Recent randomized clinical trials have demonstrated that transcatheter aortic valve implantation (TAVI) reduces mortality in high-risk patients with aortic stenosis who are not candidates for aortic valve replacement (AVR). In similar patients who are acceptable candidates for AVR, TAVI provides equivalent outcomes to AVR. In this study, 900 patients with severe aortic stenosis at high surgical risk were evaluated as possible candidates for TAVI. Of these, 595 (66.1%) had neither TAVI nor AVR and constituted the medical arm. In addition to the best available conservative care, 345 patients (39.3%) in this group had balloon aortic valvuloplasty. The AVR arm consisted of 146 patients (16.2%) and the TAVI arm of 159 patients (17.6%). The AVR group had significantly lower clinical risk compared to the medical and TAVI groups, with lower mean age, Society of Thoracic Surgeons score, and logistic European System for Cardiac Operative Risk Evaluation score. Patients in the medical and balloon aortic valvuloplasty group had significantly higher B-type natriuretic peptide levels compared to those in the AVR and TAVI groups and had, on average, lower ejection fractions. The medical and balloon aortic valvuloplasty group was followed for a median of 206 days; the mortality rate was 46.6% (n = 277). The AVR group was followed for 628 days; 39 patients died (26.7%). In 399 days of follow-up, the mortality rate in the TAVI group was 30.8% (n = 49). In conclusion, patients with severe AS who did not undergo TAVI or AVR had high mortality. In properly selected patients, TAVI and AVR improve outcomes. Renal failure is the strongest correlate for adverse outcomes, irrespective of treatment group.
Transcatheter aortic valve implantation (TAVI) has emerged as a less invasive and effective treatment modality for patients with severe aortic stenosis (AS). The Placement of Aortic Transcatheter Valves (PARTNER) study, a large, multicenter, randomized trial, examined patients with severe AS who were not suitable candidates for aortic valve replacement (AVR) or were at high surgical risk. TAVI was shown to be superior to conservative treatment, including balloon aortic valvuloplasty (BAV). All-cause mortality was lower in those who underwent TAVI, as was the composite end point of death from any cause or repeat hospitalization, as well as cardiac symptoms. In the PARTNER arm that compared TAVI and AVR, 1-year survival was equivalent. However, as previously reported, up to 75% of patients who were screened for TAVI were not eligible for randomization. This study was undertaken to assess the clinical profile, outcomes, and predictors of mortality for these patients according to treatment mode.
Methods
This registry analysis was approved by the institutional review board of the MedStar Health Research Institute. A detailed registry was created prospectively of all patients referred for possible participation in the PARTNER trial; a cohort of 900 patients with severe AS at high surgical risk who were evaluated from April 2007 to May 2011 form the basis of this report.
Severe AS was defined as a mean gradient ≥40 mm Hg or a calculated aortic valve area <1 cm 2 . Patients who met the inclusion criteria for PARTNER were enrolled and randomly assigned to treatment. Two cardiac surgeons and an interventional cardiologist assessed the operability of each patient. Among patients enrolled in the PARTNER trial, operable candidates entered cohort A of the trial and, during the pivotal trial, were randomized between TAVI and AVR. Of the entire AVR group, only 19 (13%) were part of the PARTNER trial. Patients deemed to be inoperable were considered for enrollment in cohort B of the trial. During the pivotal trial, cohort B patients were randomized to either TAVI by the transfemoral approach or medical management with palliative BAV. Of the medical and BAV group, only 29 patients (4.9%) were part of the PARTNER trial. Once the 2 arms of the PARTNER trial were closed, patients continued to undergo TAVI or AVR in a nonrandomized continued-access program.
TAVI was performed using the Edwards SAPIEN valve (Edwards Lifesciences, Irvine, California); valve size was selected on the basis of the annular size measured by transesophageal echocardiography. The access of choice was transfemoral. In cases of peripheral vascular disease or small iliac arteries, suitable patients underwent TAVI using a transapical approach. The treatment strategy was chosen by a multidisciplinary team consisting of an interventional cardiologist, a cardiac surgeon, and the patient’s primary cardiologist. Patients not selected for either TAVI or AVR underwent BAV if they had critical AS with deteriorating symptoms or to further evaluate the reversibility of the observed pulmonary hypertension, left ventricular dysfunction, or mitral regurgitation. All patients were followed clinically by telephone or office visit. Figure 1 illustrates the treatment strategy for the 900 patients included in this registry.
Statistical analysis was performed using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina). Continuous variables are presented as mean ± SD and categorical variables as proportions and percentages. Follow-up days are presented as median (interquartile range [IQR]). Differences among continuous variables were assessed using Student’s t test. Categorical variables were compared using chi-square or Fisher’s exact tests as indicated. Significance was set at p <0.05. To compare the different groups, 1-way analysis of variance was used. Associations among mortality and clinical, electrocardiographic, echocardiographic, and hemodynamic variables were studied using Cox proportional-hazards regression analysis. To determine independent correlates of mortality, we initially performed a univariate Cox proportional-hazards regression analysis using all variables recorded in the clinical electrocardiographic, echocardiographic, and hemodynamic categories. In each group, all univariate correlates of mortality with p values ≤0.05 (Society of Thoracic Surgeons [STS] score, logistic European System for Cardiac Operative Risk Evaluation [EuroSCORE] score, New York Heart Association class, renal failure, the ejection fraction, pulmonary artery systolic pressure, aortic systolic pressure, and atrial fibrillation) were then used in a stepwise multivariate Cox regression model. Cumulative survival curves were constructed using the Kaplan-Meier method, and significance was assessed using the log-rank statistic. Hospital stay was calculated as the time from surgery to discharge or to death.
Results
Baseline characteristics are listed in Table 1 . Unsurprisingly, patients who underwent AVR who were selected because they were deemed to have relatively favorable operative risk were younger (p <0.001) and had lower STS score and logistic EuroSCORE than those in the other 2 groups. Moreover, New York Heart Association class IV heart failure was present in fewer AVR patients (p <0.001).
| Variable | Medical/BAV | AVR | TAVI ⁎ | p Value |
|---|---|---|---|---|
| (n = 595) | (n = 146) | (n = 159) | ||
| Age (years) | 82.1 ± 8.2 | 79.0 ± 8.0 | 84.4 ± 5.8 | <0.001 |
| Men | 267 (44.8%) | 74 (50.6%) | 68 (42.7%) | 0.34 |
| STS score | 12.1 ± 6.3 | 8.5 ± 4.9 | 11.8 ± 3.9 | <0.001 |
| Logistic EuroSCORE | 43.1 ± 22.7 | 26.6 ± 18.2 | 42.3 ± 21.4 | <0.001 |
| New York Heart Association class IV | 368 (61.8%) | 39 (26.7%) | 91 (57.2%) | <0.001 |
| Diabetes mellitus | 196 (32.9%) | 53 (36.3%) | 51 (32.0%) | 0.92 |
| Systemic hypertension † | 497 (83.5%) | 129 (88.3%) | 142 (89.3%) | 0.09 |
| Coronary artery disease | 381 (64.0%) | 92 (63.1%) | 91 (57.2%) | 0.11 |
| Chronic obstructive pulmonary disease | 116 (19.4%) | 14 (9.6%) | 22 (13.8%) | 0.01 |
| Renal failure | 243 (41.0%) | 51 (34.9%) | 64 (40.2%) | 0.17 |
| Previous cerebrovascular accident or transient ischemic attack | 116 (16.0%) | 16 (10.9%) | 43 (27.0%) | <0.001 |
| Arrhythmia | 195 (32.7%) | 39 (26.7%) | 50 (31.4%) | 0.15 |
| Peripheral vascular disease | 172 (28.9%) | 38 (26.0%) | 42 (26.4%) | 0.48 |
| Previous coronary artery bypass grafting | 180 (30.2%) | 31 (21.2%) | 54 (33.9%) | 0.01 |
⁎ Transfemoral approach, n = 110 (69.1%); transapical approach, n = 49 (30.9%).
† History of systemic hypertension diagnosed and/or treated with medication or currently being treated with diet and/or medication by a physician.
Patients who did not undergo TAVI or AVR stood out for adverse features ( Table 2 ). As a group, they had the lowest left ventricular ejection fractions (p = 0.002) and the highest B-type natriuretic peptide levels (p <0.001). The degree of AS differed only slightly among the 3 treatment groups ( Table 2 ). Aortic valve area was statistically smallest in TAVI-treated patients (p <0.001 by echocardiography and p = 0.03 by catheter measurement), and the mean gradient was significantly greater (p <0.001 by echocardiography and catheter measurements) in the same group.
| Variable | Medical/BAV | AVR | TAVI ⁎ | p Value |
|---|---|---|---|---|
| (n = 595) | (n = 146) | (n = 159) | ||
| Laboratory values | ||||
| Hemoglobin level (mg%) | 11.6 ± 1.7 | 12.2 ± 1.7 | 11.8 ± 5.8 | 0.07 |
| Creatinine (mg%) | 1.4 ± 1.2 | 1.3 ± 0.8 | 1.3 ± 1.6 | 0.34 |
| High-sensitivity C-reactive protein (mg/dl) | 19.5 ± 31.5 | 12.7 ± 27.1 | 12.5 ± 21.3 | 0.13 |
| B-type natriuretic peptide (pg/ml) | 1,780 ± 1,399 | 854 ± 820 | 729 ± 726 | <0.001 |
| Echocardiographic parameters | ||||
| Ejection fraction (%) | 47.4 ± 17.5 | 52.3 ± 15.4 | 51.2 ± 15.9 | 0.002 |
| Septal thickness (mm) | 1.32 ± 0.2 | 1.34 ± 0.2 | 1.36 ± 0.2 | 0.23 |
| Pulmonary artery systolic pressure (mm Hg) | 51.1 ± 16.1 | 45.1 ± 16.8 | 48.5 ± 17.6 | 0.006 |
| Aortic valve area (cm 2 ) | 0.74 ± 0.19 | 0.75 ± 0.18 | 0.65 ± 0.28 | <0.001 |
| Vmax (m/s) | 3.9 ± 0.7 | 4.1 ± 0.7 | 4.3 ± 0.6 | <0.001 |
| Mean gradients (mm Hg) | 39.8 ± 24.6 | 43.6 ± 16.4 | 49.3 ± 16.0 | <0.001 |
| Hemodynamic parameters | ||||
| Aortic valve area (cm 2 ) | 0.7 ± 0.3 | 0.67 ± 0.2 | 0.6 ± 0.18 | 0.03 |
| Mean gradients (mm Hg) | 42.9 ± 20.6 | 49.1 ± 19.5 | 55.3 ± 21.1 | <0.001 |
| Pulmonary artery systolic pressure (mm Hg) | 53.8 ± 23.1 | 47.3 ± 16.3 | 50.9 ± 19.7 | 0.006 |
| Cardiac output (L/min) | 4.2 ± 1.3 | 4.6 ± 1.2 | 4.4 ± 1.4 | 0.07 |
| 2- or 3-vessel coronary artery disease | 252 (42.3%) | 57 (39.0%) | 68 (42.7%) | 0.42 |
⁎ Transfemoral approach, n = 110 (69.1%); transapical approach, n = 49 (30.9%).
Figure 2 shows Kaplan-Meier survival curves for the 3 groups. The median follow-up duration was 206 days (IQR 76 to 411) in the medical and BAV group, 628 days (IQR 211 to 911) in the AVR group, and 399 days (IQR 167 to 669) in the TAVI group. The median time from screening to mortality was 151 days (IQR 48.5 to 336), 41 days (IQR 7 to 116), and 70 days (IQR 14 to 405) days in the medical and BAV, AVR, and TAVI groups, respectively. One-year all-cause mortality in the AVR and TAVI groups was similar and was significantly lower than in the medical and BAV group (21.2% and 21.3% vs 36.4%, p <0.001, respectively). During a median follow-up period of 212 days (IQR 71 to 417) in the medical group, the mortality rate was 34% (n = 82). In the BAV group, during a median follow-up period of 192 days (IQR 79 to 409), the mortality rate was 55% (n = 195; p <0.01).
Figure 3 compares the 30-day mortality rate observed in this analysis to that predicted by the STS score and the logistic EuroSCORE. In the medical and BAV group, 30-day mortality was 10.1% observed, 12.3% by STS score, and 43.1% by logistic EuroSCORE. In the AVR group, rates were 12.8% observed, 8.4% by STS score, and 25.6% by logistic EuroSCORE. In the TAVI group, rates were 11.7% observed, 11.8% by STS score, and 41.2% by logistic EuroSCORE. The STS score odds ratio for 30-day mortality in the medical and BAV group was 1.05 (p = 0.01) and was 1.003 (p = 0.70) with the logistic EuroSCORE. In the AVR group, the STS score odds ratio was 1.09 (p = 0.07) and was 1.007 (p = 0.60) with the logistic EuroSCORE. In the TAVI group, the STS score odds ratio was 1.14 (p = 0.03) and was 1.03 (p = 0.04) with the logistic EuroSCORE. In all groups (medical and BAV, AVR, and TAVI) the mortality of patients with STS scores ≥15 versus <15 was 125 (59.2%) versus 243 (35.2%) (p <0.001).
In the medical and BAV group, the causes of death were known to be cardiac, noncardiac, and unknown in 108 (38.9%), 78 (28.1%), and 91 (32.8%) patients, respectively. In the AVR group, rates were 14 (35.8%), 19 (48.7%), and 6 (15.3%), respectively. In the TAVI group, rates were 12 (24.4%), 35 (71.4%), and 2 (4.1%), respectively ( Figure 4 ).
Factors associated with mortality are listed in Table 3 . After multivariate adjustment, the strongest correlates for mortality were renal failure (hazard ratio [HR] 1.75, p = 0.002) and atrial fibrillation (HR 1.46, p = 0.03).
