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Predictors and Progression of Aortic Stenosis in Patients With Preserved Left Ventricular Ejection Fraction
Predictors and Progression of Aortic Stenosis in Patients With Preserved Left Ventricular Ejection Fraction Mads Ersboll, MD, PhDa,b, Phillip J. Schulte, PhDc, Fawaz Al Enezi, MDa, Linda Shaw, MSc, Lars Køber, MD, DMscib, Joseph Kisslo, MDa, Irfan Siddiqui, MDa, Jonathan Piccini, MDa, Donald Glower, MDa, J. Kevin Harrison, MDa, Thomas Bashore, MDa, Niels Risum, MD, PhDa, James G. Jollis, MDa, Eric J. Velazquez, MDa,c, and Zainab Samad, MD, MHSa,* We aimed to characterize the hemodynamic progression of aortic stenosis (AS) in a contemporary unselected cohort of patients with preserved left ventricular ejection fraction. Current guidelines recommend echocardiographic surveillance of hemodynamic progression. However, limited data exist on the expected rate of progression and whether clinical variables are associated with accelerated progression in contemporarily managed patients with AS. We conducted a retrospective analysis of patients presenting with AS and explored the trajectory of AS mean gradient over time using generalized estimating equations and fit a longitudinal linear regression model with adjustment for baseline clinical variables. A total of 1,558 patients (median age 72; interquartile range 65 to 79) having mild (n [ 982), moderate (n [ 363), or severe AS (n [ 213) were included. In patients with mild AS at baseline (n [ 983), 303 (31%) had progressed to moderate/severe AS/AVR within 5 years of the index echo. In patients with moderate AS, 159 of 363 (44%) had progressed to severe AS/AVR within 2 years of the index echo. The annual change in mean gradient was dependent on baseline AS severity. Average annual increases in mean gradient were 6.8% (95% confidence interval 6.0 to 7.6) and 7.1% (95% confidence interval 4.8 to 9.3) in patients with mild and moderate AS, respectively. In the subset of patients with mild AS at baseline, age (p [ 0.0310) and gender (p [ 0.0270) had significant interaction with change in mean gradient over time. In patients with moderate AS, age (p <0.0001), gender (p [ 0.0346), renal dysfunction (p [ 0.0036), and hyperlipidemia (p [ 0.0010) demonstrated significant interaction with change in mean gradient over time. In conclusion, although average disease progression was slower than previously reported, a significant proportion of patients with mild and moderate AS progressed to higher grades within the currently recommended time windows for echocardiographic follow-up. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;-:-e-) The studies that form the current evidence on rates of progression in patients with mild-to-moderate aortic stenosis (AS) are now relatively old and based on small populations including both younger patients with bicuspid aortic valves and patients with depressed left ventricular ejection fraction (LVEF).1e6 To improve our understanding of the hemodynamic progression of AS and its predictors and to better inform clinical decisions regarding follow-up intervals, we undertook a comprehensive analysis of a large contemporary cohort of patients with calcific AS and preserved LVEF without concomitant significant aortic regurgitation. The specific objectives were to (1) characterize disease progression using all available echocardiographic information over time and (2) identify baseline a Division of Cardiology, Department of Medicine and cThe Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina and bThe Heart Center, Department of Cardiology, University of Copenhagen, Rigshospitalet, Denmark. Manuscript received August 12, 2014; revised manuscript received and accepted September 26, 2014. See page 6 for disclosure information. *Corresponding author: Tel: (919) 668-1524; fax: (919) 668-3575. E-mail address: [email protected] (Z. Samad).
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clinical variables associated with more rapid disease progression. Methods The data sources for the present study included the Duke Echocardiography Laboratory Database (DELD), Duke Enterprise Data Unified Content Explorer (DEDUCE), and the Duke Databank for Cardiovascular Diseases (DDCD). The DELD includes a prospectively maintained digital archive of all clinical echocardiograms performed at Duke University Hospital (DUH) and its satellite clinics linked to a corresponding searchable reporting database since 1995. DEDUCE is an online research query tool that provides investigators at DUH with access to clinical information collected as a by-product of patient care. It accesses data that have been compiled into the Decision Support Repository from clinical and billing sources including demographic information, International Classification of Diseases, Ninth Revision, codes, and Current Procedure Terminology codes. The DDCD comprises prospectively gathered in-hospital data on all patients who underwent cardiac catheterization and/or cardiac surgery at DUH since 1969 and long-term follow-up information. www.ajconline.org
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Figure 1. Consort diagram showing the derivation of the study population.
For the purpose of the present study, data from DELD, DEDUCE, and DDCD were linked from January 1, 1995, to December 31, 2012, to form a cohort of unique patients with detailed echocardiographic and clinical information. The study population for the present analysis consisted of all patients 18 years with mild, moderate, or severe AS in the presence of an LVEF >50% with at least 1 follow-up echocardiogram at least 90 days from the index echocardiogram. Patients were excluded based on their index echocardiogram if they had a history of valvular intervention, congenital heart disease, rheumatic valve disease, solid organ transplantation, hypertrophic obstructive cardiomyopathy, bicuspid aortic valve, more than mild aortic regurgitation, absence of clinical information in DEDUCE, or missing aortic mean gradient. The study was carried out under the approval of the Duke Institutional Review Board. The severity of AS was graded according to the continuous wave Doppler aortic mean pressure gradient. Partition values for mild AS (mean gradient <25 mm Hg), moderate
AS (mean gradient 25 to 40 mm Hg), and severe AS (mean gradient >40 mm Hg) were as recommended in current guidelines7 and according to laboratory practice. LVEF was obtained from the echocardiographic report and was visually estimated according to standard laboratory practice. Left ventricular (LV) hypertrophy was graded according to LV septal thickness into normal (0.6 to 1.0 cm), mild (1.1 to 1.3 cm), moderate (1.4 to 1.6 cm), or severe (>1.7 cm).8 Mitral regurgitation was classified into none/trivial, mild, moderate, or severe according to the guideline criteria.7 Information on medical and cardiovascular history at baseline was obtained from DEDUCE administration and billing resources and DDCD for patients with a previous cardiac catheterization and combined. For the purpose of identifying co-morbid conditions, we defined all instances of myocardial infarction, coronary artery bypass grafting, and percutaneous coronary intervention recorded before the index echocardiography as previous cardiovascular events. For conditions including hypertension, diabetes, hyperlipidemia,
Valvular Heart Disease/Predictors and Progression of Aortic Stenosis in Patients With Preserved LVEF
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Table 1 Clinical and echocardiographic findings according to aortic stenosis severity on the index echocardiogram Characteristic
Severity of AS Mild (n¼982)
Age, median (IQR) (Years) Women Hypertension by history Coronary Heart Disease Diabetes Mellitus Peripheral artery disease Prior cerebrovascular disease Renal Dysfunction Smoker Hyperlipidemia Heart failure Atrial fibrillation Chronic obstructive pulmonary disease Prior myocardial infarction Prior percutaneous coronary intervention Prior coronary bypass AS mean gradient, median (IQR) (mm Hg) Moderate to severe LVH* Mitral regurgitation (moderate-severe)
72 525 578 355 251 103 139 73 216 341 191 117 43 148 73 99 14 248 76
(64-79) (53.5%) (58.9%) (36.2%) (25.6%) (10.5%) (14.2%) (7.4%) (22.0%) (34.7%) (19.5%) (11.9%) (4.4%) (15.1%) (7.4%) (10.1%) (11-18) (25.3%) (7.7%)
Moderate (n¼363) 72 170 210 157 84 32 53 21 86 123 108 50 22 50 27 52 31 128 17
(66-79) (46.8%) (57.9%) (43.3%) (23.1%) (8.8%) (14.6%) (5.8%) (23.7%) (33.9%) (29.8%) (13.8%) (6.1%) (13.8%) (7.4%) (14.3%) (27-35) (35.3%) (4.7%)
Severe (n¼213) 74 112 112 87 45 7 27 15 47 75 79 41 12 21 6 15 50 103 20
(65-80) (52.6%) (52.6%) (40.8%) (21.1%) (3.3%) (12.7%) (7.0%) (22.1%) (35.2%) (37.1%) (19.2%) (5.6%) (9.9%) (2.8%) (7.0%) (45-58) (48.4%) (9.4%)
Overall (n¼1558) 72 807 900 599 380 142 219 109 349 539 378 208 77 219 106 166 19 479 113
(65-79) (51.8%) (57.8%) (38.4%) (24.4%) (9.1%) (14.1%) (7.0%) (22.4%) (34.6%) (24.3%) (13.4%) (4.9%) (14.1%) (6.8%) (10.7%) (13-31) (30.7%) (7.3%)
AS ¼ Aortic stenosis; LVH ¼ Left ventricular hypertrophy. * LVH was graded according to LV septal thickness into normal (0.6-1.0 cm), mild (1.1-1.3 cm), moderate (1.4-1.6 cm) or severe (>1.7 cm).
Table 2 Observed and estimated rates of progression in patients with mild- and moderate aortic stenosis on their index echocardiogram Observed progression Kaplan Meier estimate, N (%) % (95%CI) Mild aortic stenosis 1 year 2 years 5 years Moderate Aortic stenosis 1 year 2 years 5 years
59/982 (6.0%) 134/982 (13.7%) 303/982 (30.9%)
6.4% (5.0-8.1) 15.5% (13.3-18.1) 44.4% (40.5-48.4)
93/363 (25.6%) 159/363 (43.8%) 244/363 (67.2%)
26.5% (22.2-31.5) 47.3% (42.1-52.9) 82.3% (77.3-86.8)
congestive heart failure, atrial fibrillation, peripheral artery disease, cerebral vascular disease, renal dysfunction, chronic obstructive pulmonary disease, and history of smoking, we considered recordings in DEDUCE up until 30 days after the index echocardiography as medical history to allow for delay in hospital coding of these chronic conditions. Continuous data are expressed as median (interquartile range [IQR] 25th to 75th percentiles); categorical variables are described as n (%). Baseline clinical characteristics and echocardiographic findings are summarized according to AS severity as assessed by mean gradient on the index echocardiogram. Time to progression in AS severity was analyzed in the subset of patients with mild or moderate disease at baseline using the Kaplan-Meier approach. For patients with mild baseline AS, progression was defined as a composite of moderate or severe AS on a follow-up echocardiogram or AVR. For patients with moderate AS, progression was defined as a composite of severe AS or AVR. Censoring in this model
was performed at the time of the last echocardiogram in our system. The Kaplan-Meier estimator was used to calculate the proportion of patients with mild AS at baseline who progressed to more advanced disease within 5 years. Similarly the proportion of patients with moderate AS at baseline who progressed to either severe AS or AVR within 2 years was estimated. In patients with mild AS at baseline, time to progression in AS severity was assessed in a Cox proportional hazards model adjusted for baseline clinical characteristics selected by the investigators before the analyses. The adjustment model consisted of age, gender, ischemic heart disease, renal dysfunction, hyperlipidemia, diabetes, and hypertension and included baseline mean gradient and year of index echo. Linearity assumptions were assessed for age, baseline mean gradient, and year of index echo; year of index echo was included in models as a restricted cubic spline to satisfy this assumption. Proportional hazard assumptions were assessed as well for all characteristics; a time-dependent transformation was applied for baseline mean gradient. To further assess disease progression, we modeled the longitudinal trajectory of the AS mean gradient over time as a continuous variable in a linear model using generalized estimating equations. An interaction with baseline AS severity (mild or moderate) allowed a separate trajectory to be estimated for each of these cohorts. However, patients with severe AS were not modeled in this analysis because a low number of patients and follow-up studied before AVR. Briefly, the generalized estimating equation method is appropriate for longitudinal data sampled at varying time intervals with a nonuniform correlation structure and yields a robust estimate of response across a specific population (baseline AS severity).9 We also explored, separately for each of the predefined baseline risk factors, an interaction
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Figure 2. Forest plot showing baseline clinical characteristics and their association with time to AS progression in patients with mild (left) and moderate (right) AS. HR ¼ hazard ratio.
Table 3 Impact of baseline clinical factors on the association between time in years and increase in mean gradient among patients with mild and moderate aortic stenosis Interaction variable
Mild aortic stenosis
Moderate aortic stenosis
Interaction Estimate (%) Interaction Estimate (%) p-value (95% CI) p-value (95% CI)
Figure 3. Random sample of 150 patients with mild (n ¼ 102), moderate (n ¼ 34), and severe (n ¼ 14) AS and all their available recordings of AS mean gradient over time.
with time in years from the index echocardiogram to evaluate which of these risk factors might be associated with more rapid rates of progression in mean gradient. The response, mean gradient, was log-transformed in these models to satisfy normality assumptions; thus, we report the expected multiplicative change in mean gradient for each baseline risk factor. All models were adjusted for year of index echo using restricted cubic splines. All analyses were performed using SAS, v 9.2 (SAS, Cary, NC). Results A total of 132,804 unique patients presented for an echocardiographic examination at the DUH Echocardiography
Age Gender Male Female Ischemic Heart Disease Renal Dysfunction No renal dysfunction Renal dysfunction Hyperlipidemia No Hyperlipidemia Hyperlipidemia Diabetes Hypertension
0.0310 0.0270
Figure 4
<0.0001 0.0346
7.7 (6.7-8.7) 6.0 (4.8-7.1)
Figure 4 9.0 (6.8-11.2) 4.6 (1.3-8.0)
0.9841
0.1474
0.5977
0.0036 6.8 (4.5-9.1) 13.8 (9.6-18.1)
0.6133
0.0010 5.7 (3.3-8.1) 12.6 (9.3-16.0)
0.1651 0.9739
0.9609 0.6645
Both models adjusted for calendar year of index study.
Laboratory from January 1, 1995, to December 31, 2012, with a total of 1,907 patients being eligible after applying the exclusion criteria (Figure 1). The population used in modeling the time to progression consisted of 1,558 patients with mild (n ¼ 982), moderate (n ¼ 363), or severe AS (n ¼ 213). The echocardiographic information used in modeling of AS mean gradient over time (n ¼ 1,331) did not include examinations performed after AVR (Figure 1). Clinical and echocardiographic findings for the study population including patients who had AVR performed before their first follow-up are presented in Table 1. Increasing baseline severity of AS was associated with higher age and increasing prevalence of heart failure, atrial fibrillation, and more severe LV hypertrophy.
Valvular Heart Disease/Predictors and Progression of Aortic Stenosis in Patients With Preserved LVEF
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The impact of baseline clinical factors on the change in mean gradient over time is presented in Table 3. The impact of age (Figure 4) on the rate of progression in mean gradient was more pronounced in patients with moderate compared with mild AS. The presence of renal disease (13.8%; 95% CI 9.6 to 18.1, vs 6.8%; 95% CI 4.5 to 9.1) or hyperlipidemia (12.6%; 95% CI 9.3 to 16.0, vs 5.7%; 95% CI 3.3 to 8.1) at baseline resulted in an approximate doubling of the yearly rate of progression in AS mean gradient in those with moderate AS at baseline (Table 3). Discussion
Figure 4. Plot demonstrating the effect of age on the yearly rate of progression in AS mean gradient in patients with mild (left) and moderate (right) AS.
In the patients with mild AS at baseline, an estimated 44.4% (95% confidence interval [CI] 40.5 to 48.4) progressed to either moderate or severe AS within 5 years. In patients with moderate AS, 47.3% (42.1 to 52.9) had progressed to either severe AS or AVR within 2 years of the index echocardiogram. Observed rates of progression and Kaplan-Meier estimates for 1, 2, and 5 years after the index echocardiogram are given in Table 2. Multivariable Cox modeling of time to progression to moderate or severe AS or AVR identified age (hazard ratio 1.02; 95% CI 1.01 to 1.03, p ¼ 0.0008) as the only significant factor associated with increased risk of progression in patients with mild baseline AS (Figure 2). In patients with baseline moderate AS, only hypertension was associated with a lower risk of progression (Figure 2). A total of 4,263 echocardiograms were performed in 1,331 patients with mild (n ¼ 954), moderate (n ¼ 286), and severe AS (n ¼ 91), where at least 2 examinations were available without intervening AVR. Median follow-up time was longer in patients with mild AS at baseline (median 3.4 years, IQR 1.7 to 6.2) compared with moderate AS (median 1.9 years, IQR 1.1 to 3.4). A random sample of 150 patients from the study population with mild, moderate, and severe AS and their observed change in mean gradient over time is presented in Figure 3. The estimated yearly increase in mean gradient was 6.8% (95% CI 6.0 to 7.6, p <0.0001) of the index mean gradient in patients with mild AS and 7.1% (95% CI 4.8 to 9.3, p <0.0001) in patients with moderate AS. For patients with severe AS, no significant effect of time could be identified because of a limited number of studies before AVR (p ¼ 0.9264). Using the median value of mean gradients in the subset of patients with moderate AS, a patient presenting with an AS mean gradient of 31 mm Hg, would be expected to increase by 2.2 mm Hg (IQR 1.5 to 2.9) in year 1 and 2.4 mm Hg (IQR 1.6 to 3.1) in year 2, with each subsequent year increasing the gradient by 7.1% (IQR 4.8 to 9.3), resulting in severe AS within 3 to 4 years.
The main findings of the present study are that in a large contemporary cohort of patients with AS and preserved LVEF (1) the time to disease progression depends significantly on baseline AS severity; (2) although the average rate of progression in AS mean gradient is slower than previous reports, a significant proportion of patients were observed to progress to higher grades of severity or AVR within the recommended time frames for echocardiographic follow-up; and (3) in a robust model, very few clinical variables are associated with significantly accelerated progression: in patients with mild AS only age and gender and in patients with moderate AS renal disease and hyperlipidemia beyond age and gender. American College of Cardiology/American Heart Association guidelines and appropriate use criteria recommend echocardiographic follow-up for mild AS and moderate AS every 3 to 5 years and 1 to 2 years, respectively, unless clinical status deteriorates.7,10,11 These recommendations, which are also followed by insurance payers and in reimbursement decisions, stem from earlier studies including patients recruited in the mid- to late-1980s by Otto et al,4,5 and Brener et al6 have reported annual rates of progression in mean gradient of 6.3 to 8 mm Hg. A subsequent study by Palta et al3 found an average increase in mean gradient of 27 mm Hg over a mean observation period of 23 months, and Rosenhek et al1 demonstrated an average increase in peak velocity of 0.24 m/s per year. Recently, lower progression rates were reported in the neutral Aortic Stenosis Progression Observation: Measuring the Effects of Rosuvastatin (ASTRONOMER) and Simvastatin and Ezetemibe in Aortic Stenosis (SEAS) trials with annual AS mean gradient increases at 3.9 and 2.7 mm Hg, respectively.12,13 The progression rates reported in the present study are significantly lower than the earlier observational studies.1,4e6 The yearly increases in mean gradient in the patients with moderate AS are comparable with that reported in the large SEAS trial.13 However, direct comparison with the SEAS population must be cautioned because of differing patient characteristics. Indeed, our study population was older and included patients with ischemic heart disease, cerebrovascular disease, peripheral artery disease, and diabetes that were all excluded from the SEAS trial.13 Given these differences and particularly the impact of older age demonstrated in our analysis, the rate of progression found in our study is likely even lower than the direct comparison would seem to suggest. The reasons for the lower average rates of progression in AS mean gradient could be multiple and potentially
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reflect a broader patient population than that included in ASTRONOMER and SEAS trials. Our study population consists of patients who underwent clinical echocardiography where the finding of AS could be primary and directly related to the referral reason or incidental to a different clinical question. Despite the low overall annual rate of progression in mean gradient, approximately 45% of patients with mild and moderate AS at baseline progressed to a more advanced stage during 2 and 5 years of follow-up, respectively. The clinical significance of progression from mild-tomoderate AS within 5 years of observation in a relatively old population should be interpreted with caution. However, 45% of patients with moderate AS progressed to either severe AS or had AVR performed within 2 years of their index study. This is in accordance with results from Rosenhek et al1 where 47% of patients with mild-moderate AS and follow-up echocardiograms after an average of 46 months developed severe AS. Current recommendations for echocardiographic surveillance designate routine follow-up at 3 to 5 years for mild AS and 1 to 2 years for moderate AS as appropriate use.10 Our results suggest that patients with risk factors for rapid progression might warrant consideration of earlier follow-up toward establishing a patient-specific trajectory of progression, which could inform treatment decisions. The trajectory of increase in AS mean gradient over time was significantly modified by age and gender in patients with mild AS; however, the magnitude of these effects on the progression were so small that they likely would have little implication on clinical management. In contrast, we found larger effects of clinical variables on hemodynamic progression in patients with moderate AS that has potential implications for patient management. Twofold increases in the rates of hemodynamic progression were observed in male patients and in patients with renal dysfunction and hyperlipidemia. All the clinical factors associated with rapid progression in our population have been identified in previous studies.3,14e20 The consistency of association between rapid progression and older age, male gender, and renal dysfunction provides a reasonable impetus toward closer surveillance in these patients than current guidelines recommend. The present study represents a retrospective analysis of clinical echocardiograms obtained in patients presenting with AS over a substantial period of time. Patients included in this study were obliged to have had repeat echocardiograms performed based on clinical request that introduces potential selection bias. Patients deemed at a low risk of progression may have been subjected to less rigorous follow-up that could affect our estimates of AS progression. Similarly, patients who did not receive follow-up echocardiograms may have done so for specific reasons or died, which could affect our estimates. Although we excluded all patients with an LVEF <50% or more than mild aortic regurgitation, which can both significantly affect the flow rate across the valve, we relied on the AS mean gradient in the DELD and, therefore, cannot exclude the presence of suboptimal aortic windows or gradient underestimation in selected patients. The present study evaluated changes in AS mean gradient over time as the outcome measure and not aortic valve area (AVA) by the continuity equation. The decision to not calculate AVA is a possible limitation of this study but must be considered in the light of the thoughtful, long-standing, and continuing efforts
in quality monitoring and improvement in this clinical laboratory. Like others, we found least variability with AS mean gradients and AVA calculations prone to measurement errors.21e25 Disclosures Dr. Ersboll received financial support for research at Duke University Medical Center from the following organizations: Copenhagen University PhD Program, The Hede Nielsen Family Foundation, Director Ib Henriksen Foundation, The Augustinus Foundation, The Knud Høgaard Foundation, The Classenske Fideicommis Anniversary Foundation, The AstraZeneca Travel Grant for young Doctors, The Christian and Otilia Brorson Travel Grant for Young Scientists, The Lægevidenskabens Fremme Foundation, Directors Jacob Madsen and Wife Olga Madsen Foundation, The Bønnelykke Foundation, and The Etly and Jørgen Stjerngren Foundation. The authors have no conflicts of interest to declare. 1. Rosenhek R, Klaar U, Schemper M, Scholten C, Heger M, Gabriel H, Binder T, Maurer G, Baumgartner H. Mild and moderate aortic stenosis. Natural history and risk stratification by echocardiography. Eur Heart J 2004;25:199e205. 2. Roger VL, Tajik AJ, Bailey KR, Oh JK, Taylor CL, Seward JB. Progression of aortic stenosis in adults: new appraisal using Doppler echocardiography. Am Heart J 1990;119:331e338. 3. Palta S, Pai AM, Gill KS, Pai RG. New insights into the progression of aortic stenosis: implications for secondary prevention. Circulation 2000;101:2497e2502. 4. Otto CM, Pearlman AS, Gardner CL. Hemodynamic progression of aortic stenosis in adults assessed by Doppler echocardiography. J Am Coll Cardiol 1989;13:545e550. 5. Otto CM, Burwash IG, Legget ME, Munt BI, Fujioka M, Healy NL, Kraft CD, Miyake-Hull CY, Schwaegler RG. Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95:2262e2270. 6. Brener SJ, Duffy CI, Thomas JD, Stewart WJ. Progression of aortic stenosis in 394 patients: relation to changes in myocardial and mitral valve dysfunction. J Am Coll Cardiol 1995;25:305e310. 7. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52:e1ee142. 8. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440e1463. 9. Hanley JA, Negassa A, Edwardes MD, Forrester JE. Statistical analysis of correlated data using generalized estimating equations: an orientation. Am J Epidemiol 2003;157:364e375. 10. Douglas PS, Garcia MJ, Haines DE, Lai WW, Manning WJ, Patel AR, Picard MH, Polk DM, Ragosta M, Ward RP, Weiner RB. ACCF/ASE/ AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 appropriate Use criteria for echocardiography. A report of the American College of Cardiology Foundation appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association,
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American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance Endorsed by the American College of Chest Physicians. J Am Coll Cardiol 2011;57:1126e1166. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA 2009;301:831e841. Chan KL, Teo K, Dumesnil JG, Ni A, Tam J. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010;121:306e314. Rossebo AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, Gerdts E, Gohlke-Barwolf C, Holme I, Kesaniemi YA, Malbecq W, Nienaber CA, Ray S, Skjaerpe T, Wachtell K, Willenheimer R. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343e1356. Nassimiha D, Aronow WS, Ahn C, Goldman ME. Association of coronary risk factors with progression of valvular aortic stenosis in older persons. Am J Cardiol 2001;87:1313e1314. Nassimiha D, Aronow WS, Ahn C, Goldman ME. Rate of progression of valvular aortic stenosis in patients > or ¼ 60 years of age. Am J Cardiol 2001;87:807e809; A809. Bahler RC, Desser DR, Finkelhor RS, Brener SJ, Youssefi M. Factors leading to progression of valvular aortic stenosis. Am J Cardiol 1999;84:1044e1048. Yilmaz MB, Guray U, Guray Y, Cihan G, Caldir V, Cay S, Kisacik HL, Korkmaz S. Lipid profile of patients with aortic
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stenosis might be predictive of rate of progression. Am Heart J 2004;147:915e918. Pohle K, Maffert R, Ropers D, Moshage W, Stilianakis N, Daniel WG, Achenbach S. Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation 2001;104:1927e1932. Wongpraparut N, Apiyasawat S, Crespo G, Yazdani K, Jacobs LE, Kotler MN. Determinants of progression of aortic stenosis in patients aged > or ¼40 years. Am J Cardiol 2002;89:350e352. Perkovic V, Hunt D, Griffin SV, du Plessis M, Becker GJ. Accelerated progression of calcific aortic stenosis in dialysis patients. Nephron Clin Pract 2003;94:c40ec45. Krafchek J, Robertson JH, Radford M, Adams D, Kisslo J. A reconsideration of Doppler assessed gradients in suspected aortic stenosis. Am Heart J 1985;110:765e773. Kisslo J. Abstracts of papers to be presented at the 38th Annual Scientific Session of the American College of Cardiology, Anaheim, California, March 19e23, 1989. J Am Coll Cardiol 1989;13:1Ae254A. Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, Iung B, Otto CM, Pellikka PA, Quinones M. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Eur J Echocardiogr 2009;10:1e25. Recommendations for continuous quality improvement in echocardiography. American Society of Echocardiography. J Am Soc Echocardiogr 1995;8:S1eS28. Minter S, Armour A, Tinnemore A, Sedberry B, Strub K, Samad Z, Velazquez EJ. Implementing a continuous quality improvement program in a high volume echocardiography laboratory. J Am Soc Echocardiogr 2013;26:B2eB128.
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.09.049
clinical variables associated with more rapid disease progression. Methods The data sources for the present study included the Duke Echocardiography Laboratory Database (DELD), Duke Enterprise Data Unified Content Explorer (DEDUCE), and the Duke Databank for Cardiovascular Diseases (DDCD). The DELD includes a prospectively maintained digital archive of all clinical echocardiograms performed at Duke University Hospital (DUH) and its satellite clinics linked to a corresponding searchable reporting database since 1995. DEDUCE is an online research query tool that provides investigators at DUH with access to clinical information collected as a by-product of patient care. It accesses data that have been compiled into the Decision Support Repository from clinical and billing sources including demographic information, International Classification of Diseases, Ninth Revision, codes, and Current Procedure Terminology codes. The DDCD comprises prospectively gathered in-hospital data on all patients who underwent cardiac catheterization and/or cardiac surgery at DUH since 1969 and long-term follow-up information. www.ajconline.org
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Figure 1. Consort diagram showing the derivation of the study population.
For the purpose of the present study, data from DELD, DEDUCE, and DDCD were linked from January 1, 1995, to December 31, 2012, to form a cohort of unique patients with detailed echocardiographic and clinical information. The study population for the present analysis consisted of all patients 18 years with mild, moderate, or severe AS in the presence of an LVEF >50% with at least 1 follow-up echocardiogram at least 90 days from the index echocardiogram. Patients were excluded based on their index echocardiogram if they had a history of valvular intervention, congenital heart disease, rheumatic valve disease, solid organ transplantation, hypertrophic obstructive cardiomyopathy, bicuspid aortic valve, more than mild aortic regurgitation, absence of clinical information in DEDUCE, or missing aortic mean gradient. The study was carried out under the approval of the Duke Institutional Review Board. The severity of AS was graded according to the continuous wave Doppler aortic mean pressure gradient. Partition values for mild AS (mean gradient <25 mm Hg), moderate
AS (mean gradient 25 to 40 mm Hg), and severe AS (mean gradient >40 mm Hg) were as recommended in current guidelines7 and according to laboratory practice. LVEF was obtained from the echocardiographic report and was visually estimated according to standard laboratory practice. Left ventricular (LV) hypertrophy was graded according to LV septal thickness into normal (0.6 to 1.0 cm), mild (1.1 to 1.3 cm), moderate (1.4 to 1.6 cm), or severe (>1.7 cm).8 Mitral regurgitation was classified into none/trivial, mild, moderate, or severe according to the guideline criteria.7 Information on medical and cardiovascular history at baseline was obtained from DEDUCE administration and billing resources and DDCD for patients with a previous cardiac catheterization and combined. For the purpose of identifying co-morbid conditions, we defined all instances of myocardial infarction, coronary artery bypass grafting, and percutaneous coronary intervention recorded before the index echocardiography as previous cardiovascular events. For conditions including hypertension, diabetes, hyperlipidemia,
Valvular Heart Disease/Predictors and Progression of Aortic Stenosis in Patients With Preserved LVEF
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Table 1 Clinical and echocardiographic findings according to aortic stenosis severity on the index echocardiogram Characteristic
Severity of AS Mild (n¼982)
Age, median (IQR) (Years) Women Hypertension by history Coronary Heart Disease Diabetes Mellitus Peripheral artery disease Prior cerebrovascular disease Renal Dysfunction Smoker Hyperlipidemia Heart failure Atrial fibrillation Chronic obstructive pulmonary disease Prior myocardial infarction Prior percutaneous coronary intervention Prior coronary bypass AS mean gradient, median (IQR) (mm Hg) Moderate to severe LVH* Mitral regurgitation (moderate-severe)
72 525 578 355 251 103 139 73 216 341 191 117 43 148 73 99 14 248 76
(64-79) (53.5%) (58.9%) (36.2%) (25.6%) (10.5%) (14.2%) (7.4%) (22.0%) (34.7%) (19.5%) (11.9%) (4.4%) (15.1%) (7.4%) (10.1%) (11-18) (25.3%) (7.7%)
Moderate (n¼363) 72 170 210 157 84 32 53 21 86 123 108 50 22 50 27 52 31 128 17
(66-79) (46.8%) (57.9%) (43.3%) (23.1%) (8.8%) (14.6%) (5.8%) (23.7%) (33.9%) (29.8%) (13.8%) (6.1%) (13.8%) (7.4%) (14.3%) (27-35) (35.3%) (4.7%)
Severe (n¼213) 74 112 112 87 45 7 27 15 47 75 79 41 12 21 6 15 50 103 20
(65-80) (52.6%) (52.6%) (40.8%) (21.1%) (3.3%) (12.7%) (7.0%) (22.1%) (35.2%) (37.1%) (19.2%) (5.6%) (9.9%) (2.8%) (7.0%) (45-58) (48.4%) (9.4%)
Overall (n¼1558) 72 807 900 599 380 142 219 109 349 539 378 208 77 219 106 166 19 479 113
(65-79) (51.8%) (57.8%) (38.4%) (24.4%) (9.1%) (14.1%) (7.0%) (22.4%) (34.6%) (24.3%) (13.4%) (4.9%) (14.1%) (6.8%) (10.7%) (13-31) (30.7%) (7.3%)
AS ¼ Aortic stenosis; LVH ¼ Left ventricular hypertrophy. * LVH was graded according to LV septal thickness into normal (0.6-1.0 cm), mild (1.1-1.3 cm), moderate (1.4-1.6 cm) or severe (>1.7 cm).
Table 2 Observed and estimated rates of progression in patients with mild- and moderate aortic stenosis on their index echocardiogram Observed progression Kaplan Meier estimate, N (%) % (95%CI) Mild aortic stenosis 1 year 2 years 5 years Moderate Aortic stenosis 1 year 2 years 5 years
59/982 (6.0%) 134/982 (13.7%) 303/982 (30.9%)
6.4% (5.0-8.1) 15.5% (13.3-18.1) 44.4% (40.5-48.4)
93/363 (25.6%) 159/363 (43.8%) 244/363 (67.2%)
26.5% (22.2-31.5) 47.3% (42.1-52.9) 82.3% (77.3-86.8)
congestive heart failure, atrial fibrillation, peripheral artery disease, cerebral vascular disease, renal dysfunction, chronic obstructive pulmonary disease, and history of smoking, we considered recordings in DEDUCE up until 30 days after the index echocardiography as medical history to allow for delay in hospital coding of these chronic conditions. Continuous data are expressed as median (interquartile range [IQR] 25th to 75th percentiles); categorical variables are described as n (%). Baseline clinical characteristics and echocardiographic findings are summarized according to AS severity as assessed by mean gradient on the index echocardiogram. Time to progression in AS severity was analyzed in the subset of patients with mild or moderate disease at baseline using the Kaplan-Meier approach. For patients with mild baseline AS, progression was defined as a composite of moderate or severe AS on a follow-up echocardiogram or AVR. For patients with moderate AS, progression was defined as a composite of severe AS or AVR. Censoring in this model
was performed at the time of the last echocardiogram in our system. The Kaplan-Meier estimator was used to calculate the proportion of patients with mild AS at baseline who progressed to more advanced disease within 5 years. Similarly the proportion of patients with moderate AS at baseline who progressed to either severe AS or AVR within 2 years was estimated. In patients with mild AS at baseline, time to progression in AS severity was assessed in a Cox proportional hazards model adjusted for baseline clinical characteristics selected by the investigators before the analyses. The adjustment model consisted of age, gender, ischemic heart disease, renal dysfunction, hyperlipidemia, diabetes, and hypertension and included baseline mean gradient and year of index echo. Linearity assumptions were assessed for age, baseline mean gradient, and year of index echo; year of index echo was included in models as a restricted cubic spline to satisfy this assumption. Proportional hazard assumptions were assessed as well for all characteristics; a time-dependent transformation was applied for baseline mean gradient. To further assess disease progression, we modeled the longitudinal trajectory of the AS mean gradient over time as a continuous variable in a linear model using generalized estimating equations. An interaction with baseline AS severity (mild or moderate) allowed a separate trajectory to be estimated for each of these cohorts. However, patients with severe AS were not modeled in this analysis because a low number of patients and follow-up studied before AVR. Briefly, the generalized estimating equation method is appropriate for longitudinal data sampled at varying time intervals with a nonuniform correlation structure and yields a robust estimate of response across a specific population (baseline AS severity).9 We also explored, separately for each of the predefined baseline risk factors, an interaction
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Figure 2. Forest plot showing baseline clinical characteristics and their association with time to AS progression in patients with mild (left) and moderate (right) AS. HR ¼ hazard ratio.
Table 3 Impact of baseline clinical factors on the association between time in years and increase in mean gradient among patients with mild and moderate aortic stenosis Interaction variable
Mild aortic stenosis
Moderate aortic stenosis
Interaction Estimate (%) Interaction Estimate (%) p-value (95% CI) p-value (95% CI)
Figure 3. Random sample of 150 patients with mild (n ¼ 102), moderate (n ¼ 34), and severe (n ¼ 14) AS and all their available recordings of AS mean gradient over time.
with time in years from the index echocardiogram to evaluate which of these risk factors might be associated with more rapid rates of progression in mean gradient. The response, mean gradient, was log-transformed in these models to satisfy normality assumptions; thus, we report the expected multiplicative change in mean gradient for each baseline risk factor. All models were adjusted for year of index echo using restricted cubic splines. All analyses were performed using SAS, v 9.2 (SAS, Cary, NC). Results A total of 132,804 unique patients presented for an echocardiographic examination at the DUH Echocardiography
Age Gender Male Female Ischemic Heart Disease Renal Dysfunction No renal dysfunction Renal dysfunction Hyperlipidemia No Hyperlipidemia Hyperlipidemia Diabetes Hypertension
0.0310 0.0270
Figure 4
<0.0001 0.0346
7.7 (6.7-8.7) 6.0 (4.8-7.1)
Figure 4 9.0 (6.8-11.2) 4.6 (1.3-8.0)
0.9841
0.1474
0.5977
0.0036 6.8 (4.5-9.1) 13.8 (9.6-18.1)
0.6133
0.0010 5.7 (3.3-8.1) 12.6 (9.3-16.0)
0.1651 0.9739
0.9609 0.6645
Both models adjusted for calendar year of index study.
Laboratory from January 1, 1995, to December 31, 2012, with a total of 1,907 patients being eligible after applying the exclusion criteria (Figure 1). The population used in modeling the time to progression consisted of 1,558 patients with mild (n ¼ 982), moderate (n ¼ 363), or severe AS (n ¼ 213). The echocardiographic information used in modeling of AS mean gradient over time (n ¼ 1,331) did not include examinations performed after AVR (Figure 1). Clinical and echocardiographic findings for the study population including patients who had AVR performed before their first follow-up are presented in Table 1. Increasing baseline severity of AS was associated with higher age and increasing prevalence of heart failure, atrial fibrillation, and more severe LV hypertrophy.
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The impact of baseline clinical factors on the change in mean gradient over time is presented in Table 3. The impact of age (Figure 4) on the rate of progression in mean gradient was more pronounced in patients with moderate compared with mild AS. The presence of renal disease (13.8%; 95% CI 9.6 to 18.1, vs 6.8%; 95% CI 4.5 to 9.1) or hyperlipidemia (12.6%; 95% CI 9.3 to 16.0, vs 5.7%; 95% CI 3.3 to 8.1) at baseline resulted in an approximate doubling of the yearly rate of progression in AS mean gradient in those with moderate AS at baseline (Table 3). Discussion
Figure 4. Plot demonstrating the effect of age on the yearly rate of progression in AS mean gradient in patients with mild (left) and moderate (right) AS.
In the patients with mild AS at baseline, an estimated 44.4% (95% confidence interval [CI] 40.5 to 48.4) progressed to either moderate or severe AS within 5 years. In patients with moderate AS, 47.3% (42.1 to 52.9) had progressed to either severe AS or AVR within 2 years of the index echocardiogram. Observed rates of progression and Kaplan-Meier estimates for 1, 2, and 5 years after the index echocardiogram are given in Table 2. Multivariable Cox modeling of time to progression to moderate or severe AS or AVR identified age (hazard ratio 1.02; 95% CI 1.01 to 1.03, p ¼ 0.0008) as the only significant factor associated with increased risk of progression in patients with mild baseline AS (Figure 2). In patients with baseline moderate AS, only hypertension was associated with a lower risk of progression (Figure 2). A total of 4,263 echocardiograms were performed in 1,331 patients with mild (n ¼ 954), moderate (n ¼ 286), and severe AS (n ¼ 91), where at least 2 examinations were available without intervening AVR. Median follow-up time was longer in patients with mild AS at baseline (median 3.4 years, IQR 1.7 to 6.2) compared with moderate AS (median 1.9 years, IQR 1.1 to 3.4). A random sample of 150 patients from the study population with mild, moderate, and severe AS and their observed change in mean gradient over time is presented in Figure 3. The estimated yearly increase in mean gradient was 6.8% (95% CI 6.0 to 7.6, p <0.0001) of the index mean gradient in patients with mild AS and 7.1% (95% CI 4.8 to 9.3, p <0.0001) in patients with moderate AS. For patients with severe AS, no significant effect of time could be identified because of a limited number of studies before AVR (p ¼ 0.9264). Using the median value of mean gradients in the subset of patients with moderate AS, a patient presenting with an AS mean gradient of 31 mm Hg, would be expected to increase by 2.2 mm Hg (IQR 1.5 to 2.9) in year 1 and 2.4 mm Hg (IQR 1.6 to 3.1) in year 2, with each subsequent year increasing the gradient by 7.1% (IQR 4.8 to 9.3), resulting in severe AS within 3 to 4 years.
The main findings of the present study are that in a large contemporary cohort of patients with AS and preserved LVEF (1) the time to disease progression depends significantly on baseline AS severity; (2) although the average rate of progression in AS mean gradient is slower than previous reports, a significant proportion of patients were observed to progress to higher grades of severity or AVR within the recommended time frames for echocardiographic follow-up; and (3) in a robust model, very few clinical variables are associated with significantly accelerated progression: in patients with mild AS only age and gender and in patients with moderate AS renal disease and hyperlipidemia beyond age and gender. American College of Cardiology/American Heart Association guidelines and appropriate use criteria recommend echocardiographic follow-up for mild AS and moderate AS every 3 to 5 years and 1 to 2 years, respectively, unless clinical status deteriorates.7,10,11 These recommendations, which are also followed by insurance payers and in reimbursement decisions, stem from earlier studies including patients recruited in the mid- to late-1980s by Otto et al,4,5 and Brener et al6 have reported annual rates of progression in mean gradient of 6.3 to 8 mm Hg. A subsequent study by Palta et al3 found an average increase in mean gradient of 27 mm Hg over a mean observation period of 23 months, and Rosenhek et al1 demonstrated an average increase in peak velocity of 0.24 m/s per year. Recently, lower progression rates were reported in the neutral Aortic Stenosis Progression Observation: Measuring the Effects of Rosuvastatin (ASTRONOMER) and Simvastatin and Ezetemibe in Aortic Stenosis (SEAS) trials with annual AS mean gradient increases at 3.9 and 2.7 mm Hg, respectively.12,13 The progression rates reported in the present study are significantly lower than the earlier observational studies.1,4e6 The yearly increases in mean gradient in the patients with moderate AS are comparable with that reported in the large SEAS trial.13 However, direct comparison with the SEAS population must be cautioned because of differing patient characteristics. Indeed, our study population was older and included patients with ischemic heart disease, cerebrovascular disease, peripheral artery disease, and diabetes that were all excluded from the SEAS trial.13 Given these differences and particularly the impact of older age demonstrated in our analysis, the rate of progression found in our study is likely even lower than the direct comparison would seem to suggest. The reasons for the lower average rates of progression in AS mean gradient could be multiple and potentially
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reflect a broader patient population than that included in ASTRONOMER and SEAS trials. Our study population consists of patients who underwent clinical echocardiography where the finding of AS could be primary and directly related to the referral reason or incidental to a different clinical question. Despite the low overall annual rate of progression in mean gradient, approximately 45% of patients with mild and moderate AS at baseline progressed to a more advanced stage during 2 and 5 years of follow-up, respectively. The clinical significance of progression from mild-tomoderate AS within 5 years of observation in a relatively old population should be interpreted with caution. However, 45% of patients with moderate AS progressed to either severe AS or had AVR performed within 2 years of their index study. This is in accordance with results from Rosenhek et al1 where 47% of patients with mild-moderate AS and follow-up echocardiograms after an average of 46 months developed severe AS. Current recommendations for echocardiographic surveillance designate routine follow-up at 3 to 5 years for mild AS and 1 to 2 years for moderate AS as appropriate use.10 Our results suggest that patients with risk factors for rapid progression might warrant consideration of earlier follow-up toward establishing a patient-specific trajectory of progression, which could inform treatment decisions. The trajectory of increase in AS mean gradient over time was significantly modified by age and gender in patients with mild AS; however, the magnitude of these effects on the progression were so small that they likely would have little implication on clinical management. In contrast, we found larger effects of clinical variables on hemodynamic progression in patients with moderate AS that has potential implications for patient management. Twofold increases in the rates of hemodynamic progression were observed in male patients and in patients with renal dysfunction and hyperlipidemia. All the clinical factors associated with rapid progression in our population have been identified in previous studies.3,14e20 The consistency of association between rapid progression and older age, male gender, and renal dysfunction provides a reasonable impetus toward closer surveillance in these patients than current guidelines recommend. The present study represents a retrospective analysis of clinical echocardiograms obtained in patients presenting with AS over a substantial period of time. Patients included in this study were obliged to have had repeat echocardiograms performed based on clinical request that introduces potential selection bias. Patients deemed at a low risk of progression may have been subjected to less rigorous follow-up that could affect our estimates of AS progression. Similarly, patients who did not receive follow-up echocardiograms may have done so for specific reasons or died, which could affect our estimates. Although we excluded all patients with an LVEF <50% or more than mild aortic regurgitation, which can both significantly affect the flow rate across the valve, we relied on the AS mean gradient in the DELD and, therefore, cannot exclude the presence of suboptimal aortic windows or gradient underestimation in selected patients. The present study evaluated changes in AS mean gradient over time as the outcome measure and not aortic valve area (AVA) by the continuity equation. The decision to not calculate AVA is a possible limitation of this study but must be considered in the light of the thoughtful, long-standing, and continuing efforts
in quality monitoring and improvement in this clinical laboratory. Like others, we found least variability with AS mean gradients and AVA calculations prone to measurement errors.21e25 Disclosures Dr. Ersboll received financial support for research at Duke University Medical Center from the following organizations: Copenhagen University PhD Program, The Hede Nielsen Family Foundation, Director Ib Henriksen Foundation, The Augustinus Foundation, The Knud Høgaard Foundation, The Classenske Fideicommis Anniversary Foundation, The AstraZeneca Travel Grant for young Doctors, The Christian and Otilia Brorson Travel Grant for Young Scientists, The Lægevidenskabens Fremme Foundation, Directors Jacob Madsen and Wife Olga Madsen Foundation, The Bønnelykke Foundation, and The Etly and Jørgen Stjerngren Foundation. The authors have no conflicts of interest to declare. 1. Rosenhek R, Klaar U, Schemper M, Scholten C, Heger M, Gabriel H, Binder T, Maurer G, Baumgartner H. Mild and moderate aortic stenosis. Natural history and risk stratification by echocardiography. Eur Heart J 2004;25:199e205. 2. Roger VL, Tajik AJ, Bailey KR, Oh JK, Taylor CL, Seward JB. Progression of aortic stenosis in adults: new appraisal using Doppler echocardiography. Am Heart J 1990;119:331e338. 3. Palta S, Pai AM, Gill KS, Pai RG. New insights into the progression of aortic stenosis: implications for secondary prevention. Circulation 2000;101:2497e2502. 4. Otto CM, Pearlman AS, Gardner CL. Hemodynamic progression of aortic stenosis in adults assessed by Doppler echocardiography. J Am Coll Cardiol 1989;13:545e550. 5. Otto CM, Burwash IG, Legget ME, Munt BI, Fujioka M, Healy NL, Kraft CD, Miyake-Hull CY, Schwaegler RG. Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95:2262e2270. 6. Brener SJ, Duffy CI, Thomas JD, Stewart WJ. Progression of aortic stenosis in 394 patients: relation to changes in myocardial and mitral valve dysfunction. J Am Coll Cardiol 1995;25:305e310. 7. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52:e1ee142. 8. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440e1463. 9. Hanley JA, Negassa A, Edwardes MD, Forrester JE. Statistical analysis of correlated data using generalized estimating equations: an orientation. Am J Epidemiol 2003;157:364e375. 10. Douglas PS, Garcia MJ, Haines DE, Lai WW, Manning WJ, Patel AR, Picard MH, Polk DM, Ragosta M, Ward RP, Weiner RB. ACCF/ASE/ AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 appropriate Use criteria for echocardiography. A report of the American College of Cardiology Foundation appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association,
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