ABSTRACT
Background
Results of observational studies assessing clinical benefits of guideline-directed medical therapy (GDMT) for heart failure (HF) in adults with congenital heart disease are conflicting. This is because these studies were based on a heterogenous population and lacked standardized criteria for assessing adequacy of HF therapy across studies. The current study addressed these limitations by studying the effect of GDMT (using a standardized GDMT score) in adults with repaired systemic biventricular congenital heart disease, systemic left ventricle, and HF with reduced ejection fraction.
Methods
HF with reduced ejection fraction was defined as stage B/C HF and systemic left ventricular EF < 50%. GDMT score was assessed at baseline encounter (baseline GDMT score) and 1-year follow-up. GDMT uptitration was calculated as defined as ∆GDMT (∆=delta or change in) score from baseline. Cox regression was used to assess the relationship between HF therapy (baseline and ∆GDMT score) and outcomes (HF hospitalization and mortality).
Results
Of 778 patients, baseline and ∆GDMT scores were 2 (1, 3) and 0.56 (0.49, 0.62), respectively. Of 778, only 258 (33%) had GDMT uptitration (∆GDMT score >0). Higher use of GDMT at baseline (adjusted hazard ratio [HR] per 1 point increase in GDMT score 0.83, 95% confidence interval [CI] 0.74, 0.92, P <.001), and increased use of GDMT over time (adjusted HR for 1 point increase in ∆GDMT score HR 0.71, 95% CI 0.62, 0.82, P <.001) were associated with lower risk of HF hospitalization. Higher baseline GDMT score (adjusted HR 0.87, 95% CI 0.76, 0.98, P =.01), and ∆GDMT score (adjusted HR 0.84, 95% CI 0.72, 0.86, P =.002) were also associated with lower mortality.
Conclusions
GDMT use at baseline, and GDMT uptitration were associated with improved outcomes and suggest a dose-dependent relationship between use of GDMT and risk of adverse outcomes. Furthermore, 67% of patients did not receive GDMT uptitration, suggesting suboptimal therapy and opportunities for improvement.
Abbreviations
CHD, Congenital heart disease; CIED, Cardiac implantable electronic devices; CI, Confidence interval; GDMT, Guideline directed medical therapy; HF, Heart failure hospitalization; HFrEF, Heart failure with reduced ejection fraction; HR, Hazard ratio; LV, Left ventricle; RV, Right ventricle; NT-proBNP, N-terminal pro-b-type brain natriuretic peptide; SGLT2i, Sodium-glucose cotransporter-2 inhibitor.
Key Points
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GDMT use was associated with lower risk of HF hospitalization mortality.
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Higher GDMT score was associated with greater clinical benefits.
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This suggests a dose-dependent relationship between the GDMT andoutcomes.
Background
There has been significant improvements in the medical and surgical management of adults with congenital heart disease (CHD), leading to improvements in long-term outcomes of this population. , However, in spite of these improvements, the life expectancy of adults with CHD remain significantly lower than the general population, and heart failure (HF) is the leading cause of mortality in this population. ,,,, The etiology of HF in CHD is multifactorial, and includes structural heart disease (valvular heart disease and baffle/conduit dysfunction), rhythm abnormalities (atrial or ventricular arrhythmias and conduction system disease), and arteriosclerotic cardiovascular disease. , The management of HF in CHD centers on early detection and treatment of these underlying etiologies to prevent (and possibly reverse) ventricular dysfunction. , Unfortunately, some patients develop progressive ventricular systolic and/or diastolic dysfunction despite these interventions, and this in turn, is associated with HF hospitalization and mortality. ,,,
In the acquired HF population, HF is broadly classified based on left ventricular (LV) ejection fraction (EF) as HF with reduced EF (HFrEF), and HF with preserved EF. , This classification has important clinical implications since the clinical benefits of HF therapy are greater in patients with HFrEF compared to those with preserved EF. ,,,,, Based on robust empirical data from multiple clinical trials, the guidelines for the management of HF recommend the use of these therapies in patients with HFrEF, and hence the term “guideline-directed medical therapy” (GDMT). ,,,,, The definition of GDMT has evolved over time as new therapies become available, and this makes it difficult to compare outcomes across studies. ,, The GDMT score, also referred to as the HF Collaboratory score, was developed to address this problem, by providing a standardized framework to assess intensity of HF therapy and enable comparison of outcomes across different studies. ,,
Adults with CHD were excluded from the landmark clinical trials that form the basis for GDMT recommendation, and hence there are no large-scale clinical trials assessing the efficacy of GDMT in this population. ,,, While several observational studies have assessed the efficacy of GDMT in adults with CHD, the clinical benefits of GDMT have not been consistent across studies. ,,,,,,, This is because these studies were based on a heterogeneous population (differences in ventricular morphology, differences in ventricular systolic function, and differences in the definition of HF), and the lack of standardized criteria for assessing intensity of HF therapy in the different studies. ,,,,,,, The current study aims to address these limitations by studying the effect of GDMT (using the standardized GDMT score) on well-defined cohort of CHD patients with HFrEF. We hypothesized that higher GDMT score was associated with lower risk of HF hospitalization and mortality in adults with CHD and HFrEF.
Methods
Study population
This is a retrospective cohort study of adults (age ≥18 years) with CHD, biventricular physiology with systemic LV, and LVEF < 50% who had >1 year of follow-up at Mayo Clinic from January 1, 2003, to December 31, 2023. The patients were identified through the Mayo Adults CHD registry. We excluded patients with Fontan physiology, congenitally corrected transposition of great arteries, d-transposition of great arteries status post atrial switch operation, and patients with unrepaired/palliated cyanotic CHD.
Definition of HFrEF
We defined HFrEF as stage B or C HF and LVEF < 50%, based on the echocardiogram performed during the first outpatient evaluation in the adult CHD clinic after January 1, 2003 (baseline encounter). Stage B HF was defined as presence of structural heart disease such as reduced LVEF without current or prior history of HF symptoms while stage C HF was defined as the presence of structural heart disease such as reduced LVEF with current or prior history of HF symptoms. , We subdivided the study group into patients with baseline LVEF ≤ 40% (HFrEF_mod/severe) vs patients with LVEF 41% to 49% (HFrEF_mild).
While the patients with LVEF ≥ 50% were excluded from the study, they were used as a reference group in estimating the incidence of HF hospitalization.
GDMT score
The HF medications and point system used for calculating GDMT score are shown in Table I . ,, While the original GDMT score included medications such as hydralazine, isosorbide dinitrate, and ivabradine, these medications were excluded from the GDMT score in the current study because these medications were not routinely used for the treatment of HF in our clinical practice. ,,
Table I
GDMT score.
| Drug class | Dose | Points |
|---|---|---|
| Beta blockers | ||
| None | 0 | |
| <50% maximum dose | 1 | |
| ≥50% maximum dose | 2 | |
| ACEI/ARB/ARNI | ||
| None | 0 | |
| <50% maximum dose | 1 | |
| ≥50% maximum dose | 2 | |
| Any ARNI dose | 3 | |
| MRA | ||
| None | 0 | |
| Any dose | 2 | |
| SGLT2i | ||
| None | 0 | |
| Any dose | 1 | |
| Maximum score | 8 |
ACEI/ARB/ARNI , angiotensin converting enzyme inhibitor/angiotensin 2 receptor blocker/angiotensin receptor/neprilysin inhibitor; GDMT , guideline-directed medical therapy; MRA , mineralocorticoid receptor antagonist; SGLT2i , sodium-glucose cotransporter-2 inhibitor.
We calculated the GDMT score at baseline encounter (baseline GDMT score) and at 1-year follow-up using each patient’s medication list at these clinical encounters. We assessed GDMT uptitration (∆GDMT score) (∆=delta or change in) as the difference between GDMT score at baseline and 1-year encounters. This was calculated as follows: ∆GDMT score = GDMT score at 1-year follow-up minus GDMT score at baseline encounter, whereby a ∆GDMT score >0 signified GDMT uptitration.
Outcomes
The primary outcome was HF hospitalization, defined as hospital admission for volume overload requiring intravenous diuretics, and the secondary outcome was all-cause mortality ascertained by review of medical records and the Accurint mortality database. HF hospitalization and all-cause mortality were assessed as time-to-event outcomes and ascertain from 1-year follow-up (time zero) until outcome of interest, last clinical encounter, or December 31, 2023.
Statistical analysis
Data were presented as mean ± standard deviation, median (Q, Q3), and count (%). Between-group comparisons were based on Fisher’s exact test, analysis of variance test, or Wilcoxon rank sum test, as appropriate. Cumulative incidence of HF hospitalization was assessed using Kaplan–Meier analysis, and between-group comparisons were based on log-rank test. Cox regression analysis was used to assess the relationship between GDMT use and titration with risks of HF hospitalization and all-cause mortality. The variables used in the univariable models were selected based on clinical relevance and included GDMT score, cardiac implantable electronic devices (CIED) at baseline encounter (ie, pacemaker or defibrillator), LV systolic dysfunction (HFrEF_mod/severe vs HFrEF_mild), echocardiographic indices, demographic indices, CHD severity, and comorbidities. Variables with P <.1 on univariable analyses were used to create the multivariable model, and the final variable selection was based on stepwise backwards selection, with P <.1 as a criterion for a variable to remain in the model. Separate models were created in the subgroup of patients with biomarker data (both N-terminal pro-b-type brain natriuretic peptide and model for end-stage liver disease, excluding international normalized ratio), and patients with cardiac catheterization data. Subgroup analysis was performed in patients with vs without CIED. All statistical analyses were performed with BlueSky Statistics software (version 7.10; BlueSky Statistics LLC, Chicago, IL), and JMP statistical software (version 17.1.0, JMP Statistical Discovery LLC, NC). P -value <.05 was considered to be statistically significant for all analyses.
Results
Baseline characteristics
Of 7,981 patients with biventricular physiology and systemic LV, 778 (10%) presented with HFrEF at baseline encounter, of which 451 had HFrEF_mild, and 327 had HFrEF_mod/severe. Among the 778 patients with HFrEF, 524 (67%) presented with stage B HF, while 254 (33%) presented with stage C HF. The underlying CHD diagnoses are shown in Supplementary Table SI.
Table II shows a comparison of baseline clinical and hemodynamic characteristics of the patients with HFrEF using the patients with preserved LVEF ( N = 7,203) as the reference group. Among the patients with HFrEF, those with HFrEF_mod/severe were older, more likely to have chronic kidney disease, and had higher MELD-XI score and N-terminal pro-b-type brain natriuretic peptide levels compared to the patients with HFrEF_mild ( Table II ). Similarly, the HFrEF_mod/severe group also had worse left atrial function, larger LV volumes, worse right atrial function, worse right ventricular (RV) systolic function, and higher pulmonary artery mean pressure and wedge pressure ( Table II ).
Table II
Baseline characteristics.
| pEF ( N = 7,203, 90%) | HFrEF_mod/severe ( N = 451, 6%) | HFrEF_mild ( N = 327, 4%) | P | |
|---|---|---|---|---|
| Demographic indices | ||||
| Age (y) | 39 ± 16 | 43 ± 17* | 46 ± 16* | <.001 |
| Male sex | 3,390 (47%) | 277 (61%) | 203 (62%) | <.001 |
| Body mass index (kg/m 2) | 27.2 ± 7.1 | 26.7 ± 5.6 | 27.9 ± 7.3 | .22 |
| CHD severity | <.001 | |||
| Mild | 1,925 (27%) | 80 (18%) | 76 (23%) | |
| moderate | 4,877 (68%) | 329 (73%) | 215 (66%) | |
| Complex | 401 (6%) | 42 (9%) | 36 (11%) | |
| Surgical/anatomic data | ||||
| # prior sternotomies | 2.2 ± 0.7 | 3.2 ± 0.8 | 3.1 ± 0.7 | <.001 |
| Pacemaker implantation | 322 (5%) | 57 (13%) | 50 (15%) | <.001 |
| LVOT disease | 1,080 (15%) | 68 (15%) | 66 (20%) | .04 |
| Comorbidities | ||||
| Hypertension | 1,757 (24%) | 135 (30%) | 118 (36%) | <.001 |
| Coronary artery disease | 347 (5%) | 48 (11%) | 46 (14%) | <.001 |
| Diabetes | 479 (7%) | 37 (8%) | 39 (12%) | .002 |
| Hyperlipidemia | 1,536 (21%) | 110 (24%) | 94 (29%) | .003 |
| Chronic kidney disease III-V | 287 (4%) | 35 (8%)* | 44 (14%)* | <.001 |
| Atrial fibrillation | 944 (13%) | 132 (29%) | 97 (30%) | <.001 |
| Atrial flutter/tachycardia | 640 (9%) | 74 (16%) | 55 (17%) | <.001 |
| Laboratory indices | ||||
| GFR (mL/min/1.73 m 2) | 95 (78; 111) | 89 (72; 105) | 81 (55; 81) | <.001 |
| MELD-XI | 9.44 (9.44; 10.78) | 9.44 (9.44; 11.78)* | 11.16 (9.44; 14.29)* | <.001 |
| NT-proBNP (pg/mL) | 182 (77; 508) | 410 (147; 1,070)* | 768 (282; 2,393)* | <.001 |
| Echocardiographic data | ||||
| Systemic indices | ||||
| LA reservoir strain (mL/m 2) | 34 ± 11 | 25 ± 10* | 19 ± 11* | <.001 |
| LV end-diastolic volume (mL/m 2) | 51 (42; 62) | 57 (45; 73)* | 83 (58; 108)* | <.001 |
| LV end-systolic volume (mL/m 2) | 20 (16; 25) | 29 (21; 38)* | 54 (35; 72)* | <.001 |
| LV ejection fraction (%) | 62 ± 5 | 45 ± 3* | 31 ± 6* | <.001 |
| LV longitudinal strain (%) | –21 ± 3 | –16 ± 3* | –12 ± 3* | <.001 |
| ≥Mod mitral regurgitation | 297 (4%) | 30 (7%) | 39 (12%) | <.001 |
| ≥Mod aortic regurgitation | 440 (6%) | 28 (6%) | 27 (8%) | .32 |
| Aortic mean gradient (mmHg) | 6 (3; 18) | 5 (2; 13) | 6 (3; 20) | .11 |
| Cardiac index (L/min/m 2) | 2.91 (2.52; 3.58) | 2.69 (2.31; 3.51) | 2.70 (2.34; 3.51) | <.001 |
| Nonsystemic indices | ||||
| RA reservoir strain (%) | 32 (23; 43) | 22 (15; 31)* | 18 (11; 31)* | <.001 |
| RA mean pressure (mmHg) | 5 (5; 10) | 5 (5; 10) | 5 (5; 15) | <.001 |
| RV systolic pressure (mmHg) | 33 (28; 43) | 38 (30; 49) | 43 (34; 59) | <.001 |
| RV free wall strain (%) | –25 (21; 28) | –21 (16; 25)* | –18 (13; 25)* | <.001 |
| ≥Mod tricuspid regurgitation | 1,257 (18%) | 129 (27%) | 93 (28%) | <.001 |
| Cardiac catheterization data | ||||
| RA mean pressure (mmHg) | 8 (6; 12) | 11 (8; 15) | 12 (8; 17) | <.001 |
| PA mean pressure (mmHg) | 22 (17; 30) | 24 (19; 37)* | 28 (222; 39)* | <.001 |
| PA wedge pressure (mmHg) | 12 (9; 16) | 14 (10; 18)* | 16 (12; 21)* | <.001 |
| Cardiac index (L/min/m 2) | 2.41 (2.08; 3.12) | 2.29 (1.89; 2.94) | 2.10 (1.78, 2.59) | .003 |
| PVR index (wu·m 2) | 3.46 (2.07; 5.79) | 5.31 (3.12; 7.98) | 4.49 (3.07, 7.99) | .004 |
Data were presented as mean, standard deviation, median (Q; Q3), and count (%). Between-group comparisons were based on Fisher’s exact test, analysis of variance test, or Wilcoxon rank sum test, as appropriate.
*Signifies statistically significant difference for pairwise comparison between HFrEF_mild vs HFrEF_mod/severe groups.
CHD , congenital heart disease; GFR , glomerular filtration rate; HFrEF , heart failure with reduced ejection fraction; LA , left atrium; LV , left ventricle; MELD-XI , model for end-stage liver disease excluding international normalized ratio; NT-proBNP , N-terminal pro-b-type brain natriuretic peptide; PA , pulmonary artery; pEF , preserved ejection fraction; PVR , pulmonary vascular resistance; RA , right atrium; RV , right ventricle.
GDMT score
Table III shows the HF medications at baseline encounter. The most common HF medications were beta blockers ( N = 361, 46%) and angiotensin converting enzyme inhibitor/angiotensin 2 receptor blocker ( N = 322, 41%). The mean and median GDMT score at baseline encounter were 2.2 ± 1.2 and 2 (1, 3), respectively. The HFrEF_mod/severe group had a higher baseline GDMT score (mean 2.4 ± 1.3 vs 2.1 ± 1.1, P <.001; median 2 [1, 3] vs 2 [1; 3], P =.001) compared to the HFrEF_mild group.
Table III
GDMT at baseline encounter.
| All | HFrEF_mod/severe ( N = 451) | HFrEF_mild ( N = 327) | P | |
|---|---|---|---|---|
| Medications | ||||
| Beta blockers | 361 (46%) | 198 (44%) | 163 (50%) | .10 |
| ACEI/ARB | 322 (41%) | 173 (38%) | 149 (46%) | .04 |
| ARNI | 68 (9%) | 26 (6%) | 42 (13%) | <.001 |
| MRA | 97 (13%) | 46 (10%) | 51 (16%) | .03 |
| SGLT2i | 77 (10%) | 34 (8%) | 43 (13%) | .01 |
| GDMT score | <.001 | |||
| 1 | 263 (34%) | 167 (37%) | 96 (29%) | |
| 2 | 238 (31%) | 140 (31%) | 98 (30%) | |
| 3 | 174 (22%) | 101 (22%) | 73 (22%) | |
| 4 | 67 (9%) | 32 (7%) | 35 (11%) | |
| 5 | 30 (4%) | 11 (2%) | 19 (6%) | |
| 6 | 6 (0.8%) | 0 | 6 (2%) |
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