In high-risk or inoperable patients with severe symptomatic aortic stenosis, transcatheter aortic valve implantation (TAVI) is a proven alternative to standard (i.e., medical) therapy or surgical aortic valve replacement. Concerns have been raised, however, about patients who survive the procedure but have short subsequent survival. The aim of this study was therefore to identify correlates of early out-of-hospital mortality (EOHM) in patients who underwent successful TAVI, rendering TAVI potentially “futile.” Patients who were discharged from the hospital and survived >30 days but <12 months after TAVI were identified (the EOHM group). Independent predictors of EOHM were explored, including patient-level factors and procedural nonfatal major complications (NFMCs). A sensitivity analysis was also performed, excluding patients with NFMCs. Among 485 patients who were discharged from the hospital and survived 30 days after TAVI, 101 (21%) were dead within 1 year. Independent predictors of EOHM included serum creatinine, liver disease, coagulopathy, mental status, body mass index, male gender, and Society of Thoracic Surgeons score. Although NFMCs were strongly associated with EOHM, patient-level risk factors for EOHM were similar between patients who did and those who did not experience NFMCs. Compared with standard therapy, TAVI patients with EOHM had similar 6-month 6-minute walk distances and functional classes, with higher rates of repeat hospitalization. In conclusion, in high-risk or inoperable patients who underwent TAVI and were discharged and alive at 30 days, EOHM was not infrequent and was determined largely by presenting characteristics and the occurrence of periprocedural NFMCs. Careful screening and minimization of NFMCs may maximize the benefit of TAVI.
In high-risk adults with severe symptomatic aortic stenosis (AS), transcatheter aortic valve implantation (TAVI) improves survival compared with medical therapy in patients not suitable for surgery, and is noninferior to surgical aortic valve replacement in high-risk surgical candidates. Additionally, quality-of-life improvements are associated with TAVI. Despite these encouraging results, all-cause mortality after TAVI in high-risk patients remains high (44% at 3 years) (Thourani VH. Three-year outcomes after transcatheter or surgical aortic valve replacement in high-risk patients with severe aortic stenosis. San Francisco, CA: American College of Cardiology Annual Scientific Sessions). Much of this mortality is not procedural but rather a result of existing co-morbidities and other contributing patient characteristics, including advanced age, that adversely influence long-term outcomes. Because the TAVI procedure does incur some patient risk as well as societal cost, it is reasonable to seek to maximize the benefit of the procedure through the application of the procedure to patients for whom meaningful clinical benefit is expected. We therefore sought to use data from the Placement of Aortic Transcatheter Valves (PARTNER) trial to characterize a cohort of patients for whom the TAVI procedure was successful but did not provide a long-term mortality benefit. To accomplish this objective, we compared those patients who underwent TAVI and were successfully discharged from the hospital and alive at 30 days after the procedure but died <1 year after the procedure with those who survived beyond 1 year to identify predictors of early out-of-hospital mortality (EOHM) after TAVI.
Methods
The PARTNER I trial incorporated 2 parallel prospective, multicenter, randomized, active-treatment-controlled clinical trials. The study design and patient selection for the randomized, multicenter PARTNER I trial have been previously described. Briefly, the PARTNER I trial enrolled patients with severe symptomatic AS (aortic valve area ≤0.8 cm 2 plus peak velocity ≥4 m/second or mean transaortic valve gradient ≥40 mm Hg) who were deemed at high risk for conventional surgery (cohort A) or inoperable (cohort B). The institutional review board at each participating site approved the study, and all patients provided written informed consent.
Clinical outcomes analyzed included all-cause and cardiovascular mortality, repeat hospitalization (because of AS or complications of the valve procedure), New York Heart Association (NYHA) functional class, and 6-minute walk distance (meters walked in 6 minutes during a monitored walk). Procedural success was defined as receipt of a valve implant during the index procedure with less than moderate aortic insufficiency. Major arrhythmia was defined as the presence of atrial fibrillation or flutter, supraventricular tachycardia, ventricular arrhythmia, or high-degree atrioventricular block. An independent clinical events committee adjudicated all adverse events.
The present analysis pooled all patients from cohorts A and B who underwent TAVI by the transfemoral (TF) or transapical (TA) approach (as treated analysis). To minimize the influence of fatal procedural events (e.g., complications) in determining 1-year survival, patients who died during their index (procedural) hospitalization or within the first 30 days after TAVI were then excluded from this analysis. In total, 519 patients underwent TAVI, of whom 29 patients died within 30 days and 5 experienced in-hospital death after 30 days. This left a total of 485 patients included in this analysis.
Patients who had undergone TAVI were then stratified into 3 groups: patients who were discharged from the index hospitalization and were alive at 30 days after TAVI but died of any cause within the year after TAVI were characterized as EOHM, and those who underwent TAVI who were alive at 1 year after TAVI were considered to have no early mortality (no EOHM). We further analyzed the EOHM group on the basis of whether a periprocedural nonfatal major complication (NFMC) had occurred. NFMCs included the occurrence (<7 days after TAVI) of any stroke, major vascular complications, major bleeding complications, and aortic valve reintervention. In a further comparison, outcomes of patients with EOHM who were discharged alive after TAVI were compared with those of 179 inoperable patients who underwent standard therapy without TAVI (medical therapy alone with or without balloon aortic valvuloplasty).
Baseline demographic, clinical, and echocardiographic characteristics were compared between patients with and those without EOHM. The Society of Thoracic Surgeons (STS) predicted risk for in-hospital or 30-day mortality for isolated surgical aortic valve replacement and logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) were computed for all patients. Baseline cognitive function was assessed using the standardized Mini Mental State Examination (MMSE). Differences between patients with EOHM and those with no EOHM were tested using chi-square or Fisher’s exact tests for dichotomous variables and Student’s t tests or Wilcoxon’s rank-sum tests for continuous variables, as appropriate. The rates of clinical outcomes in the EOHM and no-EOHM groups were assessed according to the method of Kaplan and Meier and compared using the log-rank test.
Multivariate Cox proportional-hazards models were constructed to identify baseline variables independently associated with EOHM. A tiered approach was used whereby the initial model included only the baseline variables with univariate associations with EOHM at a level of p ≤0.10. A second model included NFMCs, added as time-dependent covariates, and the final model included only those variables that remained significant after multivariate adjustment. As a sensitivity analysis, an additional model was constructed, restricting the data set to subjects without NFMCs. A second sensitivity analysis was performed by redefining patients with EOHM as those who survived to hospital discharge and 30 days after TAVI but died <6 months after TAVI; the results of this analysis was similar to the primary analysis and thus is not shown. All statistical analyses were performed with the use of SAS version 9.2 (SAS Institute Inc., Cary, North Carolina), and a 2-sided α level of 0.05 was used to determine statistical significance.
Results
A total of 485 patients in the PARTNER I randomized trial were discharged from the hospital and survived ≥30 days after TAVI and were therefore included in the primary analysis. Of these, 101 (21%) were dead within 1 year (categorized as EOHM), and 384 (79%) survived for ≥1 year (categorized as no EOHM).
Baseline characteristics of the EOHM and no-EOHM groups are listed in Table 1 . Also included, for comparison, are the baseline characteristics of the 179 patients randomized to standard therapy. There were similar rates of TA and TF access in the EOHM and no-EOHM groups (18% TA in the EOHM group vs 19% TA in the no-EOHM group, p = 0.79).
| Variable | Early Out-of-Hospital Mortality (n = 101) | No Early Out-of-Hospital Mortality (n = 384) | Standard Therapy (n = 179) | p-Value EOHM vs No EOHM | p-Value EOHM vs ST |
|---|---|---|---|---|---|
| Age (median, IQR) | 84.68 [78.26, 88.47] | 84.42 [79.56, 88.43] | 84.75 [79.10, 88.55] | 0.92 | 0.97 |
| Age ≥ 80 years | 71 (70%) | 282 (73%) | 128 (72%) | 0.53 | 0.83 |
| Male | 62 (61%) | 199 (52%) | 84 (47%) | 0.09 | 0.02 |
| Body Mass Index (median, IQR) (kg/m 2 ) | 25.05 [21.63, 28.94] | 26.63 [22.86, 30.69] | 25.25 [22.15, 29.44] | 0.007 | 0.23 |
| STS Score (median, IQR) | 12.00 [9.70, 15.80] | 10.95 [9.50, 12.90] | 11.50 [8.80, 15.00] | 0.009 | 0.26 |
| STS > 10 | 72 (71%) | 261 (68%) | 117 (66%) | 0.52 | 0.34 |
| LogEuroSCORE (median, IQR) | 26.61 [16.18, 43.08] | 24.06 [14.64, 37.50] | 26.00 [16.19, 41.48] | 0.17 | 0.73 |
| Diabetes mellitus | 33 (33%) | 159 (41%) | 63 (35%) | 0.11 | 0.67 |
| Hyperlipidemia | 73 (72%) | 309 (81%) | 141 (79%) | 0.07 | 0.22 |
| Smoker | 47 (47%) | 185 (48%) | 86 (48%) | 0.77 | 0.81 |
| Hypertension | 89 (88%) | 342 (89%) | 153 (86%) | 0.74 | 0.54 |
| Heart Failure NYHA class 3/4 | 95 (94%) | 360 (94%) | 168 (94%) | 0.91 | 0.95 |
| Coronary Artery Disease | 77 (76%) | 279 (73%) | 133 (74%) | 0.47 | 0.72 |
| Peripheral Vascular disease | 38 (38%) | 145 (38%) | 45 (25%) | 0.94 | 0.03 |
| Porcelain aorta | 8 (8%) | 26 (7%) | 20 (11%) | 0.69 | 0.38 |
| Prior balloon aortic valvuloplasty | 21 (21%) | 45 (12%) | 39 (22%) | 0.02 | 0.85 |
| Major Arrhythmia | 58 (57%) | 175 (46%) | 90 (50%) | 0.03 | 0.25 |
| Coagulopathy | 6 (6%) | 6 (2%) | 3 (2%) | 0.02 | 0.07 |
| Creatinine ≥ 2 mg/dl | 28 (28%) | 62 (16%) | 35 (20%) | 0.008 | 0.12 |
| Liver disease | 6 (6%) | 7 (2%) | 6 (3%) | 0.03 | 0.36 |
| Chronic obstructive pulmonary disease | 44 (44%) | 158 (41%) | 94 (53%) | 0.66 | 0.15 |
| Oxygen Dependent | 16 (16%) | 46 (12%) | 46 (26%) | 0.30 | 0.06 |
| Chest wall radiation | 4 (4%) | 15 (4%) | 15 (8%) | 1.00 | 0.16 |
| Chest wall deformities | 3 (3%) | 11 (3%) | 9 (5%) | 1.00 | 0.55 |
| MMSE (median, IQR) | 27.0 [24.5, 29.0] | 28.0 [25.0, 29.0] | 28.0 [25.0, 30.0] | 0.02 | 0.03 |
| Anemia | 78 (77%) | 255 (67%) | 129 (73%) | 0.04 | 0.42 |
| Mean AV Gradient (mmHg, median, IQR) | 40.24 [32.22,49.24] | 42.19 [33.25, 52.44] | 40.66 [32.64, 49.90] | 0.14 | 0.53 |
| Peak AV Gradient (mmHg, median, IQR) | 66.74 [51.67, 82.32] | 70.09 [56.53, 86.60] | 70.11 [56.46, 86.44] | 0.12 | 0.22 |
| Aortic Valve Area (EOA) (cm 2 , median (IQR) | 0.65 [0.51, 0.77] | 0.63 [0.53, 0.76] | 0.64 [0.50, 0.74] | 0.68 | 0.98 |
| Baseline LVEF (%, median, IQR) | 55 [43, 60] | 57 [45, 62] | 55 [41, 60] | 0.14 | 0.85 |
NFMCs were more frequent in patients experiencing EOHM (28% with EOHM vs 16% without EOHM, p = 0.007; Table 2 ). Among NFMCs, major vascular complications (17% vs 10%, p = 0.04) were more frequent in patients with EOHM compared with those without EOHM. A total of 54 patients developed major vascular complications, of whom 52 (96%) had TF access and 2 (4%) had TA access. There was a trend toward more frequent major bleeding (16% vs 9%, p = 0.06) but no difference in the rates of any stroke or the need for any aortic valve reintervention. The rate of new permanent pacemaker implantation was similar in the EOHM and no-EOHM groups (6% vs 12%, p = 0.23) and was not found to be a significant univariate predictor of EOHM. The rate of postprocedural moderate or severe paravalvular aortic insufficiency was similar in patients with EOHM compared with those without EOHM (12% vs 9%, p = 0.46). TF or TA access was not a significant univariate predictor of EOHM (TA vs TA: hazard ratio 1.02, 95% confidence interval 0.62 to 1.68, p = 0.93).
| Variable | EOHM (n = 101) | No EOHM (n = 384) | p-Value | Independent Hazard of EOHM [95% CI] |
|---|---|---|---|---|
| Any NFMC ∗ | 28 (28%) | 62 (16%) | 0.007 | 1.81 [1.16, 2.83] |
| Stroke (any) | 7 (7%) | 14 (4%) | 0.17 | 3.19 [1.82, 5.62] |
| Aortic valve re-intervention | 5 (5%) | 6 (2%) | 0.057 | 3.74 [1.61, 8.67] |
| Major bleeding | 16 (16%) | 36 (9%) | 0.06 | 2.43 [1.54, 3.83] |
| Major vascular complications | 17 (17%) | 37 (10%) | 0.04 | 1.71 [1.00, 2.90] |
∗ Non-fatal major complications: Complications occurring within 7 days of index TAVR.
In a multivariate model examining the independent correlates of EOHM ( Table 3 ), baseline and preprocedural characteristics independently associated with EOHM included serum creatinine, liver disease, coagulopathy, total MMSE score, body mass index (BMI) and STS score. Of note, these correlates (and the strengths and magnitude of their associations with EOHM) remained independently associated with EOHM in a model excluding patients without NFMCs ( Table 3 ).
| Variable | Hazard Ratio | p Value |
|---|---|---|
| 3a. All patients | ||
| Body Mass Index (lbs/in²) | 0.95 [0.92, 0.99] | 0.0095 |
| Coagulopathy | 3.46 [1.49, 8.03] | 0.0039 |
| Serum creatinine | 1.08 [1.03, 1.14] | 0.0029 |
| Liver disease | 2.69 [1.15, 6.31] | 0.0225 |
| Total Mini Mental State Exam Score | 0.95 [0.90, 1.00] | 0.0454 |
| STS Risk Score | 1.06 [1.02, 1.11] | 0.0034 |
| 3b. Patients without NFMC | ||
| Body Mass Index (lbs/in²) | 0.94 [0.90, 0.99] | 0.0181 |
| Coagulopathy | 3.47 [1.24, 9.70] | 0.0177 |
| Serum creatinine | 1.09 [1.03, 1.15] | 0.0031 |
| Liver disease | 3.00 [1.07, 8.39] | 0.0365 |
| Male | 2.09 [1.23, 3.54] | 0.0063 |
| Total Mini Mental State Exam Score | 0.93 [0.88, 0.99] | 0.0238 |
| STS Risk Score | 1.08 [1.03, 1.13] | 0.0008 |
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