Although transcatheter aortic valve replacement (TAVR) has expanded the proportion of patients with aortic stenosis (AS) who are candidates for valve replacement, some patients remain untreated, and their outcomes are not clear. We evaluated 172 consecutive patients with severe symptomatic AS referred for TAVR who declined (n = 55) or were not candidates for (n = 117) intervention. We examined clinical and echocardiographic variables associated with mortality. There were 77 deaths, and mean follow-up was 17.9 ± 10.9 months for survivors. Mortality rate at 1 and 2 years was 39.2% and 52.6%, respectively. There was a significant difference in mortality rate between patients who declined the procedure and those who were not candidates (p = 0.001), with 1-year mortality rates of 20.6% and 48.4%, respectively. On multivariate analysis, 4 variables were independently associated with all-cause mortality: New York Heart Association Class IV heart failure (hazard ratio [HR] 2.6, 95% confidence interval [CI] 1.6 to 4.2, p <0.001), glomerular filtration rate <48 ml/min (HR 2.1, 95% CI 1.3 to 3.4, p = 0.002), albumin <3.9 g/dl (HR 1.9, 95% CI 1.2 to 3.1, p = 0.007), and ejection fraction <50% (HR 1.9, 95% CI 1.4 to 3.0, p = 0.01). In this new era with expanded treatment options, patients with severe symptomatic AS who remain untreated after referral for TAVR experience a mortality rate of 39% at 1 year. The presence of advanced heart failure, renal dysfunction, low albumin, and/or left ventricular dysfunction identifies patients at higher risk of mortality.
Aortic stenosis (AS) is a common valvular disorder, and patients with untreated severe AS experience high rates of mortality. Although surgical aortic valve replacement (SAVR) was once the only definitive treatment option, transcatheter aortic valve replacement (TAVR) has become an alternative for many patients and may permit treatment in patients at high or prohibitive risk for SAVR or in patients who decline SAVR. Recent data from a controlled clinical trial suggest that patients at prohibitive surgical risk randomized to nonsurgical treatment experience a mortality rate of >50% at 1 year. However, the natural history of a general population with severe symptomatic AS who do not undergo TAVR or SAVR is not established in this new era. We evaluated rates and predictors of mortality in a cohort of patients with severe symptomatic AS referred for TAVR but who remained untreated.
Methods
This study evaluated consecutive patients referred for possible TAVR at a single institution. Inclusion criteria included adults aged ≥18 years, severe AS defined by valve appearance consistent with severe stenosis plus an effective orifice area (EOA) <1.0 cm 2 and/or an indexed EOA <0.6 cm 2 /m 2 by transthoracic echocardiography (TTE), symptoms attributed to AS by a TAVR clinic physician, complete TTE study, subjects not enrolled in a clinical trial, and no TAVR or SAVR procedure. A total of 629 adult patients with severe symptomatic AS were seen in the TAVR clinic. Of these, TAVR was performed in 320 cases, SAVR was performed in 115 cases, and 194 cases remained untreated. Of the 194 untreated patients meeting these inclusion criteria, 19 died while being evaluated for TAVR, and 3 were excluded because of <3 months of follow-up; the final study population was 172 patients. At the study institution, patients were evaluated for both approved and investigational indications for TAVR, and TAVRs were performed using both self-expanding and balloon-expandable devices. All patients referred for TAVR were presented at a multidisciplinary team that included cardiothoracic surgeons, interventional cardiologists, and cardiac imagers. All patients evaluated for SAVR were presented with the option of referral for TAVR if the patient was a potential candidate. Conversely, all patients evaluated for TAVR who were possible candidates for SAVR were presented with this option. All patients with other diseases that may have contributed to their symptoms were considered for appropriate workup or referral. The study was approved by the institutional review board and was granted a waiver of informed consent.
Clinical data were abstracted from electronic chart review. All patients had at least 1 detailed history and physical examination by a physician in the specialty TAVR clinic. All-cause mortality was assessed using the social security death index. The Society of Thoracic Surgery (STS) score for expected operative mortality at 30 days was calculated with an online calculator (version 2.81).
Echocardiography with Doppler was performed for clinical indications. TTE performance followed recommended standardized guidelines and included comprehensive study of all cardiac structures including a thorough examination of the aortic valve using all available windows for Doppler interrogation and use of a Piedoff probe when appropriate. Echocardiograms were performed using Philips iE33 (Philips Healthcare, Andover, Massachusetts) or Accuson Sequoia 512 (Siemens, Malvern, Pennsylvania) systems and were archived in standard Digital Imaging and Communications in Medicine format. Images were reviewed and analyzed using Synapse Cardiovascular Client version 4.08 (Fujifilm Medical Systems, Valhalla, New York). TTE studies were interpreted by a blinded, experienced, board-certified cardiologist. All measurements were performed according to societal guidelines.
Comparisons were performed using the chi-square tests for categorical variables and t tests or Mann–Whitney U tests for continuous variables. Cox regression, Kaplan–Meier curves, and log-rank tests were used to compare outcomes on univariate analyses. To determine variables independently associated with mortality, a multivariate Cox regression analysis was performed that included age, gender, and variables with a p <0.05 on univariate analysis. Median values of laboratory tests were used as cutpoints. p Values <0.05 were considered significant. Statistical analyses were performed using IBM SPSS (version 20, SPSS) for Macintosh (IBM Corporation; Armonk, New York).
Results
The final study population consisted of 172 subjects and included 55 patients who declined TAVR and/or SAVR, and 117 subjects who were deemed not to be candidates for either procedure. Mortality events occurred in 44.8% (77 of 172) of patients, and mean follow-up was 17.9 ± 10.9 months for survivors. Mortality was observed in 39.2% at 1 year and 52.6% at 2 years.
Baseline patient and echocardiographic characteristics are provided in Tables 1 and 2 . Patients who declined any procedure (vs patients who were not a candidate for either procedure) were older and had lower rates of New York Heart Association Class IV symptoms (p = 0.01), with no other significant differences between baseline clinical and echocardiographic characteristics.
| Variable | Overall (n=172) | Patient Declined (n=55) | Not Candidate (n=117) | p |
|---|---|---|---|---|
| Mean age (years) | 79.6 ±9.9 | 82.4 ±8.3 | 78.3 ±10.4 | 0.01 |
| Male | 52% | 51% | 52% | 0.88 |
| Body Mass Index (kg/m2) | 28.3 ± 7.3 | 28.3 ± 7.4 | 28.3 ± 7.2 | 0.98 |
| Hypertension | 95% | 95% | 96% | 0.73 |
| Hyperlipidemia | 76% | 75% | 76% | 0.83 |
| Current smoker | 12% | 11% | 13% | 0.71 |
| Diabetes mellitus | 33% | 35% | 32% | 0.70 |
| Prior myocardial infarction | 28% | 20% | 32% | 0.11 |
| Coronary artery disease | 61% | 63% | 61% | 0.78 |
| Coronary revascularization | 47% | 49% | 45% | 0.64 |
| Lung disease | 35% | 35% | 35% | 0.95 |
| Home oxygen | 19% | 16% | 20% | 0.61 |
| Atrial fibrillation/flutter | 40% | 40% | 39% | 0.93 |
| Prior stroke/TIA | 22% | 27% | 20% | 0.26 |
| Angina pectoris | 19% | 13% | 21% | 0.17 |
| NYHA Class, median | III (III-IV) | III (III-III) | III (III-IV) | 0.03 |
| I | 9% | 9% | 9% | |
| II | 13% | 11% | 15% | |
| III | 47% | 62% | 39% | |
| IV | 31% | 18% | 38% | |
| Hemoglobin (g/dL) | 11.7 ±2.0 | 11.9 ±1.9 | 11.6 ±2.0 | 0.41 |
| Albumin (g/dL) | 3.9 ± 0.5 | 4.0 ± 0.5 | 3.8 ± 0.5 | 0.03 |
| Glomerular filtration rate (mL/min), median | 47.6 (31.2-70.5) | 52.3 (37.1-73.5) | 45.5 (23.1-69.2) | 0.06 |
| ≥60 mL/min | 38% | 40% | 37% | |
| 30 to <60 mL/min | 40% | 55% | 33% | |
| <30 mL/min | 23% | 6% | 31% | |
| STS Score Mortality (%) | 6.3 ± 3.8 | 6.4 ± 4.2 | 6.2 ± 3.6 | 0.82 |
| Valvuloplasty | 6% | 2% | 9% | 0.09 |
| Aspirin | 67% | 73% | 64% | 0.26 |
| Beta-blocker | 67% | 71% | 66% | 0.51 |
| ACE-I/ARB | 37% | 29% | 40% | 0.16 |
| Statin | 56% | 51% | 59% | 0.32 |
| Variable | Overall (n=172) | Patient Declined (n=55) | Not Candidate (n=117) | p |
|---|---|---|---|---|
| LV ejection fraction, median | 60% (45-70) | 65% (50-70) | 60% (43-65) | 0.15 |
| ≥50% | 73% | 78% | 71% | |
| 30 to <50% | 17% | 16% | 18% | |
| <30% | 9% | 6% | 11% | |
| LV mass index (g/m 2 ) | 123.9 ± 37.6 | 121.2 ± 36.9 | 125.2 ± 38.0 | 0.52 |
| LV end-diastolic diameter (cm) | 4.8 ± 0.9 | 4.8 ± 0.8 | 4.8 ± 1.0 | 0.95 |
| LV end-systolic diameter (cm) | 3.4 ± 1.1 | 3.2 ± 1.0 | 3.5 ± 1.2 | 0.24 |
| Left atrial diameter (cm) | 4.6 ± 0.8 | 4.6 ± 0.8 | 4.6 ± 0.8 | 0.92 |
| Aortic regurgitation ≥2+ | 7% | 4% | 9% | 0.18 |
| Mitral regurgitation ≥2+ | 20% | 13% | 23% | 0.11 |
| Tricuspid regurgitation ≥2+ | 29% | 27% | 29% | 0.81 |
| Mitral stenosis ≥2+ | 1% | 0% | 1% | 0.62 |
| AV EOA (cm 2 ) | 0.72 ± 0.17 | 0.68 ± 0.18 | 0.73 ± 0.17 | 0.09 |
| AV mean gradient (mm Hg) | 37.7 ± 16.8 | 39.7 ± 15.8 | 36.8 ± 17.2 | 0.30 |
| AV peak velocity (m/sec) | 4.0 ± 0.8 | 4.1 ± 0.8 | 3.9 ± 0.8 | 0.12 |
The reasons that patients were not a candidate for TAVR or SAVR (n = 117) included unfavorable aortic root and valve anatomy (n = 5, 4.3%), other significant valve disease (n = 10, 8.5%), incompatible annulus size (n = 19, 16.2%), severe cardiomyopathy without contractile reserve (n = 1, 0.9%), inadequate vascular access and not amenable to an apical approach (n = 8, 6.8%), prohibitive co-morbidities (n = 39, 33.3%), active cancer with a poor prognosis (n = 15, 12.8%), significant dementia (n = 9, 7.7%), or other causes (n = 11, 9.4%).
The relation between clinical characteristics and all-cause mortality is provided in Table 3 . Patient demographics, risk factors, and baseline medications were not associated with a difference in mortality. Advanced heart failure and low hemoglobin, albumin, and glomerular filtration rate each were associated with a difference in mortality ( Figure 1 ). The relation between echocardiographic findings and all-cause mortality is provided in Table 4 . In this cohort with severe symptomatic AS, gradations of AS severity and other valvular findings were not associated with mortality, whereas reduced left ventricular ejection fraction and increased left ventricular size were significantly associated with increased mortality. Balloon valvuloplasty was not associated with a difference in all-cause mortality (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.17 to 1.66, p = 0.27).
| Variable | Unadjusted HR | 95% CI | p |
|---|---|---|---|
| Increased Age (per +10 years) | 0.87 | 0.71-1.08 | 0.21 |
| Male | 1.34 | 0.85-2.10 | 0.21 |
| Hypertension | 0.83 | 0.26-2.63 | 0.75 |
| Hyperlipidemia | 0.94 | 0.57-1.55 | 0.80 |
| Current smoker | 0.93 | 0.45-1.93 | 0.84 |
| Diabetes mellitus | 1.16 | 0.73-1.86 | 0.53 |
| Prior myocardial infarction | 1.27 | 0.78-2.08 | 0.33 |
| Coronary artery disease | 0.89 | 0.65-1.64 | 0.89 |
| Prior coronary revascularization | 0.76 | 0.48-1.20 | 0.23 |
| Lung disease | 1.29 | 0.82-2.04 | 0.28 |
| Home oxygen | 1.29 | 0.76-2.22 | 0.35 |
| Atrial fibrillation or flutter | 1.00 | 0.63-1.58 | 0.99 |
| Stroke or transient ischemic attack | 0.92 | 0.53-1.59 | 0.75 |
| Angina pectoris | 0.99 | 0.56-1.77 | 0.98 |
| NYHA Class IV (vs. I-III) | 3.21 | 2.02-5.11 | <0.001 |
| Hemoglobin <11.8 g/dL | 1.75 | 1.11-2.77 | 0.02 |
| Albumin <3.9 g/dL | 2.10 | 1.33-3.30 | 0.001 |
| GFR <48 mL/min | 2.15 | 1.35-3.43 | 0.001 |
| STS Score Mortality (per +1%) | 1.05 | 0.99-1.11 | 0.06 |
| Aspirin | 1.04 | 0.65-1.68 | 0.86 |
| Beta-blocker | 0.67 | 0.41-1.04 | 0.07 |
| ACE-I/ARB | 1.27 | 0.80-2.00 | 0.31 |
| Statin | 1.21 | 0.77-1.90 | 0.41 |
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