Abstract
Background
To describe the impact of clinical presentation among patients with aortic stenosis (AS) undergoing aortic valve replacement (AVR).
Methods
We analyzed a real-world dataset including patients from 29 US hospitals (egnite Database, egnite). Patients over 18 years old with moderate or greater AS undergoing AVR were included. Patients were classified into 3 groups according to the acuity and severity of clinical presentation prior to AVR: (i) asymptomatic, (ii) progressive signs and symptoms (progressive valve syndrome [PVS]), and (iii) acute or advanced signs and symptoms (acute valve syndrome [AVS]). Mortality and heart failure hospitalization after AVR were examined with Kaplan-Meier estimates, with results compared using the log-rank test.
Results
Among 2,009,607 patients in our database, 17,838 underwent AVR (78.6% transcatheter AVR, 21.4% surgical AVR). Age was 76.5 ± 9.7 years, and 40.2% were female. Prior to AVR, 2504 (14.0%) were asymptomatic, 6116 (34.3%) presented with PVS, and 9218 (51.7%) presented with AVS. At 2 years, the estimated rate of mortality for asymptomatic, PVS, and AVS were 5.8% (4.6%-7.0%), 7.6% (6.7%-8.4%), and 17.5% (16.5%-18.5%), respectively, and the estimated rate of hospitalization with heart failure for asymptomatic, PVS, and AVS were 11.1% (9.5%-12.6%), 19.0% (17.8%-20.2%), and 41.5% (40.2%-42.8%), respectively. After adjustment, patients presenting with AVS had increased risk of mortality after AVR (hazard ratio, 2.2; 95% CI, 1.8-2.6).
Conclusions
From a large, real-world database of patients undergoing AVR for AS, most patients presented with AVS, which was associated with an increased risk of mortality and heart failure hospitalization.
Graphical abstract
Two-year mortality or hospitalization with heart failure after aortic valve replacement (AVR) for aortic stenosis per initial clinical presentation. From the egnite database, 17,838 patients with aortic stenosis underwent AVR. Patients were classified in 3 groups according to their clinical presentation pre-AVR. Before AVR, 14% were asymptomatic, 34.3% presented with progressive symptoms or progressive valve syndrome (PVS), and 51.7% presented with acute valve syndrome (AVS). Two-year mortality or hospitalization with heart failure post-AVR was the lowest in asymptomatic patients (14.9%) and increased with the severity and acuity of clinical presentation pre-AVR: PVS 23% and AVS 47.3%.
Highlights
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Seventeen thousand eight hundred thirty-eight patients with aortic stenosis underwent aortic valve replacement (AVR).
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Patients were classified into 3 groups according to their clinical presentation pre-AVR.
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Asymptomatic (14%), progressive valve syndrome (PVS; 34.3%), and acute valve syndrome (AVS; 51.7%).
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Two-year death post-AVR per presentation: asymptomatic 5.8%, PVS 7.6%, and AVS 17.5%.
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Two-year heart failure hospitalization: asymptomatic 11.1%, PVS 19.0%, and AVS 41.5%.
Aortic stenosis (AS) is a progressive disease characterized by periods of latency and variable evolution. Clinically, patients often present with no symptoms, especially in the early phase of the disease, and as valve degeneration and cardiac damage progress, a variety of symptoms and clinical manifestations occur. While some patients experience slow progression and develop mild symptoms such as fatigue and dyspnea, others present with a more unpredictable course, with more dramatic manifestations such as acute heart failure, syncope, shock, and even sudden death. Appropriate classification and characterization of these different clinical presentations is important, both for prognosis and therapeutic purposes. In the current manuscript, we explored the patterns of clinical presentation of AS among patients undergoing aortic valve replacement (AVR), and we propose a new classification related to the severity and acuity of the clinical presentation of AS: asymptomatic (no signs or symptoms), progressive signs or symptoms (progressive valve syndrome [PVS], and acute or advanced signs or symptoms (acute valve syndrome [AVS]). We evaluated the relationship of these classifications with outcome during the 2 years after AVR.
Methods
The study population was drawn from 2,009,607 patients from 29 US institutions in the egnite Database (egnite) with appropriate permissions. Data were prepared for the present study following initial data quality assessments by a clinical team and evaluated for study inclusion and exclusion criteria. Key inclusion criteria included a documented diagnosis of moderate or greater AS per natural language processing (NLP)-based analysis of echocardiographic report(s), record of AVR procedure (which served as the study index date for purposes of this study), time from index date to censoring date >0 days, and ≥18 years of age at index. Patients were censored at date of last encounter within the health system or date of death. Key exclusion criteria included documented diagnosis of moderate or greater aortic regurgitation, AVR with missing date or prior to January 1, 2018 (for data quality purposes), and missing date of birth.
The resulting population was stratified into 3 cohorts based on severity and acuity of clinical presentation prior to AVR: (i) asymptomatic, with no signs or symptoms, (ii) progressive signs or symptoms of AS (PVS), such as New York Heart Association (NYHA) class II (dyspnea, fatigue, angina, or dizziness), diagnosed diastolic heart failure, edema, or elevated B-type natriuretic peptide (BNP) (100 < BNP < 400 pg/mL and/or 1000 pg/mL < N-terminal pro-B-type natriuretic peptide [NT-proBNP] < 1500 pg/mL), and (iii) acute or advanced signs and symptoms of AS (AVS), such as NYHA classes III-IV (any of hospitalization with heart failure, pulmonary edema, and syncope), left ventricle ejection fraction <50%, systolic heart failure, elevated BNP (BNP ≥400 pg/mL and/or NT-proBNP ≥1500 pg/mL), new-onset atrial fibrillation, hypotension, cardiogenic shock, new-onset ventricular arrhythmia, endocarditis, and resuscitation from cardiac arrest.
Patients were classified in one group based on the presence of ≥1 of the higher specified signs or symptoms, irrespective of the presence of other lesser signs or symptoms from the lower severity group. Patients were allocated to a specific cohort according to a 6-month lookback from the day before the index AVR.
Patients with AS were also classified according to AS severity (moderate, moderate-to-severe, and severe) per the documented diagnosis of AS in echocardiographic reports generated in the context of usual clinical practice. All available echocardiograms documented for a given patient were used to grade AS severity, and in the event of more than one available diagnosis, the date of the report with the first most severe documented diagnosis was used. Information on prespecified patient characteristics of interest was extracted as defined in Supplemental Table 1 , with symptoms, acuity/severity of clinical presentation, comorbidity history, and treatment events identified according to relevant International Classification of Diseases, 10th Revision (ICD-10) codes, lab values, and/or echocardiographic report data documented in the 6 months lookback from index AVR, with definitions adjudicated by a clinical reviewer as well as a medical coding expert where relevant. Both the presence and severity of valve disease were derived from echocardiographic reports using a clinically reviewed and verified NLP algorithm (via random deidentified sampling exercise of 8000 echocardiographic reports) with an overall accuracy of >99% ( Supplemental Table 2 ). NYHA II was defined by the presence of any of the following ICD-10 codes pre-AVR: dyspnea, dizziness, angina, and fatigue. NYHA III-IV was defined by the presence of any of the following ICD-10 codes pre-AVR: admission with heart failure, pulmonary edema, or syncope.
Two-year outcomes were evaluated using Kaplan-Meier (KM) estimates. The primary endpoint was all-cause mortality, where patients were censored at last clinical encounter. Information on patient death was extracted from medical records and reflects health care system/sites understanding of patient’s mortality. Secondary end points were hospitalization with heart failure and the composite of all-cause mortality or hospitalization with heart failure.
Statistical Analysis
Patient characteristics were reported either as n (%) for categorical variables or as mean (SD) or median (interquartile range) for continuous variables as appropriate. KM estimates for all-cause mortality, hospitalization with heart failure, and the composite of all-cause mortality or hospitalization with heart failure post-AVR were reported per clinical presentation groups. Multivariable hazards analysis (Cox proportional hazards regression) was performed to simultaneously assess risk factors of interest for mortality, hospitalization with heart failure, and the composite of mortality or hospitalization with heart failure. A complete sensitivity analysis was also performed in which patients were allocated to cohorts according to a 12-month lookback from index AVR for presentation characteristics of interest. Unless otherwise stated, a p-value <0.05 was considered statistically significant, but with Bonferroni corrections for multiple comparisons. Analyses were completed using the following or greater: DataBricks 13.3 LTS; Apache Spark 3.4.1; Scala 2.12; R version 4.2.2; R survival package 3.5.3.
Results
Study Population
Among a total of 2,009,607 patients with available echocardiographic reports and available clinical information, 17,838 underwent AVR (78.6% transcatheter, 21.4% surgical) for ≥moderate AS ( Figure 1 ). Mean age was 76.5 ± 9.7 years, and 40.2% were female. At time of AVR, 2504 (14.0%) were asymptomatic, 6116 (34.3%) had PVS, and 9218 (51.7%) presented with AVS. The detailed lists of signs and symptoms included under each mode of presentation are shown in Table 1 . Baseline characteristics per mode of clinical presentation are shown in Table 2 . In general, patients presenting with AVS before AVR were older, more often male, had more comorbidities such as diabetes, coronary artery disease, and prior percutaneous revascularization, and presented more often with concomitant valve disease such as moderate or greater mitral or tricuspid valve regurgitation compared with asymptomatic patients or patients with PVS. Patients with AVS also had lower aortic valve peak velocity, lower mean gradient, and lower left ventricle ejection fraction before AVR.
| Clinical presentation | N = 17,838 |
|---|---|
| No signs or symptoms | 2504 (14.0%) |
| Progressive valve syndrome (PVS) | 6116 (34.3%) |
| New York Heart Association class II ∗ | 4575 (74.8%) |
| Dyspnea | 3999 (65.4%) |
| Diastolic heart failure | 2997 (49%) |
| Fatigue | 870 (14.2%) |
| Edema | 630 (10.3%) |
| Elevated natriuretic peptide † | 529 (8.6%) |
| Dizziness | 488 (8%) |
| Angina | 446 (7.3%) |
| Acute or advanced valve syndrome (AVS) | 9218 (51.7%) |
| New York Heart Association class III-IV ‡ | 5918 (64.6%) |
| Admission with heart failure | 4651 (50.5%) |
| Left ventricle ejection fraction <50% (echocardiography) | 3307 (35.9%) |
| Systolic heart failure | 3212 (34.8%) |
| High natriuretic peptide § | 2227 (24.2%) |
| New-onset atrial fibrillation | 1943 (21.1%) |
| Syncope | 1494 (16.2%) |
| Hypotension | 1295 (14%) |
| Pulmonary edema | 1049 (11.4%) |
| Cardiogenic shock | 357 (3.9%) |
| New-onset ventricular arrhythmia | 329 (3.6%) |
| Endocarditis | 76 (0.8%) |
| Resuscitation from cardiac arrest | 39 (0.4%) |
∗ Any of dyspnea, dizziness, angina, and fatigue.
† Defined as 100 pg/mL < BNP < 400 pg/mL and/or 1000 pg/mL < NT-proBNP < 1500 pg/mL.
‡ Any of admission with heart failure, pulmonary edema, or syncope.
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