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Predictors of Mortality and Outcomes of Therapy in Low-Flow Severe Aortic Stenosis

A Placement of Aortic Transcatheter Valves (PARTNER) Trial Analysis
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.112.001290Circulation. 2013;127:2316–2326

    Abstract

    Background—

    The prognosis and treatment of patients with low-flow (LF) severe aortic stenosis are controversial.

    Methods and Results—

    The Placement of Aortic Transcatheter Valves (PARTNER) trial randomized patients with severe aortic stenosis to medical management versus transcatheter aortic valve replacement (TAVR; inoperable cohort) and surgical aortic valve replacement versus TAVR (high-risk cohort). Among 971 patients with evaluable echocardiograms (92%), LF (stroke volume index ≤35 mL/m2) was observed in 530 (55%); LF and low ejection fraction (<50%) in 225 (23%); and LF, low ejection fraction, and low mean gradient (<40 mm Hg) in 147 (15%). Two-year mortality was significantly higher in patients with LF compared with those with normal stroke volume index (47% versus 34%; hazard ratio, 1.5; 95% confidence interval, 1.25–1.89; P=0.006). In the inoperable cohort, patients with LF had higher mortality than those with normal flow, but both groups improved with TAVR (46% versus 76% with LF and 38% versus 53% with normal flow; P<0.001). In the high-risk cohort, there was no difference between TAVR and surgical aortic valve replacement. In patients with paradoxical LF and low gradient (preserved ejection fraction), TAVR reduced 1-year mortality from 66% to 35% (hazard ratio, 0.38; P=0.02). LF was an independent predictor of mortality in all patient cohorts (hazard ratio, ≈1.5), whereas ejection fraction and gradient were not.

    Conclusions—

    LF is common in severe aortic stenosis and independently predicts mortality. Survival is improved with TAVR compared with medical management and similar with TAVR and surgical aortic valve replacement. A measure of flow (stroke volume index) should be included in the evaluation and therapeutic decision making of patients with severe aortic stenosis.

    Clinical Trial Registration—

    URL: http://www.clinicaltrial.gov. Unique identifier: NCT0053089.4.

    Introduction

    Aortic valve replacement (AVR) is indicated for patients with severe aortic stenosis (AS) associated with either symptoms or left ventricular (LV) dysfunction.1,2 Severe AS is generally defined as an aortic valve area ≤1.0 cm2 and a mean transvalvular gradient of ≥40 mm Hg. However, many patients with symptomatic and severe AS may have lower gradients resulting from LV systolic dysfunction (so-called low flow [LF], low ejection fraction [LEF]), high afterload with pronounced LV concentric remodeling (paradoxical LF, normal ejection fraction [NEF]), and from errors or assumptions inherent in the measurement of gradient and valve area.37 These patients have a prognosis similar to or worse than that for patients with classic AS, both with and without surgery.614 However, little is known about the prognostic value of LF independently of gradient and EF and its treatment.

    Clinical Perspective on p 2326

    Transcatheter AVR (TAVR) has recently emerged as an alternative to open surgical AVR (SAVR) in both inoperable and high-risk patients with severe AS.1518 To better understand the implications of LF in severe AS, we used core echocardiographic laboratory data to examine the prognostic implications of LF, low gradient (LG), and LEF in the prospective, randomized Placement of Aortic Transcatheter Valves (PARTNER) trial and to examine the comparative benefits of medical management (MM), SAVR, and TAVR.

    Methods

    Study Population

    The PARTNER trial was a multicenter, randomized, clinical trial comparing TAVR with standard therapy (SAVR) in high-risk patients (cohort A)16 and included a prespecified cohort of patients who were not considered to be suitable candidates for surgery (inoperable; cohort B).15 All patients had symptoms (New York Heart Association classes II–IV) and severe AS. Inclusion criteria for this trial included a site-measured echocardiographic aortic valve area of <0.8 cm2 (or indexed aortic valve area <0.5 cm2/m2) and either a mean transvalvular gradient ≥40 mm Hg or a peak aortic jet velocity ≥4.0 m/s (64 mm Hg). Important exclusion criteria included substantial coronary artery disease requiring revascularization, EF <20%, or severe (4+) aortic or mitral regurgitation. Patients were treated with the Edwards SAPIEN balloon-expandable bovine pericardial heart valve system (Edwards Lifesciences). The primary end point for the study (both cohorts) was all-cause mortality at ≥1 year, but follow-up has continued, allowing subsequent analyses with adjudicated events.17,18 All echocardiograms were analyzed by an independent core laboratory.19 The database for the study is maintained at the Cardiovascular Research Foundation (New York, NY), where independent statistical analyses can be requested by investigators.

    In this analysis, patients with evaluable echocardiograms were classified into 2 groups based on baseline echocardiographic stroke volume index (SVI) of ≤35 mL/m2 (LF) or normal flow (NF).2,4 The LF group was then further divided on the basis of EF <50% (LF LEF) or normal EF (LF NEF) and gradient <40 mm Hg (LF LG) or ≥40 mm Hg (LF with normal gradient; Figure 1). In all groups, patients were analyzed by cohort (cohort A, high risk; cohort B, inoperable) and treatment received (MM, SAVR, or TAVR).

    Figure 1.

    Figure 1. Flow chart of patients enrolled in the Placement of Aortic Transcatheter Valves (PARTNER) trial and then subdivided by flow, ejection fraction, gradient, cohort inclusion, and treatment. A indicates high-risk cohort; B, inoperable cohort; LEF, low ejection fraction; LF, low flow; LG, low gradient; MM, medical management; NEF, normal ejection fraction; NF, normal flow; NG, normal gradient; SAVR, surgical aortic valve replacement; and TAVR, transcatheter aortic valve replacement.

    Echocardiographic Measurements

    All baseline and follow-up echocardiograms were interpreted by an independent core laboratory housed at the Duke Clinical Research Institute. Study work flow, reproducibility testing, image acquisition and analysis, and quality assurance data have been published.19 All chamber parameters were measured in standard views according to the recommendations of the American Society of Echocardiography.20 LV volumes and EFs were measured with the biplane Simpson volumetric method combining apical 4-chamber and 2-chamber views when possible; if image quality was inadequate, EF was estimated visually in 5-percentage-point increments. Stroke volume and cardiac output were calculated by Doppler using the velocity-time integral of the LV outflow tract and its diameter in midsystole of the aortic annulus in the parasternal long-axis view.19,20

    Statistical Analysis

    All analyses were performed with data from the intention-to-treat population, which included all patients who underwent randomization, regardless of the treatment actually received. However, only patients with echocardiographic data to allow classification by stroke volume could be included in this report (971 patients, 92%). Categorical variables were compared with the use of the Fisher exact test or χ2 test. Continuous variables are presented as mean±SD or median (interquartile range) for variables with a skewed distribution and compared with the use of the Wilcoxon rank-sum test. Survival curves for time-to-event variables were constructed on the basis of all available follow-up data with the use of Kaplan-Meier estimates and were compared with the use of the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model. We examined univariate predictors of mortality for 5 baseline echocardiographic variables relating to flow (LF, LG, LEF, aortic regurgitation, mitral regurgitation). Significant variables were then examined in pairwise analyses with each other and in several adjusted multivariable models in the various patient cohorts. Baseline variables entered into the multivariate Cox regression for adjustment were those that showed a statistically significant difference between the LF and NF groups. All statistical analyses were performed with the use of SAS software (version 9.2).

    Results

    Baseline Characteristics of Patients With LF

    PARTNER trial patients with evaluable echocardiograms (n=971) were classified into LF (n=530, 55%) or NF (n=441, 45%) on the basis of a calculated Doppler SVI of ≤35 or >35 mL/m2, respectively (Table 1 and Figure 1). LG (≤40 mm Hg) was present in 45% of patients, and aortic valve area >0.8 cm2 was present in 19% of patients. Patients with LF were of an age (84 years) similar to that of patients with NF but were more likely to be male (59% compared with 47%) and had slightly higher Society of Thoracic Surgeons (STS) risk scores and logistic EUROscores. The LF group had more comorbid conditions, including coronary disease, prior pacemaker, a trend to more heart failure symptoms, and higher pulmonary artery and capillary wedge pressures, than those with NF. Procedure success was similar in the 2 groups, with a slightly longer length of stay for those with LF. Patients with LF had numerous echocardiographic differences compared with those with NF, including larger LV size (both diastolic and systolic), lower EF, lower gradient, lower calculated aortic valve areas, less aortic regurgitation, and more mitral regurgitation (Table 1). At 30 days of follow-up, there were nonsignificant trends to greater all-cause mortality in patients with LF compared with NF. For subsequent analyses, the patients with LF were further subdivided on the basis of an LVEF <50% or ≥50% and gradient ≤40 or >40 mm Hg. LF and LEF (mean EF, 37±9%) were present in 225 patients (23% of the total study population), and 147 of these patients also had a low mean transvalvular gradient (mean gradient, 29±7 mm Hg, 15% of total population; Figure 1). Paradoxical LF with NEF was present in 304 patients (31% of the total population), and 139 of these patients also had LG (14% of the total population). Patients with LF and NEF had smaller LV end-diastolic volume (100 mL) than those with LEF (149 mL; P<0.0001).

    Table 1. Comparison of Low-Flow and Normal-Flow Patients

    Low FlowNormal FlowP Value
    Baseline characteristics
    n (%)530 (55)441 (45)
    Age, mean±SD, y83.5±7.784.1±6.90.65
    Male, %59.246/3<0.0001
    BMI, median (IQR), kg/m226.0 (23.0–30.4)25.4 (22.5–28.9)0.006
    STS score, median (IQR)11.2 (10.0–14.0)11.0 (9.3–13.0)0.02
    Log EUROscore, median (IQR)29.3 (17.0–43.2)23.0 (16.0–34.0)<0.0001
    DM, %401360.13
    NYHA class IV, %52460.07
    CAD, %78700.004
    Prior CABG, %4734<0.0001
    Prior stroke or TIA, %29260.29
    Rheumatic fever, %140.002
    Prior pacemaker, %2515<0.0001
    Procedure
    Successful implantation, %97970.85
    26-mm valve, %53440.08
    Hemodynamic support (CPB/IABP), %640.28
    Conversion to open surgery, %221
    Time in hospital after the procedure, mean±SD, d7.45±3.387.07±3.710.056
    Hemodynamics, mean±SD
    PAP, mm Hg30.7±11.528.1±9.60.02
    PCWP, mm Hg22.4±9.318.9±7.40.0005
    Aortic gradient, mm Hg40.1±15.142.8±16.70.14
    AVA, cm20.7±0.20.6±0.20.5
    CI, L·min−1·m21.93±0.582.23±0.75<0.0001
    Echocardiographic parameters
    LVEDD, mean±SD, cm4.61±0.794.36±0.75<0.0001
    LVESD, mean±SD, cm3.49±0.953.01±0.87<0.0001
    LVEDV, mean±SD, mL126±50116±440.05
    LVESV, mean±SD, mL69±4154±32<0.0001
    Ejection fraction, %49±1457±11<0.0001
    Stroke volume, mL57±2063±210.0001
    Stroke volume index, mL/m226.8±5.644.3±8.0<0.0001
    Mean aortic gradient, mm Hg40.3±14.347.4±14.2<0.0001
    AVA, cm20.56±0.160.74±0.19<0.0001
    Baseline AR, % moderate/severe818<0.0001
    Baseline MR, % moderate/severe25160.0005
    In-hospital events (adjudicated), %
    Death1280.06
    CV death740.1
    Stroke/TIA440.79
    Vascular complications12150.11
    New PPM430.88
    30-d events (adjudicated), %
    Death1390.08
    CV death750.09
    Stroke/TIA440.98

    AR indicates aortic regurgitation; AVA, aortic valve area; BMI, body mass index; CABG, coronary artery bypass graft; CAD, coronary artery disease; CI, cardiac index; CPB, cardiopulmonary bypass; CV, cardiovascular; DM, diabetes mellitus; IABP, intra-aortic balloon pump; IQR, interquartile range; LVEDD, left ventricular end-diastolic dimension; LVEDV, left ventricular end-diastolic volume; LVESD, left ventricular end-systolic dimension; LVESV, left ventricular end-systolic volume; MR, mitral regurgitation; NYHA, New York Heart Association; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PPM, permanent pacemaker; STS, Society of Thoracic Surgeons; and TIA, transient ischemic attack

    Mortality of Patients With LF Severe AS

    When the intention-to-treat combined (inoperable and high-risk) cohorts of the PARTNER trial were used, all-cause mortality at 2 years was higher in patients with LF versus NF (47.1% versus 33.7%; hazard ratio [HR], 1.58; 95% confidence interval [CI], 1.28–1.95; P<0.0001; Figure 2A). There was no additional increase in mortality when the LF patients were further divided into those with LEF and those with NEF (Figure 2B) and those with LG versus those with normal gradient (Figure 2C), although the overall mortality in all of these subgroups remained high, approximating 50% at 2 years. A sensitivity analysis revealed no difference with a cut point for EF of 40% (HR, 1.07; P=0.647) versus an EF of 50% (HR, 1.07; P=0.606).

    Figure 2.

    Figure 2. Kaplan–Meier all-cause mortality analysis to 2 years is shown for patients with low flow (LF) vs normal flow (NF; A), LF with low ejection fraction (LEF) vs normal ejection fraction (NEF; B), and LF with LEF and low gradient (LG) vs normal gradient (NG; C). CI indicates confidence interval; HR, hazard ratio; and ITT, intention to treat.

    Effect of TAVR and SAVR on Outcome in LF Severe AS

    Treatment with both open surgery and TAVR in LF patients was associated with a marked improvement in both 1-year and 2-year survival (Figure 3). Compared with MM, which had a 2-year mortality of 76%, the mortality with TAVR and SAVR ranged from 38% to 46%. The difference between MM and TAVR in the inoperable cohort was statistically significant (relative risk, 0.49; 95% CI, 0.33–0.72; P=0.0002; Figure 3A), whereas there was no significant difference between TAVR and SAVR in the high-risk group (relative risk, 0.86; 95% CI, 0.58–1.29; P=0.47; Figure 3B). There was a small early hazard associated with SAVR in the first 30 days. After 30 days, the mortality curves in the high-risk group of patients initially diverge with a statistically significant lower mortality for TAVR at 6 months compared with SAVR (15.6% versus 24.7%; relative risk, 0.60; 95% CI, 0.37–0.98; P=0.04) that is no longer significant at 1 year. Similar results and trends were apparent in the LF LEF (Figure I in the online-only Data Supplement) and LF with LEF and LG groups of patients. In particular, for patients with LF, LEF, and LG (Figure 4), mortality at 2 years was markedly reduced from 80.0% to 47.1% (HR, 0.43; 95% CI, 0.19–0.98; P=0.04) with TAVR versus MM in inoperable patients, and there was no difference in high-risk patients between TAVR and SAVR (42.9% versus 37.1%; HR, 1.25; 95% CI, 0.66–2.36; P=0.50).

    Figure 3.

    Figure 3. Treatment for patients with low-flow (LF) severe aortic stenosis enrolled in the Placement of Aortic Transcatheter Valves (PARTNER) trial. A, Comparison of transcatheter aortic valve replacement (TAVR) and medical management (MM) in inoperable cohort B. B, Comparison of TAVR and surgical aortic valve replacement (SAVR) in high-risk cohort A. ITT indicates intention to treat.

    Figure 4.

    Figure 4. Two-year mortality is shown for both trial cohorts of patients with low flow (LF) with low ejection fraction (LEF) and low gradient (LG). A, Cohort B; B, cohort A.

    Comparison of Effects of AVR in LF Versus NF Severe AS

    Patients with LF are compared with those with NF in Figure 5. In the high-risk cohort, it is apparent that the patients with LF had higher mortality than the NF patients at 2 years both with TAVR (40% versus 25%) and with SAVR (38% versus 29%; Figure 5A). In the inoperable group of patients, the absolute difference in mortality between MM and TAVR was greater in the LF patients (76.2% versus 45.9%) than in the NF group (54.7% versus 38.5%), although the risk reductions were similar (Figure 5B).

    Figure 5.

    Figure 5. Comparison of treatment in patients with low-flow (LF) vs normal-flow (NF) severe aortic stenosis in the Placement of Aortic Transcatheter Valves (PARTNER) trial high-risk cohort A (A) and inoperable cohort B (B). MM indicates medical management; and TAVR, transcatheter aortic valve replacement.

    Results in Patients With Paradoxical LF and Normal EF

    The results of treatment on mortality in LF NEF (mean EF, 58±5%) patients are shown in Figure 6 and in Figure II in the online-only Data Supplement. Treatment with TAVR reduced mortality compared with MM (P<0.001). For inoperable patients, mortality was reduced from 73% with TAVR to 43% in MM patients (HR, 0.48; 95% CI, 0.28–0.80; P=0.004), and there was no difference in high-risk patients between TAVR and SAVR (39.0% versus 38.3%; HR, 0.91; 95% CI, 0.57–1.45; P=0.69; Figure II in the online-only Data Supplement). For patients with LF, NEF, and LG (Figure 6), the difference between MM and TAVR in inoperable patients was significant at 1 year (66% versus 35%; HR, 0.38; 95% CI, 0.16–0.87; P=0.02), and there was a trend to benefit at 2 years (77% versus 57%; HR, 0.51; 95% CI, 0.25–1.04; P=0.06).

    Figure 6.

    Figure 6. All-cause mortality at 2 years is compared for both Placement of Aortic Transcatheter Valves (PARTNER) cohorts in patients with low flow (LF) or normal flow (NF) with low gradient (LG). A, Inoperable cohort B; B, high-risk cohort A. TAVR indicates transcatheter aortic valve replacement.

    Multivariable Analysis

    For the combined cohorts, both LF and LG were significant univariate predictors of 1-year (Table I in the online-only Data Supplement) and 2-year (Table 2) mortality, whereas baseline aortic regurgitation, mitral regurgitation, and LEF were not significant. In a pairwise multivariable analysis of LF and LG, only LF was an independent predictor of an increase in mortality. Adding other baseline variables into the model resulted in the following multivariable predictors of 2-year mortality: LF (HR, 1.44; P=0.0006), higher STS risk score (HR, 1.06; P<0.0001), and major arrhythmia (HR, 1.31; P=0.0086).

    Table 2. Univariate and Multivariable Predictors of 2-Year Mortality by Cohort

    2-Year Mortality
    HRRangeP Value*
    Combined cohorts A+B
    Univariate
    LF1.531.25–1.880.0001*
    LG1.251.02–1.520.0284*
    LEF1.200.98–1.480.0769
    AR0.980.73–1.330.9187
    MR1.250.99–1.570.0585
    Multivariable
    LF1.441.17–1.780.0006*
    STS score1.061.03–1.08<0.0001*
    Arrhythmia1.311.07–1.610.0086*
    Cohort A
    Univariate
    LF1.531.25–1.880.0001*
    LG1.251.02–1.520.0284*
    LEF1.200.98–1.480.7690
    AR0.980.73–1.330.9187
    MR1.250.99–1.570.0585
    Multivariable
    LF1.431.08–1.890.0131*
    STS score1.061.02–1.100.0011*
    Arrhythmia1.321.01–1.740.0440*
    Cohort B
    Univariate
    LF1.561.15–2.120.0045*
    LG1.270.95–1.700.1073
    LEF1.351.00–1.840.0514
    AR0.930.62–1.380.7205
    MR1.050.74–1.490.7964
    Multivariable
    LF1.541.12–2.110.0074*
    BMI0.970.95–1.000.0332*
    STS1.041.01–1.070.0038*
    PACER1.551.08–2.210.0175*
    TAVR0.550.41–0.750.0002*

    AR indicates aortic regurgitation; BMI, body mass index; LEF, low ejection fraction; LF, low flow; LG, low gradient; PACER, new permanent pacemaker; STS, Society of Thoracic Surgeons; and TAVR, transcatheter aortic valve replacement.

    *P values are based on the Cox proportional hazards model.

    †Significant.

    In the high-risk operable cohort A, the only univariate echocardiographic predictor of 1-year mortality was LF (HR, 1.43; P=0.0287; Table I in the online-only Data Supplement). At 2 years, univariate predictors included LF and LG. In multivariable analysis, STS risk score and major arrhythmia were predictors of 1-year mortality, and LF, STS risk score, and major arrhythmia were predictors of 2-year mortality (Table 2).

    Finally, in the inoperable cohort B, univariate predictors of increased 1-year mortality included LF and LEF, but LF was the only significant variable at 2 years and when analyzed pairwise with either LG or LEF (Table 2). In multivariable analysis, the significant predictors at both 1 and 2 years were LF, body mass index, STS risk score, new permanent pacemaker for increased mortality, and TAVR for improved survival.

    Discussion

    The major findings of this study are as follows. First, in patients with severe AS, LF, defined by a SVI ≤35 mL/m2, is associated with a significant 50% increase in 2-year all-cause mortality compared with patients with NF. Second, the impact of LF on subsequent mortality was independent in multivariable analysis and was a more powerful predictor of outcome than EF or mean transvalvular gradient. Third, patients with severe AS and LF and those with concomitant LEF and LG treated with TAVR had improved survival compared with patients treated medically. Fourth, in both the inoperable and high-risk cohorts of PARTNER, LF patients had a worse prognosis than NF patients but experienced similar benefits with therapy (TAVR was better than MM for inoperable patients and TAVR was similar to SAVR in high-risk patients). Fifth, patients with paradoxical LF (NEF, with normal gradient or LG) also had a worse prognosis, improvement with therapy compared with MM, and similar outcomes with TAVR versus SAVR. Taken together, these findings suggest that an assessment of LF based on SVI may be useful in the evaluation of all patients with severe AS. In addition, surgery and transcatheter AVR should be considered in patients with LF despite their increased mortality compared with NF patients.

    Pathophysiology of LF

    LF AS with LG has classically been further categorized by the EF. Among patients with LEF, LF may be attributed to poor contractile function of the LV. More recently, Hachicha and colleagues4 described a cohort of patients with LF AS with LG but with an EF of at least 50%, called paradoxical LF AS. Although these patients typically have slightly lower EFs than their comparators with NF and normal gradients, the LF in these cases has been attributed to higher global LV afterload, a restrictive physiology with pronounced LV concentric hypertrophy, and reduced LV compliance and filling.7,21,22 It may also be associated with greater subendocardial fibrosis and reduced longitudinal deformation.23 Nonrandomized data suggest that regardless of the origin, patients with LF AS with LG have worse outcomes with and without surgery yet may still benefit from valve replacement compared with MM.6,814

    In our analysis of patients with severe AS and predominantly not LGs, a low stroke volume was an important independent predictor of midterm all-cause mortality compared with patients with NF. Although current guidelines emphasize the importance of EF in the evaluation of patients with AS for surgery even when asymptomatic, our data suggest that EF may be less important after adjustment for flow. A unifying hypothesis for these findings is that a low forward output from the LV, whether a result of afterload mismatch with high impedance, impaired myocardial contractility, restrictive physiology, or other mechanism, is a more important determinant of outcome than the mechanism for the decrease in flow. Further study may help to elucidate whether a specific SVI or change in stroke volume should be used to guide the timing of valve replacement.

    Benefit of AVR in LF Severe AS

    Several nonrandomized studies have sought to elucidate the impact of an LF state on surgical outcome in patients with severe AS. Patients with LEF and LF AS have poorer outcomes, often stratified according to the hemodynamic response to dobutamine and whether the LV exhibits contractile reserve.7,9,12 Patients with flow reserve are more likely to improve with valve replacement, whereas results for those without flow reserve have varied. Previous studies are limited by various definitions for LF, gradient, and valve area, as well as the biases associated with cohort studies. Our analysis is the first to include randomization, and we found a significant benefit from valve replacement. Whether this should affect the decision to intervene, suggesting that valve replacement be based on SVI or the response of SVI to dobutamine (flow reserve) rather than EF, may require further prospective evaluation.

    The current American College of Cardiology/American Heart Association guidelines, first published in 2006, have no specific recommendation on the indication for AVR in patients with LF AS with LG.1 The recent European Society of Cardiology guidelines state that AVR should be considered (Class IIa) in symptomatic patients with classic LF AS (LF, LG, and LEF) if there is evidence of flow or contractile reserve.2 In addition, a new recommendation (Class IIa) is included for symptomatic patients with paradoxical LF AS with LG (preserved EF). LF was defined as in this study (SVI ≤35 mL/m2). Because of the limited data on the natural history and outcome of surgery in these patients, the level of evidence was C.2 The data in the present study provide new evidence for these recommendations and stress the importance of measuring and reporting SVI in patients with severe AS.

    The finding that early survival is improved with TAVR versus SAVR in LF severe AS is intriguing. Possible explanations include the less invasive nature of TAVR, detrimental effects of cardiopulmonary bypass on patients with limited flow or contractile reserve, and larger effective orifice area with SAPIEN TAVR compared with standard bioprostheses. In 1 nonrandomized comparison of TAVR and SAVR in patients with LEF, there did appear to be better recovery of EF with TAVR compared with SAVR.14 One possible explanation for this finding may involve the heightened afterload sensitivity of patients with LF, LG, and LEF to the effects of patient-prosthesis mismatch.10,2426 In the Clavel et al14 study, the indexed aortic valve area after the procedure was larger with TAVR than with SAVR; however, in our study, we found no difference in the discharge indexed aortic valve area in LF patients.

    Paradoxical LF Severe AS

    The impact of paradoxical LF, LG severe AS with an NEF has been debated. Several studies have suggested that these patients have a poorer prognosis and improved survival after surgery.4,6,7,13,14 However, a substudy of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial found that outcomes in asymptomatic patients with LF were no worse than in those with NF.27 Treatment decisions in these studies were not randomized, and patients in the Jander et al27 study were asymptomatic with less severe AS. Nonetheless, aortic valve events occurred in almost 50% of the LF group within 5 years.

    Our findings confirm the high frequency and worse prognosis of symptomatic patients with LF severe AS and preserved ventricular function. We also demonstrate that these patients derive significant and similar benefit with transcatheter and surgical valve replacement and that this benefit is observed in patients with both high gradients and LGs. Our analysis is the first to compare outcomes in this patient population in a randomized trial with centrally adjudicated core echocardiographic laboratory measures and the first to demonstrate an improvement in survival with TAVR compared with MM. Unlike prior studies, EF was not a differentiating factor in the prognosis of LF patients in our study, suggesting that flow, rather than the mechanism for reduced flow, is the key prognostic factor.

    Clinical Implications

    It is well established that standard parameters of AS severity, including aortic valve area, whether measured in the cardiac catheterization laboratory or with echocardiography, vary with flow.3 A more comprehensive evaluation of AS severity may include the use of valvular resistance,5,28 valvulo-arterial impedance,21,22 or projected valve area at NF.25 Although these measures add utility in a comprehensive evaluation of AS, our findings suggest that SVI should be included in the assessment of patients with severe AS.

    Stroke volume may vary with changes in loading conditions, volume status, and other patient factors. Yet relying on EF may be misleading because the stroke volume associated with a particular EF may vary from one patient to another, depending on the ventricular size, volume status, systemic arterial resistance and compliance, and other variables.22 A comprehensive approach to patient assessment is warranted, and stroke volume is a crucial piece of information to determine prognosis and to inform treatment decisions. It may be particularly important in symptomatic patients with LG, in whom decision making with regard to valve replacement is more difficult.

    Limitations

    We analyzed LF using the Doppler-derived 2-dimensional LV outflow tract diameter and velocity-time integral. The definition of LF is not standardized in the literature, but we chose a definition (SVI ≤35 mL/m2) that has been commonly used4,6,7,13,14,22 and was included in the recent European Society of Cardiology guidelines.2 We also performed sensitivity and specificity testing of various SVI values for mortality, and 35 mL/m2 was nearly optimal in a receiver-operating characteristic curve analysis. It is possible that a 3-dimensional echocardiographic or computed tomography assessment of the outflow tract dimensions or invasive hemodynamic assessment could lead to different values and conclusions.5,29,30 The velocity-time integral assessed by LV outflow tract flow may also be directly affected by the presence of aortic regurgitation and indirectly by mitral regurgitation, both of which differed in prevalence at baseline between LF and NF subjects. Nonetheless, neither aortic nor mitral regurgitation had an independent predictive value for subsequent mortality.

    Our analysis was retrospective and subject to the limitations of an observational study. Treatment was not prospectively randomized in any of the LF subgroups, and the comparisons and conclusions should be validated in a prospective trial. Nonetheless, it is an analysis of a large, randomized study with core laboratory echocardiographic data and thus is the largest available database of patients with severe AS in which to examine the impact of LF on outcome and therapy. The findings of dobutamine stress echocardiographic evaluation performed in some of the PARTNER trial patients with LG would be of interest for this study but were not collected prospectively and were not available for this analysis. Finally, our results cannot be extrapolated to patients with severe obstructive coronary artery disease, who were not included in the PARTNER trial.

    Conclusions

    LF, defined by the echocardiographic SVI ≤35 mL/m2, is a surprisingly common finding in patients with severe AS. It is a more powerful predictor of subsequent mortality than either EF or mean gradient. In patients with severe AS, LF with both LEF and NEF is associated with increased 2-year mortality compared with patients with NF. TAVR improves survival compared with MM and provides a similar outcome compared with SAVR. An assessment of flow (SVI) should be included in the evaluation and therapeutic decision making of patients with severe AS.

    Acknowledgments

    We acknowledge the assistance of Thomas C. McAndrew, MS (Cardiovascular Research Foundation, New York, NY), with the statistical analyses.

    Footnotes

    Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.

    The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.112.001290/-/DC1.

    Correspondence to Howard C. Herrmann, MD, Director, Interventional Cardiology Program, Hospital of the University of Pennsylvania, 9038 Gates Pavilion, 3400 Spruce St, Philadelphia, PA 19104. E-mail

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    Clinical Perspective

    Patients with symptomatic and severe aortic stenosis may have low mean transvalvular gradients and reduced stroke volume (low flow) resulting from left ventricular systolic dysfunction, high afterload, and pronounced left ventricular concentric remodeling or measurement errors. Little is known about the prognostic value of low flow independently of gradient and ejection fraction or the response of these patients to surgical or transcatheter aortic valve replacement. In this analysis of the Placement of Aortic Transcatheter Valves (PARTNER) trial, we found that low flow w(defined by a stroke volume index ≤35 mL/m2) is independently associated with a 50% increase in 2-year all-cause mortality. In inoperable patients, transcatheter aortic valve replacement improved survival relative to medical management. In high-risk patients, transcatheter aortic valve replacement and surgical aortic valve replacement had similar outcomes. Finally, similar results were observed in patients with paradoxical low-flow (normal ejection fraction) severe aortic stenosis. These findings suggest that an assessment of flow based on stroke volume index may be useful in the evaluation of patients with severe aortic stenosis. In addition, surgery and transcatheter aortic valve replacement should be considered in patients with low flow despite their increased mortality compared with patients with normal flow.

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