Left ventricular systolic dysfunction in patients with severe aortic stenosis (AS) is associated with poor outcome. This analysis was designed primarily to describe the clinical course of a large series of consecutive patients with severe AS and low ejection fraction (EF) (<40%) who, because of high surgical risk, were referred for transcatheter aortic valve implantation consideration. A cohort of 270 patients with severe AS and low EF (<40%) who were referred to participate in a clinical trial of transcatheter aortic valve implantation was studied. Clinical, hemodynamic, and periprocedural complications and follow-up mortality data were collected and compared between patients with low mean transvalvular gradients (≤40 mm Hg, n = 170 [63%]) and high transvalvular gradients (>40 mm Hg, n = 100 [37%]). Patients with low gradients were younger (mean age 79.8 ± 9.1 vs 83.8 ± 7.7 years, p <0.001) and had higher incidences of coronary artery disease and renal failure. Mean aortic valve area was larger (0.73 ± 0.23 vs 0.53 ± 0.18 cm 2 , p <0.001), while mean EF (26.4 ± 6.9% vs 30.5% ± 6.6%, p <0.001), cardiac output (3.7 ± 1.1 vs 4.1 ± 1.3 L/min, p = 0.04), and cardiac index (1.9 ± 0.5 vs 2.1 ± 0.6 L/min/m 2 , p = 0.04) were lower in patients with lower gradients compared to those with higher gradients, respectively. Mortality was higher in patients with low gradients (53.8%) at a mean follow-up of 151 days compared to those with high gradients (41%) at a mean follow-up of 256 days (p = 0.01). In conclusion, patients with severe AS and low EF with low transvalvular gradients are at higher risk for worse outcomes compared to patients with high transvalvular gradients. Surgery or transcatheter aortic valve implantation treatment and high baseline transvalvular gradient are associated with EF improvement.
Patients with severe aortic stenosis (AS) and reduced left ventricular ejection fraction (EF) have a poor prognosis when treated medically. Consequently, despite relatively high operative risk, surgical aortic valve replacement (SAVR) is recommended for such patients. Operative risk is particularly high in patients with low transvalvular mean gradients. Transcatheter aortic valve implantation (TAVI) has been introduced as an alternative to SAVR in high-risk patients with severe AS. This analysis was designed primarily to describe the clinical course of a large series of consecutive patients with severe AS and low EF (<40%) who, because of high surgical risk, were referred for TAVI consideration. Second, we sought to compare the clinical courses of patients with low transvalvular gradients (≤40 mm Hg) to those of patients with similarly severe AS and higher transvalvular gradients (>40 mm Hg). Finally, in patients with severe AS and low EF (<40%), we sought to compare the EF response to TAVI, SAVR, or balloon aortic valvuloplasty (BAV).
Methods
From April 2007 to December 2010, 890 consecutive patients with severe symptomatic AS, defined as aortic valve area <1 cm 2 or aortic valve index <0.5 cm 2 /m 2 , who were referred for participation in a randomized TAVI trial (Placement of Aortic Transcatheter Valves [PARTNER]) were prospectively entered into a dedicated database and thus considered for this analysis. All patients were screened and gave written consent for the study. Those with severe AS (aortic valve area <1 cm 2 or aortic valve index <0.5 cm 2 /m 2 ) and low EF (<40%) were included (n = 270).
The study population was divided into 2 groups: patients with low mean transvalvular gradients (≤40 mm Hg, n = 170 [63%]) and those with high transvalvular gradients (>40 mm Hg, n = 100 [37%]). Within this cohort, 38 patients (14%) underwent TAVI; 232 were excluded from the TAVI trial and received treatment on the basis of the decisions made by a multidisciplinary team (interventional cardiologist, cardiac surgeon, and primary cardiologist). Medical treatment without other intervention was given to 55 (20.3%), BAV to 144 (53.3%), and SAVR to 33 (12.2%). All patients were followed by telephone contact or office visit.
All patients underwent transthoracic echocardiography and Doppler studies. Two-dimensional images were obtained from parasternal long- and short-axis, apical 4-chamber, and subcostal 4-chamber views. Transthoracic echocardiograms were reviewed to assess the pericardium, valvular anatomy and function, and cardiac function. Continuous-wave Doppler was used to measure maximum jet velocity. The left ventricular EF was calculated using biplane Simpson’s methods; transvalvular pressure gradient was determined using the Bernoulli formula, and aortic valve area was calculated using the continuity equation on the basis of measurement of left ventricular outflow tract diameter in a parasternal long-axis view for calculation of a circular cross-sectional area, outflow tract velocity from an apical approach using pulsed Doppler, and the maximum aortic jet from the continuous-wave Doppler recording.
Right-sided cardiac catheterization was performed with a 7Fr Swan-Ganz catheter (Edwards Lifesciences, Irvine, California). We carefully measured right atrial pressures (amplitudes of a and v waves and mean pressure), right ventricular systolic and diastolic pressures, pulmonary artery pressures (systolic, diastolic, and mean), and pulmonary capillary wedge pressures (a and v waves and mean pressure). Cardiac output was determined using the thermodilution method. Left-sided cardiac catheterization was carried out from the femoral artery. Aortic valve area was calculated using the Gorlin formula.
The BAV procedure was performed according to standard techniques via the retrograde femoral approach. Heparin (10 to 70 U/kg) was administrated in all patients after insertion of an 8Fr to 13Fr sheath. Peak and mean gradients, together with thermodilution cardiac outputs, were recorded. To stabilize the balloon position across the valve before balloon inflation, the right ventricle was paced at a high rate (180 to 200 beats/min) until the systemic blood pressure decreased to <50 mm Hg. Pacing was continued until the balloon was fully deflated.
SAVR was performed under standard anesthesia and followed standard surgical techniques, extracorporeal circulation, and myocardial protection methods. Patients underwent anticoagulation using 3 mg/kg heparin sulfate to maintain an activated clotting time of ≥480 seconds. Bioprostheses (Carpentier-Edwards Perimount Magna, sizes 19 to 25 mm; Edwards Lifesciences) were implanted and concomitant coronary artery bypass surgery was done in 15 patients (45.4%).
The TAVI procedure was performed using the Edwards Sapien (Edward Lifesciences) balloon-expandable prosthesis. Overall, 21 patients (55.2%) received 23-mm valves and 17 patients (44.7%) received 26-mm valves. The procedures were performed by the transfemoral approach in 26 (68.4%) and by the transapical approach in 12 (31.6%). All procedures were done under adjuvant transesophageal guidance.
Continuous variables are presented as mean ± SD and categorical variables as percentages. Days of follow-up are presented as median and interquartile intervals (25th to 75th percentiles). Differences between continuous variables were assessed using Student’s t tests. Paired tests were analyzed using paired Student’s t tests. Categorical variables were compared using chi-square or Fisher’s exact tests as indicated. Significance was set at p <0.05. Cumulative survival curves were constructed using the Kaplan-Meier method and compared using log-rank tests.
The effects of clinical characteristics, echocardiographic and hemodynamic variables, and the type of treatment option were studied using multivariate logistic regression analysis to identify variables associated with improvement in the EF after BAV, SAVR, or TAVI.
Results
Baseline clinical characteristics of low- and high-gradient patients are listed in Table 1 . Those with low gradients were younger by 4 years (p <0.001) and more often had coronary heart disease, as evidenced by more previous myocardial infarctions (p = 0.01) and coronary bypass surgery (p <0.001). They also more often had renal insufficiency (p = 0.03).
| Variable | Peak Transvalvular Gradient (mm Hg) | p Value | |
|---|---|---|---|
| ≤40 (n = 170) | >40 (n = 100) | ||
| Age (years) | 79.8 ± 9.1 | 83.8 ± 7.7 | <0.001 |
| Women | 65 (38.2%) | 45 (45%) | 0.25 |
| Society of Thoracic Surgeons score (%) | 14.2 ± 7.0 | 13.9 ± 7.7 | 0.75 |
| Logistic European System for Cardiac Operative Risk Evaluation score | 57.5 ± 21.9 | 54.0 ± 21.5 | 0.22 |
| Body surface area (m 2 ) | 1.85 ± 0.26 | 1.82 ± 0.25 | 0.49 |
| Cardiogenic shock | 7 (4%) | 7 (7%) | 0.29 |
| New York Heart Association class IV | 126 (74%) | 70 (70%) | 0.51 |
| Diabetes mellitus | 76 (45%) | 33 (33%) | 0.06 |
| Systemic hypertension ⁎ | 147 (86%) | 88 (88%) | 0.63 |
| Hyperlipidemia | 144 (85%) | 73 (73%) | 0.02 |
| Coronary artery disease | 133 (78%) | 64 (64%) | 0.01 |
| Previous myocardial infarction | 85 (50%) | 34 (34%) | 0.01 |
| Previous coronary artery bypass grafting | 77 (45%) | 27 (27%) | <0.001 |
| Chronic obstructive pulmonary disease | 37 (22%) | 20 (20%) | 0.74 |
| Creatinine clearance <60 ml/min | 103 (61%) | 47 (47%) | 0.03 |
| Previous cerebrovascular accident/transient ischemic attack | 36 (21%) | 24 (24.0%) | 0.57 |
| Atrial fibrillation | 66 (39%) | 35 (35%) | 0.55 |
| Peripheral vascular disease | 51 (30%) | 29 (29%) | 0.88 |
⁎ History of systemic hypertension diagnosed and/or treated with medication or currently being treated with diet and/or medication by a physician.
Table 2 compares the echocardiographic and hemodynamic measurements of the 2 groups. Aortic valve area was larger (p <0.001), while the EF and cardiac output were lower (p <0.001 and p <0.04, respectively). Importantly, pulmonary artery wedge pressure was similar between the 2 groups. B-type natriuretic peptide was higher but not significantly so in those with low gradients.
| Variable | Peak Transvalvular Gradient (mm Hg) | p Value | |
|---|---|---|---|
| ≤40 (n = 170) | >40 (n = 100) | ||
| Laboratory values | |||
| Hematocrit (%) | 36.0 ± 4.9 | 35.2 ± 4.6 | 0.18 |
| Hemoglobin (mg/dl) | 11.7 ± 1.7 | 11.5 ± 1.6 | 0.26 |
| Creatinine (mg/dl) | 1.8 ± 1.4 | 1.6 ± 1.3 | 0.2 |
| B-type natriuretic peptide (pg/ml) | 1,920 ± 1,330 | 1,503 ± 1,141 | 0.07 |
| Echocardiographic parameters | |||
| EF (%) | 26.4 ± 6.9 | 30.5 ± 6.6 | <0.001 |
| Ventricular septal thickness (mm) | 1.25 ± 0.2 | 1.33 ± 0.27 | 0.01 |
| Aortic valve area (cm 2 ) | 0.80 ± 0.16 | 0.66 ± 0.17 | <0.001 |
| Vmax (m/s) | 3.3 ± 0.5 | 4.2 ± 0.6 | <0.001 |
| Mean transvalvular aortic gradient (mm Hg) | 27.6 ± 8.9 | 47.3 ± 13.8 | <0.001 |
| Pulmonary artery systolic pressure (mm Hg) | 48.9 ± 15.8 | 54.1 ± 16.3 | 0.03 |
| Moderate to severe mitral regurgitation | 55 (32.3%) | 20 (20%) | 0.02 |
| Moderate to severe tricuspid regurgitation | 27 (15.8%) | 17 (17%) | 0.8 |
| Hemodynamic parameters | |||
| Aortic valve area (cm 2 ) | 0.73 ± 0.23 | 0.53 ± 0.18 | <0.001 |
| Mean gradients across aortic valve (mm Hg) | 27.2 ± 9.4 | 58.2 ± 12.7 | <0.001 |
| Pulmonary artery systolic pressure (mm Hg) | 54.6 ± 15.6 | 57.5 ± 15.4 | 0.16 |
| Pulmonary capillary wedge pressure (mm Hg) | 22.3 ± 8.8 | 22.5 ± 8.5 | 0.88 |
| Cardiac output (L/min) | 3.7 ± 1.1 | 4.1 ± 1.3 | 0.04 |
| Treatment modality | |||
| Medical | 46 (27.0%) | 9 (9.0%) | <0.001 |
| BAV | 88 (51.7%) | 56 (56%) | 0.49 |
| SAVR | 20 (11.7%) | 13 (13%) | 0.73 |
| TAVI | 16 (9.4%) | 22 (22%) | 0.003 |
| EF after intervention | (n = 91) | (n = 79) | |
| Δ EF immediately after intervention (BAV, TAVI, or SAVR) | 4.9 ± 8.1 | 9.3 ± 11.2 | 0.004 |
The treatment strategy used varied widely, but some trends are notable, because the choice of therapy was associated with outcome. Those with low gradients were more frequently treated medically (27% vs 9%, p <0.001) and less commonly with TAVI compared to patients with high gradients (9.4% vs 22%, p = 0.003). Importantly, only 21.1% of this group underwent either form of valve replacement compared to 35.0% of those in the high-gradient group.
Kaplan-Meier curves were used to compare overall survival for low- and high-gradient patients without regard to treatment strategy ( Figure 1 ) . Those with low gradients (n = 92) had a mortality rate of 53.8% during a median follow-up period of 151 days (interquartile range 55 to 348), and those with high gradients had a mortality rate of 41% (n = 41) during a median follow-up period of 246 days (interquartile range 88 to 550) (p = 0.01).
Figure 2 illustrates survival curves comparing observations with regard to treatment modality. In those with medical therapy alone, the mortality rate was 56.3% (n = 31). The addition of BAV (n = 79) offered no advantage; survival was 54.8%. Mortality rate was significantly better in the relatively small groups that underwent TAVI (n = 12 [31.5%]) and SAVR (n = 10 [30.3%]). Thus, those with either form of valve replacement had significantly better survival than those with medical therapy alone or with BAV plus medical treatment. The effects of patient selection for SAVR and TAVI are the likely explanation.
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