.6 ± 1.8 | 0.15 |
| Mean NT-proBNP ± SD, pg/ml | 1,325 ± 2,142 | 1,046 ± 1,772 | 0.75 |
| Hypoglycaemia, n (%) | 0 (0) | 0 (0) | – |
| Fracture, n (%) | 0 (0) | 0 (0) | – |
| Amputation, n (%) | 0 (0) | 0 (0) | – |
| Dehydration, n (%) | 0 (0) | 1 (6.7) | 0.23 |
| Urinary tract infection, n (%) | 0 (0) | 0 (0) | – |
| Allergy, n (%) | 0 (0) | 0 (0) | – |
| DKA, n (%) | 0 (0) | 0 (0) | – |
| Key: BUN = blood urea nitrogen; Cr = creatinine; DKA = diabetic ketoacidosis; eGFR = estimated glomerular filtration rate; HF = heart failure; NT-proBNP = N-terminal pro-B-type natriuretic peptide; SD = standard deviation | |||
Discussion
This study demonstrated that early dapagliflozin administration significantly reduced HF admission within one year of treatment compared with late dapagliflozin administration. However, no difference in side effects was observed between the two groups.
As patients were not randomised into the two groups, possible differences in baseline clinical characteristics may ensue; therefore, PSM was performed; however, no significant differences were observed in the clinical characteristics between the two groups after PSM. From a basic medical point of view, dapagliflozin has been demonstrated to reduce sympathetic nerve excitation and to have diuretic and renal protective effects.10,11 Therefore, it was hypothesised that dapagliflozin might be used for both patients with chronic heart failure and those with decompensated HF. Empagliflozin administration to patients with decompensated HF has improved congestion in both the short and medium terms.12 Moreover, it has been reported that early and complete congestion relief improves prognosis.13,14 Therefore, it was hypothesised that early dapagliflozin administration to improve congestion at an early stage would improve prognosis by reducing the number of HF hospitalisations. Our study results revealed that HF hospitalisation was suppressed after dapagliflozin administration in the early dapagliflozin administration group; this may be attributed to the possible association of early dapagliflozin administration with a complete reduction in congestion.
A recent study demonstrated that the effects of dapagliflozin differ over time, suggesting that its early administration may further reduce cardiovascular mortality and hospitalisation. According to this study, the beneficial effects of dapagliflozin manifest in the early phase of administration.15 Another study demonstrated that natriuresis and intracardiac filling pressures are favourably modified within days of treatment initiation;16 this mechanism might confer clinical benefits in cases of early dapagliflozin administration in patients with HF. However, this study was limited to patients with HF with mildly reduced or preserved ejection fraction, and our study focused on all patients with HF. A previous study reported that dapagliflozin administration could reduce HF hospitalisations even when stratified by EF, consistent with this study.17 In addition, our study demonstrated that early dapagliflozin administration did not increase side effects. Although our study had a limited number of cases, dapagliflozin may be safely used, even if administered early after congestion diagnosis. The study findings and long-term clinical outcomes require further validation in prospective studies.
Our study had several limitations. First, the number of patients with decompensated HF was small. Second, the study design was retrospective, inciting possible selection bias. Therefore, PSM was performed to overcome baseline differences. Third, the study focused only on Japanese patients with decompensated HF; thus, the results may not be applicable to other populations. Finally, the study cohort was limited to dapagliflozin administration; thus, whether the results are applicable to other SGLT2 inhibitors, such as empagliflozin, remains unknown. Therefore, further prospective studies are required to confirm the study results.
Overall, in this study, early dapagliflozin administration significantly reduced HF admission within one year of treatment, although no differences were observed in the EF, GFR, haemoglobin level, NT-proBNP level, and side effects.
Key messages
- Compared with late administration, early dapagliflozin administration significantly reduced heart failure-related admission within one year of treatment
- Early administration of dapagliflozin did not increase side effects within one year of treatment
- No significant differences were observed between early and late dapagliflozin administration in glomerular filtration rate, ejection fraction, haemoglobin level, and NT-proBNP level within one year of treatment
Conflicts of interest
None declared.
Funding
None.
Study approval
The study protocol was approved by the ethics committee of Nagoya Heart Center and was conducted in accordance with the tenets of the Declaration of Helsinki.
Acknowledgement
The authors thank the staff in the catheterisation laboratory of Nagoya Heart Center for their assistance with this work.
References
1. McMurray JJV, Solomon SD, Inzucchi SE et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/NEJMoa1911303
2. McDonagh TA, Metra M, Adamo M et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2022;24:4–131. https://doi.org/10.1002/ejhf.2333
3. Tsutsui H, Ide T, Ito H et al. JCS/JHFS 2021 guideline focused update on diagnosis and treatment of acute and chronic heart failure. J Card Fail 2021;27:1404–44. https://doi.org/10.1016/j.cardfail.2021.04.023
4. Griffin M, Rao VS, Ivey-Miranda J et al. Empagliflozin in heart failure: diuretic and cardiorenal effects. Circulation 2020;142:1028–39. https://doi.org/10.1161/CIRCULATIONAHA.120.045691
5. Voors AA, Angermann CE, Teerlink JR et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med 2022;28:568–74. https://doi.org/10.1038/s41591-021-01659-1
6. McDonagh TA, Metra M, Adamo M et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–726. https://doi.org/10.1093/eurheartj/ehab368
7. Ponikowski P, Voors AA, Anker SD et al. 2016 ESC guidelines for the diagnosis treatment of acute chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128
8. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. 2013 KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1–150. https://doi.org/10.1038/kisup.2012.73
9. Austin PC. Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat 2011;10:150–61. https://doi.org/10.1002/pst.433
10. Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol 2020;75:422–34. https://doi.org/10.1016/j.jacc.2019.11.031
11. Hallow KM, Helmlinger G, Greasley PJ et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab 2018;20:479–87. https://doi.org/10.1111/dom.13126
12. Biegus J, Voors AA, Collins SP et al. Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial. Eur Heart J 2022;44:41–50. https://doi.org/10.1093/eurheartj/ehac530
13. Bettencourt P, Azevedo A, Pimenta J et al. N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation 2004;110:2168–74. https://doi.org/10.1161/01.CIR.0000144310.04433.BE
14. Kociol RD, McNulty SE, Hernandez AF et al. Markers of decongestion, dyspnea relief, and clinical outcomes among patients hospitalized with acute heart failure. Circ Heart Fail 2013;6:240–5. https://doi.org/10.1161/CIRCHEARTFAILURE.112.969246
15. Vaduganathan M, Claggett BL, Jhund P et al. Time to clinical benefit of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction: a prespecified secondary analysis of the DELIVER randomized clinical trial. JAMA Cardiol 2022;7:1259–63. https://doi.org/10.1001/jamacardio.2022.3750
16. Nassif ME, Qintar M, Windsor SL et al. Empagliflozin effects on pulmonary artery pressure in patients with heart failure: results from the EMBRACE-HF trial. Circulation 2021;143:1673–86. https://doi.org/10.1161/CIRCULATIONAHA.120.052503
17. Dewan P, Solomon SD, Jhund PS et al. Efficacy and safety of sodium-glucose co-transporter 2 inhibition according to left ventricular ejection fraction in DAPA-HF. Eur J Heart Fail 2020;22:1247–58. https://doi.org/10.1002/ejhf.1867
