Abstract
Background
Heart failure (HF) hospitalization is a marker of HF progression, and it is associated with mortality in adults with congenital heart disease (CHD). The purpose of this study was to assess the effect of guideline directed medical therapy (GDMT) on HF readmission and mortality in CHD patients with HF with reduced ejection fraction (HFrEF). We hypothesized that higher GDMT use was associated with lower risk of HF readmission and mortality.
Method
Retrospective study of CHD patients and HFrEF, admitted for HF (2003-2023). GDMT use was assessed at hospital discharge (baseline) and 1-year follow-up using a standardized GDMT score. GDMT uptitration was assessed as difference between GDMT score at baseline versus 1-year follow-up.
Results
Of 153 patients (age 51 ± 15 years, 39% males, left ventricular EF 29 ± 7%), the median baseline GDMT score was 2 (1, 3). Baseline GDMT score was associated with lower risk of HF readmission (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.54, 0.92, p < 0.001) and mortality (HR 0.71, 95%CI 0.50, 0.93, p < 0.001) per 1-unit increase in baseline GDMT score. Among patients with 1-year follow-up (N = 128), GDMT uptitration was associated with lower risk of HF readmission (HR 0.72, 95%CI 0.49, 0.94, p < 0.001) and mortality (HR 0.69, 95%CI 0.41, 0.92, p = 0.02) per 1-unit increase. Patients with GDMT uptitration (N = 49, 38%) had greater improvement in neurohormonal activation and left ventricular systolic function, consistent with a lower risk of HF readmission and mortality in that group.
Conclusions
GDMT optimization was associated with lower risk of HF readmission and all-cause mortality amongst adults with CHD. Further studies are required to determine whether strategies to improve GDMT optimization would improve clinical outcomes in this population.
Keywords: Medical therapy, Heart failure, Mortality, Prognostication
What is already known about this subject?
Heart failure (HF) hospitalization is a marker of HF progression, and it is associated with mortality in adults with congenital heart disease (CHD).
What does this study add?
Optimization of guideline directed medical therapy (GDMT) (higher GDMT use at hospital discharge as well as GDMT uptitration after discharge) after an index heart failure (HF) admission was associated with lower risk of HF readmission and all-cause mortality in congenital heart disease (CHD) patients with HF with reduced ejection fraction.
How might this impact on clinical practice?
Further studies are required to determine whether strategies to improve GDMT optimization (rapid uptitration with close monitoring, and early outpatient follow-up after discharge) would improve clinical outcomes in this population.
1. Introduction
Heart failure (HF) is the leading cause of mortality in adults with congenital heart disease (CHD) [[1], [2], [3], [4]]. HF hospitalization is a marker of HF progression, and CHD admitted for HF, have a 3 to 5-fold increase in risk of mortality compared to patients without prior HF admission, and this risk is highest within the first 1 year following HF admission [1,5,6]. Furthermore, the risk of readmission for HF is high in this population (about 20-40% within 5 years), and HF readmission is associated with 2 to 5-fold increase in mortality risk compared to CHD patients without HF readmission [1,5,6]. Collectively, these data suggest that CHD patients with prior HF admission represent a high risk group, and hence there is an urgent need for interventions to improve outcomes in this population.
Guideline-directed medical therapy (GDMT) for HF is associated with a lower risk of HF readmission and mortality in patients with HF with reduced ejection fraction (HFrEF) due to acquired heart disease [[7], [8], [9]]. Comparable data are lacking in adults with CHD and a history of HF hospitalization, owing in part to the heterogeneity of this population and the absence of standardized criteria for assessing GDMT optimization. This represents an important unmet clinical need and knowledge gap, given the adverse prognostic implications of HF in the CHD population. The current study aimed to address this gap by evaluating the association between GDMT, quantified using a standardized GDMT score, and the risks of HF readmission and mortality among adults with CHD and HFrEF. We hypothesized that a higher GDMT score would be associated with a lower risk of HF readmission and mortality in this population.
2. Methods
2.1. Study population
In this retrospective cohort study, we reviewed the Mayo Adults Congenital Heart Disease (MACHD) registry and identified adults (age ≥18 years) with CHD, biventricular physiology with systemic left ventricle (LV), and LVEF ≤40% who were admitted for acute decompensated HF between January 1, 2003 and December 31, 2023. Patients with unrepaired/palliated cyanotic heart disease were excluded. The patients were classified based on CHD complexity as mild/simple, moderate, and severe/complex CHD using the criteria from the guidelines for the management of adults with CHD [10]. For the patients with multiple HF admissions, we selected the first HF admission after January 1, 2003, as the index HF admission for this study. We excluded patients who died as well as the patients who underwent heart transplantation or implantation of ventricular assist device during the index HF admission. The date of discharge following the index HF admission was used as the baseline encounter for the study, and the data obtained during the index HF admission were used to define the baseline characteristics of the cohort.
HFrEF was defined as current or prior history of symptoms and signs of congestion (dyspnea, fatigue, orthopnea, or paroxysmal nocturnal dyspnea, elevated jugular pressure, pedal edema, etc.) and laboratory evidence consistent with congestion such as elevated N terminal pro-B-type brain natriuretic peptide [NT-proBNP]) [7,11]. HF admission was defined as hospital admission for volume overload (pulmonary and/or systemic congestion) due to acute decompensated HF requiring intravenous diuretics [7,12].
2.2. Study objectives
(i) Assess the relationship between GDMT use at hospital discharge and outcomes (HF readmission and all-cause mortality). (ii) Assess the relationship between GDMT uptitration during follow-up and outcomes (HF readmission and all-cause mortality). This analysis was restricted to the patients who had outpatient clinic visit at 1-year post hospital discharge.
2.3. Exposure: guideline directed medical therapy
We assessed the intensity of HF therapy using the GDMT score. The GDMT score, also referred to as the HF Collaboratory score, was developed to provide a standardized framework for assessing the intensity of HF therapy and for comparing HF therapy optimization across different studies [13,14]. The HF medications and point system used for calculating GDMT score are shown in Supplementary Table S1.
Baseline GDMT score: We calculated the GDMT score at hospital discharge (baseline GDMT score) using the medication list at hospital discharge. The patients were dichotomized into 2 groups using the median baseline GDMT score as the cutoff (baseline GDMT score >2 versus ≤2).
GDMT uptitration: In addition to the baseline GDMT score, we calculated GDMT score at 1-year post hospital discharge using medication list obtained at the time of 1-year (9-15 months) clinic visit. We assessed GDMT uptitration (Δ GDMT score) as the difference between GDMT score at baseline and 1-year encounters. This was calculated as follows: Δ GDMT score = GDMT score at 1-year follow-up minus GDMT score at baseline encounter, whereby a Δ GDMT score >0 signified GDMT uptitration (GDMT uptitration(+) group) while GDMT score ≤0 signified no GDMT uptitration (GDMT uptitration(−) group).
2.4. Outcomes
The study outcomes were HF readmission and all-cause mortality. These outcomes were assessed as time-to-event outcomes and ascertained from the date of discharge from index HF admission (time zero) until outcome, last clinical encounter, or December 31, 2023. The patients who did not reach the study endpoints were censored on the date of last clinical encounter, date of heart transplantation or implantation of ventricular assist device, or December 31, 2023.
2.5. Study variables
Echocardiography: Echocardiograms obtained at the time of index HF admission, and at 1-year outpatient follow-up were reviewed, and offline image analyses performed using standardized imaging protocol [15,16].
Biomarkers: NT-proBNP levels, model for end-stage liver disease excluding international normalized ratio score and estimated glomerular filtration rate obtained at index HF admission and at 1-year follow-up were reviewed for this study.
Safety Indices. Adverse events associated with GDMT include bradycardia, hypotension, hyperkalemia, and renal dysfunction [7]. As a result, we assessed the following safety indices (heart rate, systolic blood pressure, serum potassium, and estimated glomerular filtration rate at time of hospital discharge), and at 1-year outpatient clinic visit.
2.6. Statistical analysis
Data were presented as mean ± standard deviation, median (Q1, Q3), and count (%). Between-group comparisons were performed using independent t-test and Wilcoxon rank sum test for continuous variables, and Fisher's exact test for categorical variable.
For study objective #1, we assessed the relationship between baseline GDMT score and outcomes (HF readmission and all-cause mortality) using multivariable Cox regression. For study objective #2, we assessed the relationship between GDMT uptitration (Δ GDMT score) and outcomes (HF readmission and all-cause mortality) using multivariable Cox regression. Because of small sample size and risk of model overfitting, we created multiple multivariable models to adjust for different covariates. Model A was adjusted for age and sex. Model B was adjusted for age and sex AND CHD severity (modeled as simple versus moderate versus complex, using the simple CHD group as the reference). Model C was adjusted for age and sex AND comorbidities (atrial fibrillation, coronary artery disease, chronic kidney disease, hypertension, and diabetes) AND pacemakers [modeled as ‘no pacemaker’ versus ‘dual chamber pacemaker’ versus ‘biventricular pacemaker,’ using the no pacemaker group as the reference). Model D was adjusted for age and sex AND echocardiographic indices (right ventricular free wall strain, LV global longitudinal strain, tricuspid regurgitation, and mitral regurgitation). Model E was adjusted for age and sex AND biomarkers (NT-proBNP and model for end-stage liver disease excluding international normalized ratio). The cumulative incidence of outcomes was assessed using Kaplan-Meier analysis and compared using log-rank test. We addressed missing data using conditional imputation [17]. All statistical analyses were performed with BlueSky Statistics software (version. 7.10; BlueSky Statistics LLC, Chicago, IL, USA), and JMP statistical software (version 18.2.0, JMP Statistical Discovery LLC, NC). P value < 0.05 was considered to be statistically significant for all analyses.
3. Results
3.1. Baseline characteristics
Overall, 153 patients met the study inclusion criteria. The mean age at hospital discharge was 51 ± 15 years, and 93 (61%) were males. Of the 153 patients, 12 (8%), 121 (79%), and 20 (13%) had simple, moderate, and complex CHD, respectively. The most common comorbidities were atrial fibrillation (40%), and hypertension (35%), and 37% of the patients had cardiac implantable electronic devices. The mean LVEF and LV global longitudinal strain were 29 ± 7% and −11.1 ± 3.9%, respectively, and 15% had ≥ moderate mitral regurgitation. Among the patients with NT-proBNP measurement at time of index HF admission (N = 129), the median NT-proBNP level was 1948 (981, 3927) pg/ml. Among the patients who underwent right heart catheterization during index HF admission (N = 61), the mean right atrial pressure and pulmonary artery wedge pressure were 15 ± 8 mmHg and 19 ± 8 mmHg, respectively. Table 1 shows the baseline clinical and hemodynamic characteristics of the cohort.
Table 1.
Baseline characteristics.
| All (N = 153) | Baseline GDMT score >2 (N = 64, 42%) | Baseline GDMT score ≤2 (N = 89, 58%) | p | |
|---|---|---|---|---|
| Demographic indices | ||||
| Age (years) | 51 ± 15 | 52 ± 15 | 51 ± 16 | 0.72 |
| Male sex | 93 (61%) | 40 (63%) | 53 (50%) | 0.71 |
| Body mass index (kg/m2) | 27.1 ± 5.7 | 26.5 ± 5.2 | 27.6 ± 5.3 | 0.72 |
| CHD severity | ||||
| Simple | 12 (8%) | 7 (11%) | 5 (6%) | 0.28 |
| moderate | 121 (79%) | 51 (80%) | 70 (79%) | |
| Complex | 20 (13%) | 6 (9%) | 14 (16%) | |
| Surgical/anatomic data | ||||
| CIED implantation | 57 (37%) | 23 (36%) | 34 (38%) | 0.77 |
| Dual chamber pacemaker | 25 (16%) | 5 (8%) | 20 (22%) | 0.06 |
| Biventricular pacemaker | 32 (21%) | 18 (28%) | 14 (16%) | 0.06 |
| Defibrillator | 43 (28%) | 19 (30%) | 24 (27%) | 0.82 |
| Comorbidities | ||||
| Hypertension | 53 (35%) | 24 (38%) | 29 (33%) | 0.53 |
| Coronary artery disease | 13 (9%) | 5 (8%) | 8 (9%) | 0.79 |
| Diabetes | 21 (14%) | 10 (16%) | 11 (12%) | 0.56 |
| Chronic kidney disease III-V | 37 (24%) | 11 (17%) | 26 (29%) | 0.08 |
| Atrial fibrillation | 61 (40%) | 26 (41%) | 35 (39%) | 0.87 |
| Laboratory indices | ||||
| Hemoglobin (g/dl) | 13.4 ± 2.7 | 13.7 ± 2.5 | 13.1 ± 2.8 | 0.16 |
| GFR (ml/min/1.73 m2) | 78 ± 29 | 83 ± 25 | 74 ± 30 | 0.05 |
| MELD-XI | 11.4 (9.4,15.7) | 10.6 (9.4, 15.1) | 11.6 (9.4, 16.6) | 0.18 |
| NT-proBNP (pg/ml) | 1948 (981, 3927) | 1911 (848, 3784) | 2207 (1042, 4149) | 0.22 |
| Echocardiography | ||||
| Systemic indices | ||||
| LA reservoir strain (ml/m2) | 19 ± 8 | 17 ± 7 | 21 ± 9 | 0.11 |
| LA volume index (ml/m2) | 44 ± 28 | 48 ± 26 | 42 ± 21 | 0.32 |
| Lateral e’ (cm/s) | 9.6 ± 4.5 | 9.3 ± 0.51 | 9.6 ± 3.8 | 0.84 |
| Lateral E/e’ | 12.8 ± 7.5 | 12.3 ± 8.9 | 11.1 ± 5.9 | 0.57 |
| Medial e’ (cm/s) | 7.1 ± 2.9 | 6.7 ± 2.6 | 7.5 ± 3.0 | 0.13 |
| Medial E/e’ | 14.2 ± 7.9 | 15.3 ± 8.2 | 12.9 ± 7.5 | 0.17 |
| LV end-diastolic volume (ml/m2) | 93 ± 28 | 98 ± 27 | 86 ± 32 | 0.34 |
| LV end-systolic volume (ml/m2) | 61 ± 27 | 66 ± 29 | 54 ± 25 | 0.35 |
| LV ejection fraction (%) | 29 ± 7 | 32 ± 7 | 28 ± 9 | 0.66 |
| LV global longitudinal strain (%) | −11.1 ± 3.9 | −11.5 ± 3.2 | −10.9 ± 3.2 | 0.82 |
| ≥Mod mitral regurgitation | 21 (14%) | 9 (14%) | 12 (14%) | 0.91 |
| LV stroke volume (ml) | 32 ± 19 | 35 ± 12 | 30 ± 16 | 0.87 |
| Cardiac index (l/minm2) | 2.68 ± 1.81 | 3.01 ± 1.12 | 3.47 ± 2.59 | 0.16 |
| Non-systemic indices | ||||
| RA reservoir strain (%) | 18 ± 10 | 19 ± 9 | 16 ± 10 | 0.21 |
| RA volume index (ml/m2) | 48 ± 29 | 43 ± 21 | 52 ± 23 | 0.33 |
| Mean RAP (mmHg) | 12 ± 6 | 10 ± 5 | 13 ± 5 | 0.005 |
| RVSP (mmHg) | 51 ± 22 | 48 ± 18 | 53 ± 22 | 0.13 |
| RV end-diastolic area (cm2) | 40 ± 19 | 39 ± 16 | 41 ± 20 | 0.78 |
| RV end-systolic area (cm2) | 29 ± 17 | 28 ± 13 | 30 ± 19 | 0.63 |
| RV fractional area change (%) | 22 ± 13 | 24 ± 11 | 18 ± 14 | 0.78 |
| RV free wall strain (%) | −17 ± 9 | −16 ± 5 | −18 ± 7 | 0.15 |
| ≥Mod tricuspid regurgitation | 50 (34%) | 18 (28%) | 32 (36%) | 0.31 |
| Cardiac catheterization (N=61) | ||||
| Mean RAP (mmHg) | 15 ± 8 | 14 ± 8 | 16 ± 8 | 0.38 |
| Mean PAP (mmHg) | 33 ± 17 | 30 ± 14 | 39 ± 21 | 0.01 |
| PAWP (mmHg) | 19 ± 8 | 16 ± 7 | 21 ± 8 | 0.009 |
| PVR (WU) | 3.62 ± 2.14 | 3.51 ± 1.93 | 3.80 ± 2.07 | 0.97 |
| CO (l/min/m2) | 4.32 ± 1.51 | 4.05 ± 1.31 | 4.55 ± 1.62 | 0.18 |
Abbreviations: CHD: Congenital heart disease; CIED: Cardiac implantable electronic device; GDMT: Guideline directed medical therapy; GFR: Glomerular filtration rate; MELD-XI: Model for end-stage liver disease excluding international normalized ratio; NT-proBNP: N terminal pro-b-type brain natriuretic peptide, RA: Right atrium; RAP: Right atrial pressure; RV: Right ventricle; RVSP: Right ventricular systolic pressure; PAP: Pulmonary artery pressure; PAWP: Pulmonary artery wedge pressure; PH: Pulmonary hypertension; PVR: Pulmonary vascular resistance; LA: Left atrium; LV: Left ventricle; CO: Cardiac output.
Footnote: Data were presented as mean ± standard deviation, median (Q, Q3), and count (%).
3.2. Index hospital admission
The median hospital stay was 6 (4, 12) days, and the fluid balance at the time of hospital discharge was −5.3 (−11.6, −2.2) liters. Table 2 shows the GDMT prescription at hospital discharge. The most common HF medications were beta blocker (N = 78, 51%), and angiotensin converting enzyme inhibitor/angiotensin-II receptor blocker (N = 72, 47%). The median baseline GDMT score was 2 (1, 3) (mean 2.39 ± 1.22). Of the 153 patients, 64 (42%) had baseline GDMT score >2, while 89 (58%) had baseline GDMT score ≤2. Compared with patients with baseline GDMT score ≤2, those with baseline GDMT score >2 had lower catheterization-derived mean pulmonary artery wedge pressure (16 ± 7 versus 21 ± 8 mmHg, p = 0.009) and mean pulmonary artery pressure (30 ± 14 versus 39 ± 21 mmHg, p = 0.01), and lower echocardiography-derived mean right atrial pressure (10 ± 5 versus 13 ± 5 mmHg, p = 0.005), (Table 1). There was no significant differences in length of hospital stay (6 [4, 12] versus 7 [4-13], p = 0.89), or fluid balance [−5.1 [−10.8, −1.7] versus −5.9 [−12.4, −3.4], p = 0.74) between the patients with baseline GDMT score >2 versus ≤2, respectively.
Table 2.
GDMT score at hospital discharge.
| Medications | |
|---|---|
| Beta blockers | 78 (51%) |
| ACEI/ARB | 72 (47%) |
| ARNI | 16 (11%) |
| MRA | 29 (19%) |
| SGLT2i | 18 (12%) |
| GDMT score | |
| 1 | 40 (26%) |
| 2 | 49 (32%) |
| 3 | 38 (25%) |
| 4 | 18 (12%) |
| 5 | 6 (4%) |
| 6 | 2 (1%) |
Abbreviations: ACEI/ARB: Angiotensin converting enzyme inhibitor/angiotensin 2 receptor blocker; ARNI: Angiotensin receptor/neprilysin inhibitor; GDMT: Guideline directed medical therapy; MRA: Mineralocorticoid receptor antagonist; SGLT2i: Sodium-glucose cotransporter-2 inhibitor.
3.3. Baseline GDMT score and outcomes (N = 153)
Of the 153 patients, 63 (41%) had HF readmission while 78 (51%) died during a median follow-up of 5.6 (1.92, 11.4) years. Additionally, 17 (11%) were listed for heart transplantation, of which 9 (6%) underwent heart transplantation. The 10-year cumulative incidence of HF readmission was 39% while the 10-year cumulative incidence of all-cause mortality was 47%. Compared to the patients with baseline GDMT score ≤2, those with GDMT score >2 had lower 10-year cumulative incidence of HF readmission (24% versus 48%, p = 0.006), and lower 10-year cumulative incidence of mortality (31% versus 57%, p = 0.009) (Fig. 1). The was a 27% decrease in the risk of HF readmission (unadjusted hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.54, 0.92, p < 0.001) per 1-unit increase in baseline GDMT score. Similarly, the was a 29% decrease in the risk of mortality (unadjusted HR 0.71, 95%CI 0.50, 0.93, p < 0.001) per 1-unit increase in baseline GDMT score. The associations between baseline GDMT score and outcomes remained statistically significant on multivariable analysis (Table 3).
Fig. 1.
Kaplan-Meier curves showing cumulative incidence of HF readmission (A) and all-cause mortality (B). Abbreviations: HF: Heart failure; GDMT: Guideline directed medical therapy.
Table 3.
Multivariable cox regression models assessing prognostic performance of baseline GDMT score.
| Adjusted hazard ratio (95% confidence interval) for HF Readmission |
|||||
|---|---|---|---|---|---|
| Model A | Model B | Model C | Model D | Model E | |
| Baseline GDMT | 0.75 (0.53, 0.94) | 0.76 (0.51, 0.96) | 0.78 (0.57, 0.98) | 0.75 (0.54, 0.95) | 0.78 (0.56, 0.98) |
| Adjusted hazard ratio (95% confidence interval) for All-cause Mortality | |||||
|
Model A |
Model B |
Model C |
Model D |
Model E |
|
| Baseline GDMT | 0.73 (0.52, 0.94) | 0.72 (0.51, 0.94) | 0.72 (0.51, 0.94) | 0.70 (0.48, 0.95) | 0.74 (0.49, 0.97) |
Abbreviations: CHD: Congenital heart disease; GDMT: Guideline directed medical therapy; HF: Heart failure; MELD-XI: Model for end-stage liver disease excluding international normalized ratio; NT-proBNP: N terminal pro-b-type brain natriuretic peptide; RV: Right ventricle; LV: Left ventricle.
Footnote: Separate models were created for HF readmission and all-cause mortality.
Model A: Model adjusted for age and sex.
Model B: Model adjusted for age and sex AND CHD severity (mild vs moderate vs complex).
Model C: Model adjusted for age and sex AND comorbidities (atrial fibrillation, coronary artery disease, chronic kidney disease, hypertension, and diabetes), and pacemaker.
Model D: Model adjusted for age and sex AND echocardiographic indices (RV free wall strain, LV global longitudinal strain, tricuspid regurgitation, mitral regurgitation).
Model E: Model adjusted for age and sex AND biomarkers (NT-proBNP, MELD-XI score).
3.4. GDMT uptitration and outcomes (N = 128)
Of the 153 patients, 25 (16%) patients were excluded from the assessment of GDMT uptitration because of HF readmission, death, heart transplantation or loss of follow-up within the 1-year post hospital discharge. The remaining 128 (84%) patients had an outpatient clinic visit at 1-year post hospital discharge, the median interval between hospital discharge and outpatient clinic visit was 12.9 (10.2, 14.4) months.
Among these 128 patients, there was a temporal increase in GDMT score from hospital discharge to 1-year follow-up (mean GDMT score 2.39 ± 1.26 versus 3.53 ± 1.41, p = 0.009; mean difference +1.14 [95%CI 0.66, 1.64]) suggesting an increase in intensity of medical therapy over time. Of the 128 patients, 49 (38%) had Δ GDMT score >0 (GDMT uptitration(+) group) while 79 (62%) had GDMT score ≤0 (GDMT uptitration(−) group).
Table 4 shows a comparison of the clinical and hemodynamic characteristics between the 2 groups. There was no difference in age, sex, CHD severity, laboratory indices, and echocardiographic indices between the GDMT uptitration(+) versus GDMT uptitration(−) groups. Both groups had temporal reduction in NT-proBNP levels at 1-year follow-up, but the magnitude of change was greater in the GDMT uptitration(+) group leading to lower NT-proBNP levels at 1-year follow-up in that group (484 [238, 1261] versus 976 [411, 2088] pg/ml, p < 0.001). Similarly, both groups had temporal improvement in LV global longitudinal strain, but the magnitude of change was greater in the group with GDMT uptitration(+) group leading to better LV systolic function at 1-year follow-up in that group (Table 4). There was a similar magnitude of reduction in Doppler-derived LV filling pressure indices (lower E/e’) in both groups (Table 4). There was no difference in the safety indices (heart rate, systolic blood pressure, serum potassium, and estimated glomerular filtration rate) between the 2 groups (Table 4).
Table 4.
Baseline characteristics of patient with follow-up at 1 Year (N = 128).
| DATA OBTAINED AT INDEX HF ADMISSION | |||
|---|---|---|---|
| Δ GDMT score >0 |
Δ GDMT score ≤0 |
p | |
| (N = 49, 38%) | (N = 79, 62%) | ||
| Demographic indices | |||
| Age (years) | 46 ± 17 | 54 ± 16 | 0.09 |
| Male sex | 31 (63%) | 47 (60%) | 0.67 |
| CHD severity | |||
| Simple | 4 (8%) | 6 (8%) | 0.76 |
| moderate | 38 (78%) | 65 (82%) | |
| Complex | 7 (14%) | 8 (10%) | |
| Surgical/anatomic data | |||
| CIED implantation | 17 (35%) | 30 (38%) | 0.71 |
| Vital signs | |||
| Heart rate (BMP) | 82 ± 13 | 79 ± 10 | 0.35 |
| Systolic blood pressure (mmHg) | 124 ± 19 | 121 ± 16 | 0.29 |
| Laboratory indices | |||
| Serum potassium (mmol/l) | 4.4 ± 0.8 | 4.5 ± 0.7 | 0.83 |
| GFR (ml/min/1.73 m2) | 82 ± 24 | 79 ± 28 | 0.79 |
| MELD-XI | 10.9 (9.4, 15.6) | 11.4 (9.4, 16.2) | 0.46 |
| NT-proBNP (pg/ml) | 1886 (782, 3984) | 2018 (933, 4221) | 0.53 |
| Echocardiography | |||
| Lateral E/e’ | 11.6 ± 7.1 | 12.1 ± 5.9 | 0.83 |
| Medial E/e’ | 14.1 ± 8.2 | 14.8 ± 6.7 | 0.66 |
| LV ejection fraction (%) | 33 ± 8 | 31 ± 9 | 0.78 |
| LV global longitudinal strain (%) | −12.1 ± 2.9 | −11.4 ± 3.1 | 0.62 |
| ≥Mod mitral regurgitation | 6 (12%) | 11 (14%) | 0.78 |
| GDMT score | |||
| Baseline GDMT score | 2.47 ± 1.21 | 2.32 ± 1.19 | 0.22 |
| DATA OBTAINED AT 1-YEAR FOLLOW-UP | |||
| Δ GDMT score >0 | Δ GDMT score ≤0 |
p |
|
|
(N=49, 38%) |
(N=79, 62%) |
||
| Vital signs | |||
| Heart rate (BMP) | 68 ± 8 | 73 ± 10 | 0.46 |
| Systolic blood pressure (mmHg) | 118 ± 15 | 126 ± 19 | 0.19 |
| Laboratory indices | |||
| Serum potassium (mmol/l) | 4.6 ± 0.5 | 4.3 ± 0.4 | 0.37 |
| GFR (ml/min/1.73 m2) | 88 ± 31 | 85 ± 29 | 0.68 |
| MELD-XI | 10.2 (9.4, 14.3) | 10.8 (9.4.14.8) | 0.55 |
| NT-proBNP (pg/ml) | 784 (338, 1361)* | 1106 (652, 2088)* | <0.001 |
| Echocardiography | |||
| Lateral E/e’ | 9.2 ± 5.8* | 10.5 ± 5.4* | 0.22 |
| Medial E/e’ | 12.2 ± 5.9* | 12.9 ± 7.5* | 0.32 |
| LV ejection fraction (%) | 38 ± 9 | 34 ± 10 | 0.72 |
| LV global longitudinal strain (%) | −14.8 ± 3.6* | −12.9 ± 3.1* | 0.02 |
| ≥Mod mitral regurgitation | 5 (10%) | 9 (11%) | 0.94 |
Abbreviations: CHD: Congenital heart disease; CIED: Cardiac implantable electronic device; HF: Heart failure; GDMT: Guideline directed medical therapy; GFR: Glomerular filtration rate; MELD-XI: Model for end-stage liver disease excluding international normalized ratio; NT-proBNP: N terminal pro-b-type brain natriuretic peptide, LV: Left ventricle.
Footnote: Data were presented as mean ± standard deviation, median (Q, Q3), and count (%). * signifies a statistically significant change from values obtained baseline (index HF admission).
Compared to the GDMT uptitration(−) group, the GDMT uptitration(+) group had lower 10-year cumulative incidence HF readmission (21% versus 43%, p < 0.001), and lower 10-year cumulative incidence of mortality (24% versus 53%, p < 0.001) (Fig. 2). The was a 38% decrease in the risk of HF readmission (unadjusted HR 0.72, 95%CI 0.49, 0.94, p = 0.01) per 1-unit increase in Δ GDMT score, independent of baseline GDMT score. Similarly, the was a 31% decrease in risk of mortality (unadjusted HR 0.69, 95%CI 0.41, 0.92, p = 0.02) per 1-unit increase in Δ GDMT score, independent of the baseline GDMT score. The associations between Δ GDMT score and outcomes remained statistically significant on multivariable analysis (Table 5).
Fig. 2.
Kaplan-Meier curves showing cumulative incidence of HF readmission (A) and all-cause mortality (B). Abbreviations: HF: Heart failure; GDMT: Guideline directed medical therapy. Footnote: Δ GDMT score >0 signifies GDMT uptitration between hospital discharge and clinic visit at 1-year post discharge.
Table 5.
Multivariable cox regression models assessing prognostic performance of GDMT uptitration.
| Hazard ratio (95% confidence interval) for HF Readmission |
|||||
|---|---|---|---|---|---|
| Model A | Model B | Model C | Model D | Model E | |
| Baseline GDMT | 0.79 (0.57, 0.96) | 0.77 (0.58, 0.97) | 0.81 (0.56, 1.05) | 0.84 (0.51, 1.03) | 0.82 (0.46, 1.12) |
| Δ GDMT | 0.71 (0.48, 0.94) | 0.72 (0.51, 0.93) | 0.76 (0.54, 0.98) | 0.72 (0.49, 0.97) | 0.74 (0.49, 0.98) |
| Hazard ratio (95% confidence interval) for All-cause Mortality | |||||
|
Model A |
Model B |
Model C |
Model D |
Model E |
|
| Baseline GDMT | 0.75 (0.54, 0.97) | 0.76 (0.54, 0.99) | 0.78 (0.31, 1.06) | 0.72 (0.35, 1.14) | 0.84 (0.44, 1.26) |
| Δ GDMT | 0.69 (0.41, 0.92) | 0.68 (0.36, 0.94) | 0.66 (0.32, 0.97) | 0.65 (0.31, 0.98) | 0.69 (0.29, 1.02) |
Abbreviations: CHD: Congenital heart disease; GDMT: Guideline directed medical therapy; HF: Heart failure; MELD-XI: Model for end-stage liver disease excluding international normalized ratio; NT-proBNP: N terminal pro-b-type brain natriuretic peptide; RV: Right ventricle; LV: Left ventricle.
Footnote: Separate models were created for HF readmission and all-cause mortality.
Model A: Model adjusted for age and sex.
Model B: Model adjusted for age and sex AND CHD severity (mild vs moderate vs complex).
Model C: Model adjusted for age and sex AND comorbidities (atrial fibrillation, coronary artery disease, chronic kidney disease, hypertension, and diabetes), and pacemaker.
Model D: Model adjusted for age and sex AND echocardiographic indices (RV free wall strain, LV global longitudinal strain, tricuspid regurgitation, mitral regurgitation).
Model E: Model adjusted for age and sex AND biomarkers (NT-proBNP, MELD-XI score).
3.5. GDMT uptitration in the outpatient clinic (N = 49)
Among the 49 patients in the GDMT uptitration(+) group, the median interval from hospital discharge to first outpatient clinic visit #1 was 1.8 (1.1, 4.3) months, and the median number of outpatient clinic visits within the first-year post hospital discharge was 2 (1-4). Fig. 3 shows the GDMT scores hospital discharge, clinic visit #1 and 1-year clinic visit. The mean GDMT score at hospital discharge was not significantly different from the GDMT score at presentation to clinic visit #1 (2.47 ± 1.21 versus 2.49 ± 1.24, mean difference 0.02 [95%CI -0.17, 0.21]) suggesting lack of medication titration since hospital discharge. However, patients received medication titration during the visit leading to a higher GDMT score at the end of the visit (2.49 ± 1.24 versus 2.93 ± 1.35, mean difference 0.44 [95%CI -0.21, 0.66]).
Fig. 3.
Bar graph showing GDMT score at hospital discharge, Clinic Visit #1 (first outpatient clinic visit after index HF admission) and 1-Year Clinic Visit for the 49 patients who received GDMT uptitration.
Similarly, the mean GDMT score at the end of clinic visit #1 was not significantly different from the GDMT score at presentation to the 1-year clinic visit (2.93 ± 1.35 versus 3.01 ± 1.42, mean difference 0.08 [95%CI -0.14, 0.23]) suggesting lack of medication titration between clinic visits. The patients received medication titration during the visit leading to a higher GDMT score at the end of the visit (3.01 ± 1.42 versus 3.69 ± 1.63, mean difference 0.68 [95%CI 0.32, 0.97]).
4. Discussion
In this study, we assessed the prognostic role of GDMT after HF admission in adults with CHD presenting with HFrEF. The main findings are as follows: (i) A higher intensity of HF therapy, assessed using the GDMT score, was associated with lower risk of HF readmission, and mortality. (ii) Only 38% of the patients received GDMT uptitration during follow-up. We observed a 38% reduction in the risk of HF readmission, and 31% reduction in all-cause mortality, per 1-unit GDMT uptitration in GDMT. Similarly, the patients who received GDMT uptitration had a greater improvement in NT-proBNP levels and LV global longitudinal strain suggesting improvement in neuro-hormonal activation and LV systolic function. (iii) GDMT uptitration occurred only during clinic visits, without any GDMT titration between visits.
Although HF is the leading cause of mortality in adults with CHD, there are limited studies assessing the role of GDMT in this population, and the available results have shown inconsistent results [[18], [19], [20], [21], [22], [23]]. This is because these studies were based on a heterogeneous population (differences in ventricular morphology, ventricular systolic function, and/or definition of HF), and the lack of standardized criteria for assessing intensity of HF therapy in the different studies [[18], [19], [20], [21], [22], [23]]. The current study addressed these limitations by restricting the study population to CHD patients with HFrEF as well as using a standardized and validated score to assess GDMT optimization. The clinical benefits of GDMT (lower risk of HF readmission and mortality) observed in the current study is consistent with results of studies conducted in patients with HFrEF due to acquired disease [7,9]. In a multicenter study involving more than 41 thousand patients with HF admission due to acquired disease, Polsinelli et al. demonstrated an association between the intensity of GDMT (assessed using GDMT score) and clinical outcomes, whereby patients with higher GDMT score at hospital discharge had lower risk of HF readmission and mortality, as well as lower cost of healthcare [9]. In a multicenter randomized study (The Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies [STRONG-HF] study), Mebazza et al. demonstrated that GDMT uptitration (increase in the number and/or dosages of HF therapy) in patients with recent HF admission was associated with lower risk of HF readmission and mortality, independent of the baseline GDMT score at hospital discharge [7]. To the best of our knowledge, this is the first study to demonstrate the clinical benefits of GDMT optimization (higher dosage at hospital discharge, and dosage uptitration during follow-up) in adults with CHD with HFrEF and recent HF admission. This is consistent with a recent study demonstrating clinical benefit of GDMT in adults with CHD in the ambulatory setting [19]. In that study, Neijenhuis et al. demonstrated that CHD patients who were already on GDMT had a 3-fold reduction in HF admission following the initiation of sodium-glucose cotransporter-2 inhibitor (i.e., GDMT uptitration) [19]. The greater improvement in LV systolic function, as reflected by LV global longitudinal strain, and the larger reduction in NT-proBNP levels, reflecting decreased congestion and neurohormonal activation, among patients who underwent GDMT uptitration provide biological plausibility for the observed findings and suggest potential mechanisms underlying the lower rates of HF readmission and mortality in this group. There was also temporal reduction in echocardiographic indices of LV filling pressures at 1-year follow-up, consistent with improved congestion, although the magnitude of change was not different between the 2 groups.
4.1. Clinical implications and future directions
Despite carrying a diagnoses of HFrEF and a recent HF admission, only 42% of patient has had GDMT score of 3 or more, only 38% of the cohort had GDMT uptitration. The observed practice patterns highlight substantial gaps in the management of HF among patients with CHD, even at a high-volume tertiary referral center, underscoring a significant unmet need and the necessity for targeted interventions to improve care and outcomes.
The clinical benefits GDMT uptitration demonstrated in this study have potential clinical applications to address this unmet need. First, there should be a standardized protocol to guide GDMT uptitration from the time of hospital discharge with the aim of achieving the maximum tolerated GDMT dosage. Such a program should include a protocol for GDMT uptitration at home and not waiting until outpatient clinic visit similar to the pattern observed in the current study. Rapid GDMT uptitration has been shown to safe and effective in the STRONG-HF study, albeit based on a different population [7]. Second, early outpatient clinic visit should be encouraged as this will provide opportunity to assess medication compliance and an opportunity for GDMT uptitration. Of note, early outpatient clinic visit with 30 days following HF admission is associated with lower risk of HF readmission and mortality in adults with CHD [5].
4.2. Strengths and limitations
The strengths of the study include a well-defined patient population (CHD with morphologic LV and HFrEF), standardized criteria for assessment of GDMT intensity (GDMT score), and a long duration of follow-up. The study limitations include retrospective study design with inherent ascertainment bias, non-randomized treatment assignment (absence of standardized HF protocols), confounding by indication, and inability to ascertain compliance with medical therapy. The study cohort comprised patients who receive care at a single tertiary referral center, and may reflect the single center expertise that may differ from clinical practice in other centers. The study timeline spanned a period of 2 decades, during which there were significant changes in the management of HF including the introduction of new pharmacological agents. These temporal changes could have influenced the treatment patterns and outcomes observed in this study. Although we restricted the study cohort to patients with biventricular physiology and HFrEF, the study group included patients with different CHD complexity (simple, moderate, and complex CHD), and heterogeneous anatomy could have influenced the choice of GDMT and in turn, outcomes of the study. We did not perform subgroup analysis based on CHD complexity because of small sample size. The analysis of GDMT uptitration is restricted to patients who had a 1-year follow-up visit, which may introduce a selection bias, as the patients likely represent a healthier subset of the original cohort. Therefore, the observed association between GDMT optimization and outcomes cannot be interpreted causally.
5. Conclusions
GDMT optimization (higher GDMT use at hospital discharge as well as GDMT uptitration after discharge) was associated with lower risk of HF readmission and all-cause mortality. The patients who received GDMT uptitration had greater improvement in neurohormonal activation and LV systolic function, consistent with a lower risk of HF readmission and mortality in that group. However, only 38% of the cohort had GDMT uptitration suggesting opportunities for improvement. Further studies are required to determine whether strategies to improve GDMT optimization (rapid uptitration with close monitoring, and early outpatient follow-up after discharge) would improve clinical outcomes in this population.
Funding
Dr. Egbe is supported by National Heart, Lung, and Blood Institute (NHLBI) grants (R01 HL158517, R01 HL160761, and R01 HL162830). The MACHD Registry is supported by the Al-Bahar Research grant.
CRediT authorship contribution statement
Zeyad Kholeif: Writing – original draft, Writing – review & editing. Mohamed Ellabbad: Writing – original draft, Writing – review & editing. William R. Miranda: Writing – original draft, Writing – review & editing. Heidi M. Connolly: Writing – original draft, Writing – review & editing. Alexander C. Egbe: Writing – original draft, Writing – review & editing.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
None.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijcchd.2026.100689.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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