Transcatheter aortic valve implantation (TAVI) is associated with improved left ventricular (LV) function in patients with aortic stenosis (AS) and LV dysfunction; however, the outcome after TAVI of patients with low left ventricular ejection fraction (LVEF) is unclear. This study aimed to characterize the baseline, procedural, and long-term outcomes of patients with low LVEF undergoing TAVI and to assess the prognostic utility of pre-TAVI balloon aortic valvuloplasty (BAV) and dobutamine stress echocardiography (DSE) to predict TAVI benefits. Consecutive patients with symptomatic severe AS who underwent TAVI from 2007 to 2013 were analyzed. Two groups were compared: normal or near normal LV function (LVEF >45%) and LVEF ≤45% at baseline. In total, 371 patients were analyzed; 272 (73%) had preserved LVEF and 99 (27%) had low LVEF. Patients with low LVEF had higher Society of Thoracic Surgeons score and EuroSCORE. Short- and long-term mortality was similar between groups (1-year rate: 22.2% vs 22.4%, p = 0.79). Of the patients with low LVEF, 24% demonstrated improvement (≥10%) in LVEF at 30 days; patients with improvement had lower mortality at 1 year than those without (8% vs 27%, p = 0.06). Contractile reserve in DSE did not predict LVEF recovery in patients with low LVEF but did predict lower mortality. LVEF recovery after BAV predicted greater LVEF improvement after TAVI. In conclusion, patients with severe AS and impaired LV function benefit from TAVI and have comparable procedural outcomes compared with patients with preserved LVEF. Both DSE and BAV provide complementary data with regard to recovery of LVEF and mortality, both periprocedural and late after TAVI.
Surgical aortic valve replacement for aortic stenosis (AS) leads to improvement in symptoms and in outcomes of patients with impaired left ventricular (LV) function compared with medical therapy and is recommended by the American College of Cardiology/American Heart Association guidelines as a class I indication. Transcatheter aortic valve implantation (TAVI) is now a viable treatment option for patients with AS and impaired LV function who were previously rejected from surgical valve replacement. TAVI provides benefit for these patients, as it is associated with improvement in left ventricular ejection fraction (LVEF). However, there are controversial reports as to the outcomes of patients with low LVEF who undergo TAVI compared with patients with normal LVEF. Accordingly, this patient population with severe AS and low LVEF presents a significant challenge to the heart team as to whether an individual patient might benefit from TAVI or if such a procedure would be futile. Frequently, such patients with AS and low LVEF would undergo either balloon aortic valvuloplasty (BAV) to assess for clinical improvement after relieving the LV outflow tract obstruction or dobutamine stress echocardiography (DSE) to assess if this is a true AS and for the presence of contractile reserve. However, this approach is based on small patient series that evaluated patients with AS treated either medically or surgically ; there are no data to support this approach as part of the evaluation before TAVI. Thus, the aims of this study were to assess the characteristics of patients with low LVEF and their procedural and long-term outcomes after TAVI. Additional objectives were to address issues that have not been sufficiently studied, including the prognostic utility of pre-TAVI BAV and DSE to predict the benefit of TAVI in patients with low LVEF.
Methods
The study was approved by the Institutional Review Board of the MedStar Health Research Institute. Consecutive patients with symptomatic severe AS who underwent TAVI from 2007 to 2013 were analyzed. Eligibility for TAVI was established based on the consensus of a multidisciplinary heart team that included a clinical cardiologist and a cardiac surgeon. Prespecified clinical and laboratory data were collected for all patients at baseline before the procedure, immediately after the procedure, during the index hospitalization, and up to 1 year. Collected data included medical history, electrocardiograms, echocardiographic studies, laboratory tests, and clinical outcomes.
Patients underwent TAVI either with the balloon-expandable Edwards SAPIEN transcatheter heart valve (Edwards Lifesciences, Irvine, California) or the self-expandable Medtronic CoreValve (Medtronic, Minneapolis, Minnesota) by way of the transfemoral, transapical, or direct aortic access, as previously described. Intraprocedural anticoagulation regimen included unfractionated heparin targeted to achieve an activated clotting time of 200 to 250 seconds for the duration of the procedure. After the procedure, all patients were treated with acetylsalicylic acid 81 mg/day indefinitely and clopidogrel 75 mg/day for 6 months according to the discretion of the treating physician.
In-hospital outcomes were collected retrospectively according to the Valve Academic Research Consortium–2 consensus document and included length of stay, blood transfusion, acute kidney injury, stroke, bleeding, vascular complications, and death. Out-of-hospital adverse events were assessed at regular follow-up (up to 1 year) by means of an outpatient clinic visit or a standardized telephone interview. All suspected events were adjudicated by a blinded interventional cardiologist.
Patients undergoing TAVI underwent a comprehensive Doppler echocardiographic study at baseline, during index hospitalization, and at 1-, 6-, and 12-month follow-up. Transaortic gradients were calculated using the simplified Bernoulli equation, and aortic valve area was calculated by the continuity equation. LVEF was calculated in all patients. Improvement in LVEF during follow-up was compared with baseline echocardiography and was defined as an increase of ≥10%. For the purpose of assessment of the main study hypothesis, patients were divided into 2 groups: those with normal or near normal LV function (LVEF >45%; preserved LVEF group) versus those with impaired LV function (LVEF ≤45%) at baseline (low LVEF group). Low-flow AS was defined as a mean transvalvular gradient of <40 mm Hg and a peak aortic jet velocity of <4.0 m/s in patients with LVEF <45% and an aortic valve area of <0.8 cm 2 (or indexed aortic valve area <0.5 cm 2 /m 2 ).
Patients with low-flow AS underwent DSE. LV outflow tract diameter was assumed to be constant at different flow states, and the baseline value was used to calculate stroke volume at baseline and during dobutamine infusion according to standard formula. Dobutamine infusion was started at 5 μg/kg/min and titrated upward to a maximum dose of 40 μg/kg/min. Presence of contractile reserve during DSE was defined as an increase in stroke volume of ≥20% compared with the baseline. All patients with contractile reserve had fixed AS, defined as an increase in valve area of <0.3 cm 2 with a final valve area of <0.8 cm 2 .
An additional predefined subgroup of patients with AS included patients with impaired LV function who underwent BAV before TAVI, as previously described. At the physician’s discretion, these patients were selected for BAV before TAVI. Briefly, BAV was performed retrograde using a standard technique. The LV aortic pressure gradient was measured with dual transducers, and cardiac output was calculated using thermodilution or the Fick method. The diameter of the balloon catheter was selected after measurement of the aortic annulus diameter using 2-dimensional echocardiography or aortic root angiography. The balloon was manually inflated for 5 to 10 seconds. Rapid pacing was used (typically at a rate of 180 to 200 beats/min) to produce a decrease in systolic blood pressure ≤50 mm Hg during balloon inflation. Hemodynamics were reassessed after successful balloon inflation and compared with the measurements before procedure. Additionally, procedural parameters and pre- and postprocedural echocardiograms were also collected. Successful BAV was defined as a >20% increase in aortic valve area or a decrease in mean gradient across the aortic valve. For the purpose of this subanalysis, patients who underwent BAV were divided according to contractile recovery after BAV, as defined by an increase of ≥10% in follow-up echocardiography that was performed before TAVI.
Statistical analysis was performed using SAS, version 9.1 (SAS Institute Inc., Cary, North Carolina). Continuous variables are expressed as mean ± SD or median (twenty-fifth to seventy-fifth percentile interquartile range), as appropriate, according to variable distribution. Categorical variables are expressed as percentages. Student t test or Wilcoxon rank sum test was used to compare continuous variables according to normality test, and the chi-square test or Fisher’s exact test was used to compare categorical variables. To assess the trend in change in LVEF in both groups, the 1-way analysis of variance test was used. Survival rates up to 1 year were computed using the Kaplan-Meier method, and differences in parameters were assessed using the log-rank test. A Cox proportional hazards analysis was performed to assess the independent predictors of 1-year mortality in each group, with adjustments made for baseline and clinical variables associated with the outcome of interest in the univariate analysis. A p value of <0.05 was considered statistically significant.
Results
A total of 371 patients were included in the analysis. Of them, 272 (73%) had preserved LVEF and 99 (27%) had low LVEF. The study cohort represented a high-risk population with an average age of 84 ± 7 years, with a Society of Thoracic Surgeons score of 10.5 ± 4.6% and logistic EuroSCORE of 29 ± 24%. The baseline characteristics of patients with preserved versus low LVEF are listed in Table 1 . Overall, patients with low LVEF constituted a higher risk group with higher Society of Thoracic Surgeons scores (12 ± 5% vs 10 ± 4%, p <0.001) and higher logistic EuroSCORE (38 ± 27% vs 26 ± 22%, p = 0.001) compared with patients with preserved LVEF. These higher risk scores were mainly driven by greater proportion of men (64% vs 43%, p <0.001), previous myocardial infarction (30% vs 9%, p <0.001), previous percutaneous coronary intervention (34% vs 25%, p = 0.08), previous coronary artery bypass surgery (50% vs 26%, p <0.001), and higher rates of pacemaker or defibrillator use (36% vs 13%, p <0.001) among patients with low LVEF compared with patients with preserved LVEF, respectively.
| Variable | LVEF | p Value | |
|---|---|---|---|
| Preserved (n = 272) | Low (n = 99) | ||
| Age (yrs) | 84 ± 7 | 84 ± 7 | 0.55 |
| Men | 117 (43) | 63 (64) | <0.001 |
| Co-morbidities | |||
| Systemic hypertension | 251 (92) | 91 (93) | 0.85 |
| Current or past smoker | 47 (24) | 19 (30) | 0.35 |
| Diabetes mellitus | 79 (29) | 34 (35) | 0.31 |
| Chronic obstructive lung disease | 84 (31) | 29 (30) | 0.85 |
| Renal failure | 144 (55) | 62 (64) | 0.13 |
| Hemodialysis | 2 (0.8) | 2 (2) | 0.30 |
| Peripheral vascular disease | 93 (36) | 36 (41) | 0.33 |
| History of coronary artery disease | 137 (79) | 68 (87) | 0.11 |
| Previous myocardial infarction | 24 (9) | 28 (30) | <0.001 |
| Previous percutaneous coronary intervention | 66 (25) | 32 (34) | 0.08 |
| Previous coronary artery bypass surgery | 70 (26) | 48 (50) | <0.001 |
| Previous valve surgery | 7 (4) | 1 (2) | 0.68 |
| History of stroke or transient ischemic attack | 58 (22) | 18 (18) | 0.48 |
| Permanent pacemaker/implantable cardioverter-defibrillator | 25 (13) | 26 (36) | <0.001 |
| Risk assessment | |||
| Society of Thoracic Surgeons score (%) | 10 ± 4 | 12 ± 5 | <0.001 |
| Logistic EuroSCORE (%) | 26 ± 22 | 38 ± 27 | 0.001 |
| Baseline echocardiography | |||
| LV end-diastolic diameter (mm) | 4.2 ± 0.6 | 5 ± 0.7 | <0.001 |
| LV end-systolic diameter (mm) | 2.7 ± 0.6 | 3.9 ± 0.7 | <0.001 |
| LVEF (%) | 60 ± 5 | 33 ± 8 | <0.001 |
| Aortic valve area (cm 2 ) | 0.6 ± 0.1 | 0.7 ± 0.1 | 0.01 |
| Mean gradient (mm Hg) | 51 ± 12 | 42 ± 13 | <0.001 |
| Peak velocity | 4.5 ± 0.5 | 4.1 ± 0.6 | <0.001 |
| Moderate/severe mitral regurgitation | 21 (9) | 15 (17) | 0.04 |
| Systolic pulmonary artery pressure (mm Hg) | 47 ± 16 | 45 ± 16 | 0.28 |
Baseline echocardiographic parameters are outlined in Table 1 . Patients with low LVEF had lower baseline LVEF (33 ± 8%) compared with patients with preserved LVEF (60 ± 5%, p <0.001). Patients with low LVEF had dilated left ventricles as represented by larger dimensions at end-systole and end-diastole. With relation to the dilated ventricle, patients with low LVEF also had higher rates of significant mitral regurgitation at baseline. Of the patients with low LVEF, 40 (40%) met the criteria for low-flow AS.
Procedural characteristics did not differ between patients with preserved and low LVEF ( Table 2 ). Most patients (74%) underwent transfemoral access with conscious sedation. No differences in procedural ( Table 2 ) or in-hospital ( Table 3 ) complications between patients in both groups were found. Short- and long-term mortality did not differ between groups ( Figure 1 ). In-hospital mortality rate of patients with low LVEF was 8.1% versus patients with preserved LVEF (9.6%, p = 0.66). The 30-day (9.1% vs 10.3%, respectively, p = 0.73) and 1-year mortality (22.2% vs 22.4%, respectively, p = 0.79) rates were similar as well. By multivariate analysis, baseline LVEF (hazard ratio [HR] 1.1, 95% confidence interval [CI] 0.63 to 2.02), male gender (HR 1.21, 95% CI 0.59 to 2.49), previous bypass surgery (HR 0.83, 95% CI 0.46 to 1.51), baseline aortic valve area (HR 3.87, 95% CI 0.42 to 35.9), baseline moderate or severe mitral regurgitation (HR 0.83, 95% CI 0.11 to 6.21), peripheral vascular disease (HR 1.24, 95% CI 0.75 to 2.06), and implanted valve size (HR 1.4, 95% CI 0.7 to 2.81) were not independent predictors of 1-year mortality. The only independent predictor of mortality was previous myocardial infarction (HR 2.4, 95% CI 1.33 to 4.35).
| Variable | LVEF | p Value | |
|---|---|---|---|
| Preserved (n = 272) | Low (n = 99) | ||
| Approach | |||
| Transfemoral | 205 (75) | 69 (70) | 0.28 |
| Transapical | 65 (24) | 30 (30) | 0.21 |
| Direct aortic | 2 (0.7) | 0 | 1.0 |
| Valve size | |||
| 23 mm | 163 (60) | 39 (40) | <0.001 |
| 26 mm | 99 (36) | 55 (56) | <0.001 |
| 29 mm | 9 (3.3) | 2 (2) | 0.74 |
| 31 mm | 3 (1.1) | 2 (2) | 0.61 |
| Sedation | |||
| Conscious sedation | 165 (60) | 58 (59) | 0.72 |
| General anesthesia | 108 (40) | 41 (41) | 0.77 |
| Fluoroscopy time (minutes) | 32 ± 202 | 93 ± 43 | 0.09 |
| Contrast volume (ml) | 117 ± 72 | 120 ± 69 | 0.76 |
| Successful valve deployment | 267 (99) | 97 (99) | 1.0 |
| Complications | |||
| Unplanned cardiopulmonary bypass | 5 (1.8) | 3 (3) | 0.45 |
| Tamponade | 4 (1.5) | 0 | 0.58 |
| Ventricular tachycardia/fibrillation | 10 (3.7) | 3 (3) | 1.0 |
| Ventricular injury | 3 (1.1) | 1 (1) | 1.0 |
| Complete atrioventricular block | 11 (4.1) | 3 (3) | 0.77 |
| Hemodynamic instability | 20 (7) | 9 (9) | 0.59 |
| Variable | LVEF | p Value | |
|---|---|---|---|
| Preserved (n = 272) | Low (n = 99) | ||
| Major vascular complications | 33 (12) | 8 (8) | 0.27 |
| Life-threatening bleed | 26 (10) | 6 (6) | 0.28 |
| Myocardial infarction | 0 | 0 | |
| Stroke | 18 (7) | 5 (5) | 0.58 |
| Acute kidney injury | |||
| Stage 1 | 20 (7.8) | 11 (11.6) | 0.27 |
| Stage 2 | 3 (1.2) | 1 (1.1) | 1.0 |
| Stage 3 | 6 (2.3) | 1 (1.1) | 0.68 |
| Moderate/severe aortic regurgitation | 10 (4.1) | 4 (4.4) | 1.0 |
| Heart failure | 53 (20) | 22 (22) | 0.56 |
| Hemodynamic compromise | 55 (20) | 20 (20) | 1.0 |
| New pacemaker | 9 (3.3) | 4 (4) | 0.75 |
| Postprocedure length of stay (days) | 7.8 ± 7.2 | 7.2 ± 6.4 | 0.45 |
| Intensive care unit stay (days) | 3.3 ± 5.5 | 2.6 ± 3 | 0.11 |
| Death | 26 (9.6) | 8 (8.1) | 0.66 |
LVEF improved significantly and continuously from baseline up to 1-year follow-up in patients with low LVEF at baseline (p <0.001; Figure 2 ). For assessment of predictors of recovery in LV function in patients with baseline low LVEF (n = 99), patients were divided according to improvement in LVEF of ≥10% at 30-day follow-up ( Table 4 ). Only 24 patients (24%) demonstrated improvement (≥10%) in LVEF at 30 days. These patients were less frequently male (odds ratio [OR] 0.41, 95% CI 0.16 to 1.0), less likely to have peripheral vascular disease (OR 0.33, 95% CI 0.11 to 1.01), and less likely to have previous coronary bypass surgery (OR 0.39, 95% CI 0.15 to 1.03). Baseline echocardiography showed that these patients tended to have slightly lower LVEF before TAVI, smaller valve area (OR 0.02, 95% CI 0 to 1.12), and significantly less LV dilatation as represented by smaller end-systolic diameter (OR 0.45, 95% CI 0.20 to 1.00; Table 4 ). Lack of improvement in LVEF after TAVI was associated with a threefold higher 1-year mortality rate (27%) compared with patients with improvement in LVEF (8%, p = 0.06).
| Variable | LVEF Improvement | p Value | |
|---|---|---|---|
| Yes (n = 24) | No (n = 75) | ||
| Age (yrs) | 84 ± 8 | 83 ± 6 | 0.28 |
| Men | 11 (46) | 52 (69) | 0.04 |
| Co-morbidities | |||
| Systemic hypertension | 21 (88) | 71 (95) | 0.36 |
| Current or past smoker | 6 (30) | 13 (30) | 0.99 |
| Diabetes mellitus | 5 (21) | 29 (39) | 0.11 |
| Chronic obstructive lung disease | 7 (30) | 22 (30) | 0.95 |
| Renal failure | 15 (63) | 47 (64) | 0.93 |
| Hemodialysis | 0 | 2 (3) | 1 |
| Peripheral vascular disease | 5 (23) | 31 (47) | 0.05 |
| History of coronary artery disease | 14 (93) | 55 (86) | 0.68 |
| Previous myocardial infarction | 8 (33) | 20 (29) | 0.66 |
| Previous percutaneous coronary intervention | 8 (33) | 25 (35) | 0.87 |
| Previous coronary artery bypass surgery | 8 (33) | 41 (56) | 0.05 |
| Previous valve surgery | 0 | 1 (2) | 1.0 |
| History of stroke or transient ischemic attack | 3 (13) | 15 (20) | 0.55 |
| Permanent pacemaker/implantable cardioverter-defibrillator | 5 (31) | 22 (39) | 0.59 |
| Risk assessment | |||
| Society of Thoracic Surgeons score (%) | 11 ± 4 | 12 ± 6 | 0.38 |
| Logistic EuroSCORE (%) | 32 ± 27 | 39 ± 28 | 0.32 |
| Baseline echocardiography | |||
| LV end-diastolic diameter (mm) | 4.8 ± 0.6 | 5 ± 0.7 | 0.16 |
| LV end-systolic diameter (mm) | 3.6 ± 0.7 | 4 ± 0.7 | 0.04 |
| LVEF (%) | 30 ± 9 | 34 ± 8 | 0.07 |
| Aortic valve area (cm 2 ) | 0.6 ± 0.1 | 0.7 ± 0.1 | 0.05 |
| Mean gradient (mm Hg) | 47 ± 17 | 41 ± 11 | 0.13 |
| Peak velocity | 4.2 ± 0.7 | 4 ± 0.5 | 0.3 |
| Moderate/severe mitral regurgitations | 5 (26) | 10 (14) | 0.5 |
| Systolic pulmonary artery pressure (mm Hg) | 42 ± 13 | 46 ± 17 | 0.32 |
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