Contemporary Guideline-Directed Medical Therapy and Outpatient Worsening Heart Failure Events in Hospitalized Patients With Heart Failure　― Preliminary Observational Study on Utilizing Predischarge Period for Optimizing Medications in Hospitalized Patients With Heart Failure (PRE-UPFRONT-HF) ―

Abstract

Background: Adherence to contemporary guideline-directed medical therapy (GDMT) and its association with incident outpatient worsening heart failure (WHF) events after discharge in hospitalized patients with heart failure (HF) remain unclear.

Methods and Results: The PRE-UPFRONT-HF study was a retrospective multicenter observational registry of patients hospitalized for HF between June 2022 and March 2023 with a left ventricular ejection fraction <50%. Data on medications at admission, discharge, and 6 months after admission were collected. Outpatient WHF was defined as intravenous diuretic therapy and/or intensification of oral diuretics in outpatient settings (e.g., without hospitalization). Less than half the 442 patients registered were on all 4 GDMT medications (β-blockers, renin-angiotensin-aldosterone system inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors) at discharge and 6 months after admission. Better GDMT implementation, defined by a simple GDMT score above the median, was significantly associated with a lower incidence of composite outcomes of death, HF hospitalization, and WHF (P<0.001), as well as outpatient WHF events alone (P=0.035), which remained significant even after adjusting for covariates. In addition, outpatient WHF was associated with subsequent worse prognoses, including mortality (hazard ratio 6.52; P<0.001).

Conclusions: GDMT implementation during hospitalization for HF is suboptimal, even in the contemporary era. Patients with better GDMT implementation at discharge had a lower incidence of outpatient WHF, which was associated with subsequent mortality.

Heart failure (HF) is affecting an increasing number of people worldwide, necessitating hospitalization, and is associated with high mortality.^1–5 Optimization of guideline-directed medical therapy (GDMT) is the cornerstone treatment to reduce morbidity and mortality in patients with HF with reduced ejection fraction (HFrEF),^6–8 and current US and European guidelines recommend in-hospital initiation of GDMT before discharge (Class I recommendation).^9,10 In addition, the Safety, Tolerability and Efficacy of Rapid Optimization Helped by NT-proBNP Testing, of Heart Failure Therapies (STRONG-HF) study demonstrated the safety and efficacy of rapid initiation and uptitration of GDMT within the first 6 weeks after discharge in patients with acute heart failure (AHF).¹¹ Despite these established recommendations and strong evidence, real-world data consistently suggest suboptimal utilization of GDMT in patients with HFrEF or HF with mildly reduced ejection fraction (HFmrEF).^12–15 However, only a few studies have reported the prescription rates of GDMT in the era of contemporary GDMT medications, including sodium-glucose cotransporter 2 (SGLT2) inhibitors.^12,16 Furthermore, of these studies, only a few have assessed temporal changes in GDMT prescriptions.¹⁷

Worsening heart failure (WHF) has traditionally been associated with the deterioration of HF signs and symptoms requiring hospitalization.¹⁸ However, recent studies, mainly subanalyses of randomized controlled trials, have consistently shown that, in addition to worsening symptoms necessitating HF hospitalization, symptoms requiring the intensification of diuretics without hospitalization are strongly associated with subsequent prognosis.^19–21 These data have led to a new definition of WHF, which includes both hospitalization for HF and the intensification of HF medications in outpatient settings.^18,22 Although previous randomized controlled trials for each guideline-recommended drug have tested its effect on prognosis (i.e., HF hospitalization and/or mortality), no study has evaluated whether optimization of GDMT during hospitalization is associated with fewer WHF events, as defined by this modern concept after discharge.

Therefore, the aims of the present study were to clarify contemporary prescription rates and doses of GDMT during hospitalization and their temporal changes during the 6 months after admission, as well as to investigate the association between outpatient WHF events and GDMT optimization at discharge in patients with HFrEF/HFmrEF hospitalized for AHF.

Methods

The Preliminary Observational Study on Utilizing Predischarge Period for Optimizing Medications in Hospitalized Patients With Heart Failure (PRE-UPFRONT-HF) was a retrospective multicenter observational study conducted at 7 hospitals across Japan: Juntendo University (Tokyo), the National Cerebral and Cardiovascular Centre (Suita), Mitsui Memorial Hospital (Tokyo), Nagoya University (Nagoya), Saitama Medical University (Kawagoe), Japanese Red Cross Fukuoka Hospital (Fukuoka), and Kobe City Medical Center General Hospital (Kobe). The study was performed in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Juntendo University. Because of the retrospective observational nature of the study, written informed consent was not required per the Ethical Guidelines for Medical and Health Research Involving Human Subjects instituted by the Japanese Ministry of Health, Labour, and Welfare. All the participants were free to withdraw from the study at any time.

All patients diagnosed with AHF based on the Framingham criteria and admitted to any of the 7 hospitals between June 2022 and March 2023 were screened for the present study.²³ Patients who met all the following criteria were included in the study: (1) patients who required intravenous furosemide administration and stayed at the hospital for more than 24 h; (2) patients with B-type natriuretic peptide (BNP) >100 pg/mL or N-terminal pro B-type natriuretic peptide (NT-proBNP) >600 pg/mL if sinus rhythm was present, or BNP >200 pg/mL or NT-proBNP >900 pg/mL if there was atrial fibrillation at admission; and (3) patients with a left ventricular ejection fraction (LVEF) <50% during the index hospitalization. Patients undergoing dialysis (including both hemodialysis and peritoneal dialysis), those with severe renal impairment (defined as an estimated glomerular filtration rate <20 mL/min/1.73 m²), acute myocarditis, takotsubo syndrome, or AHF due to acute coronary syndrome were excluded.

Baseline characteristics, including age, sex, clinical comorbidities, vital signs, blood test data, and HF medication data, were obtained retrospectively at the time of admission for the index hospitalization. In addition, vital signs, blood test data, and HF medication data were collected at discharge from the index hospitalization and 180 (±30) days after admission, if available. Clinical events, including death, HF hospitalization, and WHF after discharge, were followed up within 1 year after admission for the index hospitalization. Outpatient WHF was defined as intravenous diuretic administration and/or intensification of oral diuretic treatment without hospitalization on the same day.^19,22

To quantify the optimization of GDMT, a simple GDMT score was calculated based on previous studies.^24–26 The simple GDMT score (total score 0–9) considered the use of renin-angiotensin system (RAS) inhibitors, including angiotensin receptor-neprilysin inhibitors (ARNI), β-blockers, mineralocorticoid antagonists (MRAs), and SGLT2 inhibitors. RAS inhibitors other than ARNI were scored 0 if not initiated, 1 for <50% of the target dose, and 2 for 50–100% of the target dose; ARNI use was scored 3, regardless of dose. Beta-blockers were scored 0 if not initiated, 1 for <50% of the target dose, and 2 for 50–100% of the target dose. MRAs and SGLT2 inhibitors were scored 0 if not initiated and 2 if initiated, regardless of dose. The target doses for HF medication, including RAS inhibitors and β-blockers, were defined according to the Japanese guidelines on the diagnosis and treatment of acute and chronic HF and a previous study that proposed a simple GDMT score^26,27 (Supplementary Table 1). Based on landmark clinical trials of these medications, the target dose of SGLT2 inhibitors was set at 10 mg/day for both empagliflozin and dapagliflozin,^28,29 and the target dose of ARNI was set at 400 mg/day.³⁰ Patients were classified into 2 groups according to the median value of the simple GDMT score at discharge (i.e., scores ≥6 and ≤5 points). Furthermore, in the sensitivity analysis, patients were classified into 2 groups according to a simple GDMT score of ≥5 points, which was the cut-off suggested in the previous study proposing the simple GDMT score.²⁵

Statistical Analysis

Normally distributed data are expressed as the mean±SD and skewed data as presented as the median with interquartile range (IQR). Categorical variables are expressed as numbers and percentages. When necessary, variables were log-transformed for further analysis. Baseline patient characteristics were compared using one-way analysis of variance or the Kruskal-Wallis test for continuous variables and Chi-squared tests for categorical variables, as appropriate. Kaplan-Meier curves for composite outcomes, including outpatient WHF, HF hospitalization, and all-cause death, were constructed, and event rates after discharge between groups were compared using log-rank tests. Cumulative incidence curves for outpatient WHF events were generated by the Fine-Gray competing risk regression analysis, with death as a competing risk. In addition, to evaluate whether outpatient WHF events affect subsequent (i.e., post-event) prognosis, we treated the onset of WHF events as a time-dependent variable and generated cumulative incidence curves for death alone, as well as a composite outcome of HF hospitalization and death from the time of the outpatient WHF event (Time 0). Furthermore, to determine whether the onset of WHF events affected subsequent outcomes independent of other prognostic factors, a multivariate Cox model including the onset of WHF events as a time-dependent covariate was constructed. Based on previous studies, the AHEAD (A: atrial fibrillation; H: hemoglobin; E: elderly; A: abnormal renal parameters; D: diabetes) score, log-transformed NT-proBNP levels, and length of stay were considered as adjustment variables for inclusion in the multivariable analyses. The AHEAD score was calculated by assigning 1 point for each of A (atrial fibrillation), H (hemoglobin <130 g/L for men and 120 g/L for women), E (elderly; age >70 years), A (abnormal renal parameters; creatinine >130 μmol/L), and D (diabetes).³¹ This risk score has been validated to discriminate short- and long-term prognoses independent of HF phenotypes in Asian patients with AHF.³²

As a sensitivity analysis, we included age, creatinine, hemoglobin, LVEF, New York Heart Association (NYHA) Class III/IV, and log NT-proBNP as adjustment variables in another multivariable analysis to balance the different baseline characteristics of patients with GDMT scores ≤5 points and those with GDMT scores ≥6 points. Multiple imputations were performed to account for missing data in this registry. Using the “mice” package in R Studio, 20 imputed datasets were generated, and the statistical results from these datasets were subsequently combined. Statistical significance was defined as a 2-tailed P<0.05. All statistical analyses were performed using R Studio statistical software (version 4.3.1; R Foundation for Statistical Computing, Vienna, Austria).

Results

During the study period, 1,130 patients were hospitalized for AHF at 7 hospitals. After excluding 48 patients who did not meet the BNP or NT-proBNP cut-off values, 464 patients with LVEF ≥50%, 112 patients undergoing dialysis or with severe renal dysfunction, 6 patients with myocarditis, 4 patients with Takotsubo syndrome, 6 patients with acute coronary syndrome, and 16 patients for other reasons (including recurrent hospitalizations), 474 patients with HFrEF/HFmrEF were eligible for inclusion in this study. To focus on GDMT at discharge and prognosis, we excluded patients who died during the index hospitalization (n=25), those without data on prognosis (n=4), and those without medications at discharge (n=3), leaving 442 patients in the analysis.

Overall, the median age of the 442 patients was 78 years, 65% were male, the median LVEF was 30%, and 58% of patients were de novo HF patients. Information on medications prescribed 6 months after admission was available for 253 (57%) patients. Median simple GDMT scores at admission, discharge, and 6 months after admission were 2 (IQR 0–5), 6 (IQR 4–7), and 6 (IQR 5–8), respectively. Temporal changes in prescriptions and doses of GDMT, including β-blockers, RAS inhibitors, MRA, and SGLT2 inhibitors, at admission, discharge, and 6 months after admission are shown in Figure 1 and Table 1. During the index hospitalization, all 4 classes of medications were initiated and uptitrated; however, only a limited number of patients achieved the maximum recommended dose of each medication by discharge. From discharge to 6 months after admission, the prescription rates of β-blockers, RAS inhibitors, and SGLT2 inhibitors exhibited modest increases, although the changes were less pronounced compared with changes between admission and discharge. Furthermore, the percentage of patients achieving maximum doses of GDMT was low even at 6 months after admission, especially for β-blockers and RAS inhibitors, whose effects were demonstrated in a dose-dependent manner. Figure 2 and Table 2 illustrate the trajectories of the number of GDMT prescriptions at the same time points, showing that less than half the patients were on all 4 GDMT medications at discharge and 6 months after admission. In addition, approximately 10% of patients were prescribed at least half the dose of all medications, and less than 1% of patients were prescribed the full dose of all medications, even at 6 months after admission.

Figure 1.

Temporal changes in guideline-directed medical therapy (GDMT) prescription rates and doses, namely β-blockers, renin-angiotensin system (RAS) inhibitors, mineralocorticoid antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2i), at admission, discharge, and 6 months after admission. ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; ARNI, angiotensin receptor-neprilysin inhibitor.

Table 1.

Temporal Changes in GDMT Prescription Rates and Doses at Admission, Discharge, and 6 Months After Admission

GDMT	β-blockers			RAS inhibitors			MRAs			SGLT2 inhibitors
	Admission	Discharge	6 months	Admission	Discharge	6 months	Admission	Discharge	6 months	Admission	Discharge	6 months
Maximum dose	33 (7)	39 (9)	45 (18)	16 (4)	26 (6)	26 (10)	32 (7)	50 (11)	31 (12)	87 (20)	203 (52)	166 (65)
Half dose or above	63 (14)	117 (26)	74 (29)	79 (18)	100 (23)	57 (22)	90 (21)	240 (54)	133 (52)	8 (2)	2 (0.5)	3 (1)
Less than half dose	122 (28)	207 (47)	104 (41)	116 (26)	219 (49)	124 (49)	11 (3)	32 (7)	20 (8)	7 (2)	2 (0.5)	2 (0.8)
None	225 (51)	81 (18)	34 (13)	232 (52)	98 (22)	47 (19)	306 (70)	121 (27)	73 (28)	342 (77)	187 (48)	86 (34)

Data are presented as n (%). GDMT, guideline-directed medical therapy; MRA, mineralocorticoid receptor antagonist; RAS, renin-angiotensin system; SGLT2, sodium-glucose cotransporter 2.

Figure 2.

Temporal changes in the total number of guideline-directed medical therapies (GDMT) prescribed at any dose, half dose, and maximum dose.

Table 2.

Temporal Changes in the Total Number of GDMT Prescribed at Any Dose, Half Dose, and Maximum Dose

No. GDMTs	Any dose			Half dose or above			Maximum dose
	Admission	Discharge	6 months	Admission	Discharge	6 months	Admission	Discharge	6 months
4	44 (10)	173 (39)	118 (47)	10 (2)	27 (6)	28 (11)	1 (0.2)	2 (0.5)	2 (0.8)
3	74 (17)	125 (28)	68 (27)	35 (8)	103 (23)	66 (26)	7 (2)	10 (3)	18 (7)
2	91 (21)	87 (20)	44 (17)	74 (17)	144 (33)	84 (33)	21 (5)	34 (9)	37 (15)
1	90 (20)	42 (10)	18 (7)	113 (26)	116 (26)	50 (20)	100 (23)	190 (49)	130 (52)
0	144 (33)	15 (3)	6 (2)	206 (47)	51 (12)	24 (10)	309 (71)	156 (40)	65 (26)

Data are presented as n (%). GDMT, guideline-directed medical therapy.

To assess the association between the simple GDMT score at discharge and post-discharge outcomes, 442 patients were classified into 2 groups based on the median simple GDMT score at discharge, namely a high GDMT score group (simple GDMT score ≥6 points; n=246) and a low GDMT score group (simple GDMT score ≤5 points; n=196). The baseline characteristics of the 2 groups are presented in Table 3. Patients with low GDMT scores were older and had more severe symptoms, higher LVEF, higher levels of creatinine, and higher NT-proBNP levels. No significant differences were observed between the 2 groups in the proportion of male patients, systolic blood pressure at discharge, history of HF duration, prevalence of myocardial infarction and diabetes, length of stay, or doses of loop diuretics at discharge.

Table 3.

Baseline Characteristics According to the Median Simple GDMT Score at Discharge

	Simple GDMT score		P value
	≤5 points (n=196)	≥6 points (n=246)
Age (years)	83 [74–87]	73 [61–81]	<0.001
Male sex	121 (62)	163 (66)	0.375
BMI (kg/m2)	20.2±3.8	22.3±5.1	0.196
SBP (mmHg)	110±17	107±18	0.075
DBP (mmHg)	64±12	66±12	0.231
Heart rate (beats/min)	75±16	73±13	0.309
NYHA Class III/IV	15 (10)	8 (4)	0.018
LVEF (%)	35 [27–41]	30 [21–37]	<0.001
Device implantation	46 (24)	44 (18)	0.184
Comorbidities
Prior history of heart failure			0.084
None	102 (53)	152 (62)
<1.5 years	32 (17)	41 (17)
≥1.5 years	59 (31)	53 (22)
Hypertension	109 (56)	140 (57)	0.907
Diabetes	58 (30)	77 (31)	0.782
Atrial fibrillation	88 (45)	90 (37)	0.086
COPD	10 (5)	11 (5)	0.931
History of myocardial infarction	28 (14)	48 (20)	0.195
History of cerebral infarction	25 (13)	30 (12)	0.958
Laboratory data at discharge
Hemoglobin (g/dL)	11.7±1.9	13.2±2.4	<0.001
Creatinine (mg/dL)	1.2 [0.9–1.7]	1.1 [0.8–1.5]	0.005
Blood urea nitrogen (mg/dL)	30 [22–41]	25 [18.90–31]	<0.001
Sodium (mEq/L)	139±4	139±4	0.661
Potassium (mEq/L)	4.3±0.5	4.3±0.5	0.916
Chloride (mEq/L)	103±5	103±4	0.07
BNP (pg/mL)	267 [147–543]	291 [127–478]	0.348
NT-proBNP (pg/mL)	2,447 [1,286–4,275]	1,503 [737–3,207]	0.012
Medications at discharge
ACEi/ARB	80 (41)	87 (35)	0.282
ARNI	26 (13)	154 (63)	<0.001
β-blockers	128 (65)	233 (95)	<0.001
MRA	91 (46)	230 (94)	<0.001
SGLT2 inhibitors	47 (24)	208 (85)	<0.001
Vericiguat	5 (3)	12 (5)	0.31
Ivabradine	0 (0)	9 (4)	0.018
Digoxin	3 (2)	6 (2)	0.739
Dose of furosemide equivalent loop diuretics at discharge (mg)	20 [10–40]	20 [0–20]	0.052
Length of stay (days)	15 [11–23]	15 [11–21]	0.656

Unless indicated otherwise, data are given as the mean±SD, median [interquartile range], or n (%). ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BMI, body mass index; BNP, B-type natriuretic peptide; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure. Other abbreviations as in Table 1.

Among the 442 patients, 23 outpatient WHF events (7 with intravenous diuretic therapy and 16 with oral diuretic intensification), 70 HF hospitalizations, and 48 deaths occurred during the 1-year follow-up. Kaplan-Meier curves for composite outcomes, including outpatient WHF, HF hospitalization, and all-cause death, revealed that the high GDMT score group had significantly lower event rates than the low GDMT score group (log-rank, P<0.001; Figure 3). Multivariable Cox proportional analysis demonstrated that the simple GDMT score ≥6 points was associated with a better prognosis even after adjusting for AHEAD score, length of stay, and log-transformed NT-proBNP (hazard ratio [HR] 0.48; 95% confidence interval [CI] 0.32–0.72; P<0.001; Table 4). Similarly, cumulative incidence curves for outpatient WHF considering death as a competing risk revealed that the high GDMT group was associated with a lower incidence of outpatient WHF events than the low GDMT group (Fine-Gray, P=0.035; Figure 3), and this association was retained even after adjusting for known risk factors, including the AHEAD score, length of stay and log NT-proBNP (HR 0.39; 95% CI 0.16–0.96; P=0.039; Table 4). For sensitivity analysis, we performed the same analysis using the simple GDMT score cut-off of ≥5 points suggested in the original study; however, the results did not change significantly (Supplementary Figure 1; Supplementary Table 2).

Figure 3.

Cumulative incidence curves of a composite outcome including outpatient worsening heart failure (WHF), hospitalization for heart failure (HHF), or death (Left), and outpatient WHF events alone (Right) in 2 groups according to simple guideline-directed medical therapy (sGDMT) scores of ≤5 vs. ≥6 points. Shaded areas represent 95% confidence intervals.

Table 4.

Association Between Simple GDMT Score at Discharge and Outpatient WHF Outcomes

Simple GDMT score	Composite outcomes including outpatient WHF, HHF, and death									Outpatient WHF events alone considering death as a competing risk
	Unadjusted model			Adjusted Model 1A			Adjusted Model 2B			Unadjusted model			Adjusted Model 1A			Adjusted Model 2B
	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value
≤5 points	Ref.			Ref.			Ref.			Ref.			Ref.			Ref.
≥6 points	0.44	0.30–0.64	<0.001	0.48	0.32–0.72	<0.001	0.50	0.33–0.78	0.002	0.41	0.17–0.96	0.041	0.39	0.16–0.96	0.039	0.32	0.12–0.89	0.029

^AModel 1 was adjusted for AHEAD (A: atrial fibrillation; H: hemoglobin; E: elderly; A: abnormal renal parameters; D: diabetes) score, length of stay, and log-transformed NT-proBNP concentration. ^BModel 2 was adjusted for age, creatinine, hemoglobin, LVEF, NYHA Class III/IV, and log-transformed NT-proBNP concentration. CI, confidence interval; HHF, hospitalization for heart failure; HR, hazard ratio; WHF, worsening heart failure. Other abbreviations as in Tables 1,3.

We also evaluated the prognostic implications of outpatient WHF events on subsequent outcomes, and the cumulative incidence curves for death alone and for a composite outcome, including HF hospitalization and death, demonstrated that patients who experienced outpatient WHF events, treated as a time-dependent variable, had higher event rates than those without an outpatient WHF event (Supplementary Figure 2; Table 5). Multivariable Cox proportional hazards analysis confirmed that outpatient WHF events remained an independent prognostic factor, even after adjusting for the AHEAD score, length of stay, and log-transformed NT-proBNP levels, for death (HR 6.52; 95% CI 2.85–14.9; P<0.001) and for the composite outcome (HR 5.68; 95% CI 2.89–11.2; P<0.001; Table 5). Another multivariable analysis adjusted for age, creatinine, hemoglobin, LVEF, NYHA Class III/IV, and log NT-proBNP, demonstrated consistent results. Furthermore, another sensitivity analysis to evaluate the association between outpatients WHF events alone and GDMT score at discharge considering death and HF hospitalization as competing risks also yielded consistent results (Supplementary Figure 3; Supplementary Table 3).

Table 5.

Cox Proportional Hazard Analysis Using Outpatient WHF Events as a Time-Dependent Variable for Subsequent Outcomes

Outpatient WHF as a time-dependent variable	Unadjusted model			Adjusted Model 1A			Adjusted Model 2B
	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value
For HHF+death	6.18	3.17–12.0	<0.001	5.68	2.89–11.2	<0.001	4.56	2.24–9.27	<0.001
For death alone	6.88	3.02–15.7	<0.001	6.52	2.85–14.9	<0.001	6.28	2.64–15.0	<0.001

^AModel 1 was adjusted for AHEAD (A: atrial fibrillation; H: hemoglobin; E: elderly; A: abnormal renal parameters; D: diabetes) score, length of stay, and log-transformed NT-proBNP concentration. ^BModel 2 was adjusted for age, creatinine, hemoglobin, LVEF, NYHA Class III/IV, and log-transformed NT-pro BNP concentration. Abbreviations as in Tables 3,4.

Discussion

In this study, data of 442 patients with HFrEF/HFmrEF who were hospitalized with AHF between June 2022 and March 2023 were analyzed. Our 3 main findings are as follows: (1) GDMT was not optimally prescribed or uptitrated even at 6 months after admission for the index hospitalization; (2) better GDMT implementation at the time of discharge, as evaluated by the simple GDMT score, was associated with lower event rates not only for a combined event of WHF, HF rehospitalization, and all-cause death but also for outpatient WHF alone; and (3) outpatient WHF events observed after discharge as a time-dependent variable were independently associated with a higher incidence of subsequent clinical outcomes, including all-cause death.

We found that the prescribed rates and doses of GDMT remained low in Japanese patients with HFrEF/HFmrEF, even in the contemporary era, which is consistent with results from other global HF registries. TITRATE-HF is one of the most contemporary HF registries and includes more than 4,000 patients with HFrEF, HFmrEF, and HF with improved ejection fraction registered between June 2022 and February 2024 in the Netherlands.¹² In that study, RAS inhibitors and β-blockers were prescribed to 87% of patients, MRAs were prescribed to 76% of patients, and SGLT2 inhibitors were prescribed to 65% of patients,¹² which are almost the same prescription rates 6 months after admission in our study. The study from the Netherlands also reported that the percentage of patients achieving maximum doses of β-blockers and RAS inhibitors was approximately 10–20%, and only 1% of patients with HFrEF achieved the target dose for all drug classes,¹² all of which are consistent with the results of the present study. Moreover, the results of TITRATE-HF and the present study demonstrated a higher percentage of GDMT prescriptions than reported previously in large-scale HF registries,^13,14,33,34 although these registries did not evaluate the prescription rates of SGLT2 inhibitors owing to the inclusion period being before guidelines recommended SGLT2 inhibitor use in patients with HF. For example, in the CHAMP-HF registry, RAS inhibitors, β-blockers, and MRAs were prescribed to 73%, 67%, and 33% of patients with HFrEF, respectively, and few patients received the target doses of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARB; 17%), ARNI (14%), and β-blockers (28%).³⁴ Similarly, in the ASIAN-HF registry, RAS inhibitors, β-blockers, and MRAs were prescribed to 77%, 79%, and 58% of patients with HFrEF, respectively, and with guideline-recommended target doses of RAS inhibitors, β-blockers, and MRAs achieved in only 17%, 13%, and 29% of patients, respectively.¹⁴ These data show that the prescription rates of GDMT, especially MRAs, improved over time, although the proportion of patients achieving maximum doses of GDMT remained suboptimal, similar to the findings of the present study. Notably, these international studies primarily focused on outpatients with HFrEF/HFmrEF and assessed GDMT prescription rates mainly at baseline, whereas our study included patients hospitalized with AHF and we evaluated GDMT prescriptions at 3 different time points, highlighting a notable strength of our study. Our results showed that GDMT prescription rates at 6 months were not fully improved relative to those at discharge, which may suggest the importance of in-hospital optimization of GDMT in patients with HFrEF/HFmrEF, considering the longer hospital stay in Japan.

Regarding the incidence of outpatient WHF, a secondary analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial reported that the incidence of an urgent HF visit with intravenous therapy was 0.4% (20 of 4,744 patients) over a median follow-up of 18.2 months.¹⁹ A secondary analysis of the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy Post-Approval Registry (MADIT-CRT) trial reported that the incidence of outpatient WHF was 2.9% (52 of 1,820 patients) over a mean follow-up of 3.3 years.³⁵ The CHAMP-HF registry reported that 1 in 4 patients with HFrEF taking oral loop diuretics experienced oral diuretic intensification, which included diuretic drug change from furosemide to torsemide or bumetanide.³⁶ As noted above, the incidence rate of outpatient WHF exhibited considerable variability based on the patient population. Considering the retrospective design of our study, our incidence rate of outpatient WHF may be underestimated, although it was within the range reported by previous studies.

We found outpatient WHF had prognostic significance for subsequent events, including mortality, in our study cohort, which is consistent previous studies. A secondary analysis of the MADIT-CRT trial was one of the first large studies to demonstrate that patients who needed treatment with intravenous diuretic therapy in outpatient settings (without hospitalization) had comparably poor mortality compared with those without such events.³⁵ In addition, a secondary analysis of the DAPA-HF trial found that the risk of death was nearly 3-fold higher following urgent intravenous diuretic therapy than in patients without a WHF event.¹⁹ Regarding outpatient intensification of oral diuretic therapy, an analysis of the nationwide Danish registry found that the intensification of oral diuretics in outpatient settings was common and associated with a higher risk of 1-year mortality.²⁰ These data support our analysis, showing that outpatient WHF, including intravenous diuretic therapy and oral diuretic intensification, was associated with a higher incidence of death and hospitalization for HF. In this context, our results (showing that optimal GDMT implementation during hospitalization, represented by a higher simple GDMT score, is associated with a lower incidence of post-discharge outpatient WHF events) are particularly important. Indeed, a secondary analysis of the DAPA-HF trial showed that the SGLT2 inhibitor dapagliflozin reduced the incidence of outpatient WHF, defined as the intensification of oral HF therapy in patients with HFrEF.¹⁹ A prespecified analysis of the Prospective Comparison of ARNI with ACEI to Determine the Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) showed a consistent beneficial effect of ARNI over enalapril on the expanded outcomes, including outpatient intensification of HF therapy and emergency department visits, in addition to cardiovascular death and HF hospitalization.²¹ Although no study has investigated the association between outpatient WHF events and the use of other medications, including β-blockers, ACEi/ARB, and MRAs, our study results are consistent with those of previous studies, and it is possible that in-hospital GDMT optimization led to lower post-discharge adverse events by preventing WHF events. However, this hypothesis needs to be evaluated in prospective large-scale randomized controlled trials.

Study Limitations

Our study has some limitations. First, this was a retrospective observational study with inherent limitations. For example, we did not have data on the etiology of HF, although the prevalence of a history of myocardial infarction did not differ between the 2 groups. Clinical event data were retrospectively obtained at each hospital, which may have led to an underestimation of our outpatient WHF incidence rate. Second, although we attempted to adjust for confounders using a validated risk score, some confounding factors remained unadjusted. Establishing causality may be challenging, and a multidiscipline approach, including virtual consult teams, remote algorithm-based medication optimization, electronic health record-based interventions, and direct-to-patient educational initiatives, may be needed. Third, data 6 months after the index hospitalization was only available for 57% of patients; this could have caused selection bias and affected the results of temporal changes in GDMT prescriptions. Fourth, owing to the retrospective study design, we could not evaluate the reasons why most patients could not achieve maximum doses of GDMT even after 6 months, which may be key information to improve GDMT prescriptions in future studies. Fifth, this study used data from only 7 high-volume centers, which may not reflect the national GDMT prescription trends, although the GDMT prescription rates were not high enough even among these hospitals.

Conclusions

In conclusion, even in the contemporary era, GDMT implementation and uptitration were suboptimal at the time of discharge and 6 months after admission for hospitalized patients with HFrEF/HFmrEF. This is the first study to demonstrate that better GDMT implementation at discharge was associated with lower outpatient WHF events, defined as oral or intravenous diuretics intensification, which were associated with subsequent mortality.

Acknowledgments

None.

Sources of Funding

This work was supported, in part, by the Japan Society for the Promotion of Science (KAKENHI Grant 22K16147).

Disclosures

Y.M. has received honoraria from Otsuka Pharmaceutical Co., EN Otsuka Pharmaceutical Co., Ltd., Novartis Pharma K.K., Bayer Inc., and AstraZeneca, and a collaborative research grant from Pfizer Japan Inc., Otsuka Pharmaceutical Co., EN Otsuka Pharmaceutical Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd. Y.H. has received speaker fees from Eli Lilly, Boehringer, AstraZeneca, Otsuka, and Novartis. R. Matsukawa has received lecture fees from AstraZeneca K.K., Boehringer Ingelheim, Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., and Otsuka Pharmaceutical Co. T. Kondo has received lecture fees from Abbott Japan LLC, AstraZeneca K.K., Boehringer Ingelheim, Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., and Novartis Pharma K.K. The remaining authors have no conflicts of interest to declare.

IRB Information

This study was approved by the Ethics Committee of Juntendo University Hospital (E24-0066).

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-1020

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