Natural History of Asymptomatic Severe Aortic Stenosis and the Association of Early Intervention With Outcomes: A Systematic Review and Meta-analysis | Valvular Heart Disease | JAMA Cardiology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.153.100.128. Please contact the publisher to request reinstatement.
1.
Falk  V, Baumgartner  H, Bax  JJ,  et al; ESC Scientific Document Group.  2017 ESC/EACTS guidelines for the management of valvular heart disease.   Eur J Cardiothorac Surg. 2017;52(4):616-664. doi:10.1093/ejcts/ezx324PubMedGoogle ScholarCrossref
2.
Nishimura  RA, Otto  CM, Bonow  RO,  et al; ACC/AHA Task Force Members.  2014 AHA/ACC guideline 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.   Circulation. 2014;129(23):e521-e643. doi:10.1161/CIR.0000000000000031PubMedGoogle Scholar
3.
Nishimura  RA, Otto  CM, Bonow  RO,  et al.  2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.   Circulation. 2017;135(25):e1159-e1195. doi:10.1161/CIR.0000000000000503PubMedGoogle ScholarCrossref
4.
Heuvelman  HJ, van Geldorp  MW, Kappetein  AP,  et al.  Clinical course of patients diagnosed with severe aortic stenosis in the Rotterdam area: insights from the AVARIJN study.   Neth Heart J. 2012;20(12):487-493. doi:10.1007/s12471-012-0309-3PubMedGoogle ScholarCrossref
5.
Taniguchi  T, Morimoto  T, Shiomi  H,  et al; CURRENT AS Registry Investigators.  Initial surgical versus conservative strategies in patients with asymptomatic severe aortic stenosis.   J Am Coll Cardiol. 2015;66(25):2827-2838. doi:10.1016/j.jacc.2015.10.001PubMedGoogle ScholarCrossref
6.
Amato  MC, Moffa  PJ, Werner  KE, Ramires  JA.  Treatment decision in asymptomatic aortic valve stenosis: role of exercise testing.   Heart. 2001;86(4):381-386. doi:10.1136/heart.86.4.381PubMedGoogle ScholarCrossref
7.
Généreux  P, Stone  GW, O’Gara  PT,  et al.  Natural history, diagnostic approaches, and therapeutic strategies for patients with asymptomatic severe aortic stenosis.   J Am Coll Cardiol. 2016;67(19):2263-2288. doi:10.1016/j.jacc.2016.02.057PubMedGoogle ScholarCrossref
8.
Owen  A, Henein  MY.  Challenges in the management of severe asymptomatic aortic stenosis.   Eur J Cardiothorac Surg. 2011;40(4):848-850. doi:10.1016/j.ejcts.2011.01.031PubMedGoogle Scholar
9.
Stroup  DF, Berlin  JA, Morton  SC,  et al.  Meta-analysis of observational studies in epidemiology: a proposal for reporting: Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.   JAMA. 2000;283(15):2008-2012. doi:10.1001/jama.283.15.2008PubMedGoogle ScholarCrossref
10.
Head  SJ, da Costa  BR, Beumer  B,  et al.  Adverse events while awaiting myocardial revascularization: a systematic review and meta-analysis.   Eur J Cardiothorac Surg. 2017;52(2):206-217. doi:10.1093/ejcts/ezx115PubMedGoogle ScholarCrossref
11.
Hanley  JA, Lippman-Hand  A.  If nothing goes wrong, is everything all right? interpreting zero numerators.   JAMA. 1983;249(13):1743-1745. doi:10.1001/jama.1983.03330370053031PubMedGoogle ScholarCrossref
12.
da Costa  BR, Juni  P.  Systematic reviews and meta-analyses of randomized trials: principles and pitfalls.   Eur Heart J. 2014;35(47):3336-3345. doi:10.1093/eurheartj/ehu424PubMedGoogle ScholarCrossref
13.
Higgins  JP, Thompson  SG, Spiegelhalter  DJ.  A re-evaluation of random-effects meta-analysis.   J R Stat Soc Ser A Stat Soc. 2009;172(1):137-159. doi:10.1111/j.1467-985X.2008.00552.xPubMedGoogle ScholarCrossref
14.
Suzuki  A, Tajiri  K, Ishizu  T,  et al.  Effect of asymptomatic severe aortic stenosis on outcomes of individuals aged 80 and older.   J Am Geriatr Soc. 2018;66(9):1800-1804. doi:10.1111/jgs.15527PubMedGoogle ScholarCrossref
15.
Wu  VC, Takeuchi  M, Nagata  Y,  et al.  Prognostic value of area of calcified aortic valve by 2-dimensional echocardiography in asymptomatic severe aortic stenosis patients with preserved left ventricular ejection fraction.   Medicine (Baltimore). 2018;97(12):e0246. doi:10.1097/MD.0000000000010246PubMedGoogle Scholar
16.
González Gómez  A, Fernández-Golfín  C, Monteagudo  JM,  et al.  Severe aortic stenosis patients with preserved ejection fraction according to flow and gradient classification: prevalence and outcomes.   Int J Cardiol. 2017;248:211-215. doi:10.1016/j.ijcard.2017.06.064PubMedGoogle ScholarCrossref
17.
Christensen  NL, Dahl  JS, Carter-Storch  R,  et al.  Relation of left atrial size, cardiac morphology, and clinical outcome in asymptomatic aortic stenosis.   Am J Cardiol. 2017;120(10):1877-1883. doi:10.1016/j.amjcard.2017.07.101PubMedGoogle ScholarCrossref
18.
Zilberszac  R, Gabriel  H, Schemper  M, Laufer  G, Maurer  G, Rosenhek  R.  Asymptomatic severe aortic stenosis in the elderly.   JACC Cardiovasc Imaging. 2017;10(1):43-50. doi:10.1016/j.jcmg.2016.05.015PubMedGoogle ScholarCrossref
19.
Nishimura  S, Izumi  C, Nishiga  M,  et al.  Predictors of rapid progression and clinical outcome of asymptomatic severe aortic stenosis.   Circ J. 2016;80(8):1863-1869. doi:10.1253/circj.CJ-16-0333PubMedGoogle ScholarCrossref
20.
Maréchaux  S, Ringle  A, Rusinaru  D, Debry  N, Bohbot  Y, Tribouilloy  C.  Prognostic value of aortic valve area by doppler echocardiography in patients with severe asymptomatic aortic stenosis.   J Am Heart Assoc. 2016;5(5):e003146. doi:10.1161/JAHA.115.003146PubMedGoogle Scholar
21.
Shibayama  K, Daimon  M, Watanabe  H,  et al.  Significance of coronary artery disease and left ventricular afterload in unoperated asymptomatic aortic stenosis.   Circ J. 2016;80(2):519-525. doi:10.1253/circj.CJ-15-0876PubMedGoogle ScholarCrossref
22.
Todaro  MC, Carerj  S, Khandheria  B,  et al.  Usefulness of atrial function for risk stratification in asymptomatic severe aortic stenosis.   J Cardiol. 2016;67(1):71-79. doi:10.1016/j.jjcc.2015.04.010PubMedGoogle ScholarCrossref
23.
Nagata  Y, Takeuchi  M, Wu  VC,  et al.  Prognostic value of LV deformation parameters using 2D and 3D speckle-tracking echocardiography in asymptomatic patients with severe aortic stenosis and preserved LV ejection fraction.   JACC Cardiovasc Imaging. 2015;8(3):235-245. doi:10.1016/j.jcmg.2014.12.009PubMedGoogle ScholarCrossref
24.
Jander  N, Hochholzer  W, Kaufmann  BA,  et al.  Velocity ratio predicts outcomes in patients with low gradient severe aortic stenosis and preserved EF.   Heart. 2014;100(24):1946-1953. doi:10.1136/heartjnl-2014-305763PubMedGoogle ScholarCrossref
25.
Zuern  CS, Rizas  KD, Eick  C,  et al.  Severe autonomic failure as a predictor of mortality in aortic valve stenosis.   Int J Cardiol. 2014;176(3):782-787. doi:10.1016/j.ijcard.2014.07.088PubMedGoogle ScholarCrossref
26.
Levy  F, Fayad  N, Jeu  A,  et al.  The value of cardiopulmonary exercise testing in individuals with apparently asymptomatic severe aortic stenosis: a pilot study.   Arch Cardiovasc Dis. 2014;107(10):519-528. doi:10.1016/j.acvd.2014.06.003PubMedGoogle ScholarCrossref
27.
Cho  EJ, Park  SJ, Song  JE,  et al.  What is the real practice of exercise echocardiographic testing in asymptomatic patients with severe aortic stenosis?   Chin Med J (Engl). 2013;126(24):4649-4654.PubMedGoogle Scholar
28.
Yingchoncharoen  T, Gibby  C, Rodriguez  LL, Grimm  RA, Marwick  TH.  Association of myocardial deformation with outcome in asymptomatic aortic stenosis with normal ejection fraction.   Circ Cardiovasc Imaging. 2012;5(6):719-725. doi:10.1161/CIRCIMAGING.112.977348PubMedGoogle ScholarCrossref
29.
Saito  T, Muro  T, Takeda  H,  et al.  Prognostic value of aortic valve area index in asymptomatic patients with severe aortic stenosis.   Am J Cardiol. 2012;110(1):93-97. doi:10.1016/j.amjcard.2012.02.056PubMedGoogle ScholarCrossref
30.
Lancellotti  P, Magne  J, Donal  E,  et al.  Clinical outcome in asymptomatic severe aortic stenosis: insights from the new proposed aortic stenosis grading classification.   J Am Coll Cardiol. 2012;59(3):235-243. doi:10.1016/j.jacc.2011.08.072PubMedGoogle ScholarCrossref
31.
Perera  S, Wijesinghe  N, Ly  E, Devlin  G, Pasupati  S.  Outcomes of patients with untreated severe aortic stenosis in real-world practice.   N Z Med J. 2011;124(1345):40-48.PubMedGoogle Scholar
32.
Kitai  T, Honda  S, Okada  Y,  et al.  Clinical outcomes in non-surgically managed patients with very severe versus severe aortic stenosis.   Heart. 2011;97(24):2029-2032. doi:10.1136/heartjnl-2011-300137PubMedGoogle ScholarCrossref
33.
Cioffi  G, Faggiano  P, Vizzardi  E,  et al.  Prognostic effect of inappropriately high left ventricular mass in asymptomatic severe aortic stenosis.   Heart. 2011;97(4):301-307. doi:10.1136/hrt.2010.192997PubMedGoogle ScholarCrossref
34.
Rosenhek  R, Zilberszac  R, Schemper  M,  et al.  Natural history of very severe aortic stenosis.   Circulation. 2010;121(1):151-156. doi:10.1161/CIRCULATIONAHA.109.894170PubMedGoogle ScholarCrossref
35.
Hristova-Antova  E, Georgievska-Ismail  Lj, Srbinovska  E, Spiroska  V, Hristova-Dimceva  A, Zanteva-Naumoska  M.  Annual rate of progression of aortic-jet velocity and survival in cases of severe asymptomatic aortic stenosis.   Prilozi. 2009;30(1):91-104.PubMedGoogle Scholar
36.
Lafitte  S, Perlant  M, Reant  P,  et al.  Impact of impaired myocardial deformations on exercise tolerance and prognosis in patients with asymptomatic aortic stenosis.   Eur J Echocardiogr. 2009;10(3):414-419. doi:10.1093/ejechocard/jen299PubMedGoogle ScholarCrossref
37.
Weisenberg  D, Shapira  Y, Vaturi  M,  et al.  Does exercise echocardiography have an added value over exercise testing alone in asymptomatic patients with severe aortic stenosis?   J Heart Valve Dis. 2008;17(4):376-380.PubMedGoogle Scholar
38.
Avakian  SD, Grinberg  M, Ramires  JA, Mansur  AP.  Outcome of adults with asymptomatic severe aortic stenosis.   Int J Cardiol. 2008;123(3):322-327. doi:10.1016/j.ijcard.2006.12.019PubMedGoogle ScholarCrossref
39.
Le Tourneau  T, Pellikka  PA, Brown  ML,  et al.  Clinical outcome of asymptomatic severe aortic stenosis with medical and surgical management: importance of STS score at diagnosis.   Ann Thorac Surg. 2010;90(6):1876-1883. doi:10.1016/j.athoracsur.2010.07.070PubMedGoogle ScholarCrossref
40.
Pellikka  PA, Sarano  ME, Nishimura  RA,  et al.  Outcome of 622 adults with asymptomatic, hemodynamically significant aortic stenosis during prolonged follow-up.   Circulation. 2005;111(24):3290-3295. doi:10.1161/CIRCULATIONAHA.104.495903PubMedGoogle ScholarCrossref
41.
Pierri  H, Nussbacher  A, Decourt  LV,  et al.  Clinical predictors of prognosis in severe aortic stenosis in unoperated patients > or = 75 years of age.   Am J Cardiol. 2000;86(7):801-804. doi:10.1016/s0002-9149(00)01088-2Google ScholarCrossref
42.
Rosenhek  R, Binder  T, Porenta  G,  et al.  Predictors of outcome in severe, asymptomatic aortic stenosis.   N Engl J Med. 2000;343(9):611-617. doi:10.1056/NEJM200008313430903PubMedGoogle ScholarCrossref
43.
Kang  DH, Park  SJ, Lee  SA,  et al.  Early surgery or conservative care for asymptomatic aortic stenosis.   N Engl J Med. 2020;382(2):111-119. doi:10.1056/NEJMoa1912846PubMedGoogle ScholarCrossref
44.
Kim  HJ, Kim  JB, Kim  HR,  et al.  Impact of valve replacement on long-term survival in asymptomatic patients with severe aortic stenosis.   Am J Cardiol. 2019;123(8):1321-1328. doi:10.1016/j.amjcard.2019.01.035PubMedGoogle ScholarCrossref
45.
Campo  J, Tsoris  A, Kruse  J,  et al.  Prognosis of severe asymptomatic aortic stenosis with and without surgery.   Ann Thorac Surg. 2019;108(1):74-79. doi:10.1016/j.athoracsur.2019.01.031PubMedGoogle ScholarCrossref
46.
Bohbot  Y, Pasquet  A, Rusinaru  D,  et al.  Asymptomatic severe aortic stenosis with preserved ejection fraction: early surgery versus conservative management.   J Am Coll Cardiol. 2018;72(23 pt A):2938-2939. doi:10.1016/j.jacc.2018.09.049PubMedGoogle ScholarCrossref
47.
Masri  A, Goodman  AL, Barr  T,  et al.  Predictors of long-term outcomes in asymptomatic patients with severe aortic stenosis and preserved left ventricular systolic function undergoing exercise echocardiography.   Circ Cardiovasc Imaging. 2016;9(7):e004689. doi:10.1161/CIRCIMAGING.116.004689PubMedGoogle Scholar
48.
Kang  DH, Park  SJ, Rim  JH,  et al.  Early surgery versus conventional treatment in asymptomatic very severe aortic stenosis.   Circulation. 2010;121(13):1502-1509. doi:10.1161/CIRCULATIONAHA.109.909903PubMedGoogle ScholarCrossref
49.
Pai  RG, Kapoor  N, Bansal  RC, Varadarajan  P.  Malignant natural history of asymptomatic severe aortic stenosis: benefit of aortic valve replacement.   Ann Thorac Surg. 2006;82(6):2116-2122. doi:10.1016/j.athoracsur.2006.07.043PubMedGoogle ScholarCrossref
50.
Iung  B, Baron  G, Butchart  EG,  et al.  A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on Valvular Heart Disease.   Eur Heart J. 2003;24(13):1231-1243. doi:10.1016/S0195-668X(03)00201-XPubMedGoogle ScholarCrossref
51.
Everett  RJ, Tastet  L, Clavel  MA,  et al.  Progression of hypertrophy and myocardial fibrosis in aortic stenosis: a Multicenter Cardiac Magnetic Resonance Study.   Circ Cardiovasc Imaging. 2018;11(6):e007451. doi:10.1161/CIRCIMAGING.117.007451PubMedGoogle Scholar
52.
Lancellotti  P, Magne  J, Dulgheru  R,  et al.  Outcomes of patients with asymptomatic aortic stenosis followed up in heart valve clinics.   JAMA Cardiol. 2018;3(11):1060-1068. doi:10.1001/jamacardio.2018.3152PubMedGoogle ScholarCrossref
53.
Kappetein  AP, Head  SJ, Généreux  P,  et al; Valve Academic Research Consortium (VARC)-2.  Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document (VARC-2).   Eur J Cardiothorac Surg. 2012;42(5):S45-S60. doi:10.1093/ejcts/ezs533PubMedGoogle ScholarCrossref
Original Investigation
July 8, 2020

Natural History of Asymptomatic Severe Aortic Stenosis and the Association of Early Intervention With Outcomes: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Clinical Trial Unit Bern, University of Bern, Bern, Switzerland
  • 2Department of Cardiothoracic Surgery, Erasmus Medical Center, Rotterdam, the Netherlands
  • 3Medtronic, Maastricht, the Netherlands
  • 4Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
  • 5Division of Cardiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
  • 6Québec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada
  • 7Department of Cardiovascular Surgery, Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas
  • 8Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands
  • 9Department of Medicine and Institute of Health Policy, Management and Evaluation, Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
  • 10Institute of Health Policy, Management and Evaluation, Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
  • 11Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland
JAMA Cardiol. 2020;5(10):1102-1112. doi:10.1001/jamacardio.2020.2497
Key Points

Question  What is the natural history of asymptomatic severe aortic stenosis, which variables predict prognosis, and can early intervention improve outcomes?

Findings  In this systematic review and meta-analysis of 29 studies with 4075 patients with 11 901 years of follow-up, the rate of all-cause death was 5 per 100 conservatively treated patients per year, of which 3 and 1 were of cardiac and sudden cause, respectively. Twenty per 100 patients per year developed an indication for intervention; early intervention was significantly associated with improved survival.

Meaning  Patients with asymptomatic severe aortic stenosis may develop indication for intervention and have deaths that are mostly cardiac but not only sudden.

Abstract

Importance  Whether intervention should be performed in patients with asymptomatic severe aortic stenosis (AS) remains debated.

Objective  To meta-analyze the natural history of asymptomatic severe AS and examine the association of early intervention with survival.

Data Sources  PubMed, Embase, and Cochrane databases were searched from inception to February 1, 2020.

Study Selection  Observational studies of adult patients with asymptomatic severe AS.

Data Extraction and Synthesis  Two investigators independently extracted study and patient characteristics, follow-up time, events, and prognostic indicators of events. Random-effects models were used to derive pooled estimates.

Main Outcomes and Measures  The meta-analysis on natural history was performed on the primary end point of all-cause death occurring during a conservative treatment period, with secondary end points consisting of cardiac death, death due to heart failure, sudden death, development of symptoms, development of an indication for aortic valve intervention, and aortic valve intervention. The primary end point for the meta-analysis of early intervention vs a conservative strategy was all-cause death during long-term follow-up. Finally, meta-analysis was performed on the association of prognostic indicators with the composite of death or aortic valve intervention found in multivariable models.

Results  A total of 29 studies with 4075 patients with 11 901 years of follow-up were included. Pooled rates per 100 patients per year were 4.8 (95% CI, 3.6-6.4) for all-cause death, 3.0 (95% CI, 2.2-4.1) for cardiac death, 2.0 (95% CI, 1.3-3.1) for death due to heart failure, 1.1 (95% CI, 0.6-2.1) for sudden death, 18.1 (95% CI, 12.8-25.4) for an indication for aortic valve intervention, 18.5 (95% CI, 13.4-25.5) for development of symptoms, and 19.2 (95% CI, 15.5-23.8) for aortic valve intervention. Early intervention was associated with a significant reduction in long-term mortality (hazard ratio, 0.38; 95% CI, 0.25-0.58). Factors associated with worse prognosis were severity of AS, low-flow AS, left ventricular damage, and atherosclerotic risk factors.

Conclusions and Relevance  Data from observational studies and a recent randomized clinical trial suggest that many patients with asymptomatic severe AS develop an indication for aortic valve intervention, and their deaths are mostly cardiac but not only sudden. Other end points besides sudden death should be considered during the decision to perform early intervention that are associated with improved survival.

×