Comparison of Early Surgical or Transcatheter Aortic Valve Replacement Versus Conservative Management in Low-Flow, Low-Gradient Aortic Stenosis Using Inverse Probability of Treatment Weighting: Results From the TOPAS Prospective Observational Cohort Study

Mohamed-Salah Annabi, Nancy Côté, Abdellaziz Dahou, Philipp E Bartko, Jutta Bergler-Klein, Ian G Burwash, Stefan Orwat, Helmut Baumgartner, Julia Mascherbauer, Gerald Mundigler, Miho Fukui, Joao Cavalcante, Henrique B Ribeiro, Josep Rodès-Cabau, Marie-Annick Clavel, Philippe Pibarot, Mohamed-Salah Annabi, Nancy Côté, Abdellaziz Dahou, Philipp E Bartko, Jutta Bergler-Klein, Ian G Burwash, Stefan Orwat, Helmut Baumgartner, Julia Mascherbauer, Gerald Mundigler, Miho Fukui, Joao Cavalcante, Henrique B Ribeiro, Josep Rodès-Cabau, Marie-Annick Clavel, Philippe Pibarot

Abstract

Background No randomized comparison of early (ie, ≤3 months) aortic valve replacement (AVR) versus conservative management or of transcatheter AVR (TAVR) versus surgical AVR has been conducted in patients with low-flow, low-gradient (LFLG) aortic stenosis (AS). Methods and Results A total of 481 consecutive patients (75±10 years; 71% men) with LFLG AS (aortic valve area ≤0.6 cm2/m2 and mean gradient <40 mm Hg), 72% with classic LFLG and 28% with paradoxical LFLG, were prospectively recruited in the multicenter TOPAS (True or Pseudo Severe Aortic Stenosis) study. True-severe AS or pseudo-severe AS was adjudicated by flow-independent criteria. During follow-up (median [IQR] 36 [11-60] months), 220 patients died. Using inverse probability of treatment weighting to address the bias of nonrandom treatment assignment, early AVR (n=272) was associated with a major overall survival benefit (hazard ratio [HR], 0.34 [95% CI, 0.24-0.50]; P<0.001). This benefit was observed in patients with true-severe AS but also with pseudo-severe AS (HR, 0.38 [95% CI, 0.18-0.81]; P=0.01), and in classic (HR, 0.33 [95% CI, 0.22-0.49]; P<0.001) and paradoxical LFLG AS (HR, 0.42 [95% CI, 0.20-0.92]; P=0.03). Compared with conservative management in the conventional multivariate model, trans femoral TAVR was associated with the best survival (HR, 0.23 [95% CI, 0.12-0.43]; P<0.001), followed by surgical AVR (HR, 0.36 [95% CI, 0.23-0.56]; P<0.001) and alternative-access TAVR (HR, 0.51 [95% CI, 0.31-0.82]; P=0.007). In the inverse probability of treatment weighting model, trans femoral TAVR appeared to be superior to surgical AVR (HR [95% CI] 0.28 [0.11-0.72]; P=0.008) with regard to survival. Conclusions In this large prospective observational study of LFLG AS, early AVR appeared to confer a major survival benefit in both classic and paradoxical LFLG AS. This benefit seems to extend to the subgroup with pseudo-severe AS. Our findings suggest that TAVR using femoral access might be the best strategy in these patients. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01835028.

Keywords: aortic stenosis; low flow; low gradient; surgical aortic valve replacement; survival; transcatheter aortic valve replacement.

Conflict of interest statement

Dr Dahou was supported by a fellowship grant from L'Agence de la santé et des services sociaux de la Capitale nationale‐ADLSSS, Québec, Québec, Canada. Dr Pibarot holds the Canada Research Chair in Valvular Heart Diseases, Canadian Institutes of Health Research. Dr Clavel is a scholar fellow from Fond de recherche du Québec en santé. The remaining authors have no disclosures to report.

Figures

Figure 1. Survival benefit associated with aortic…
Figure 1. Survival benefit associated with aortic valve replacement (AVR) in low‐flow, low‐gradient aortic stenosis (LFLG AS) using inverse probability of treatment weighting (IPTW).
In A, early (ie, ≤3 months) AVR (red line) is compared with conservative management or clinical surveillance and delayed AVR (blue line). The forest plot in (B) shows the weighted hazard ratio (HR) associated with AVR in the different study subgroups. In (C), the survival curves are stratified according to the initial management strategy and the severity of AS, excluding patients with indeterminate AS severity. The survival curves are adjusted using IPTW. The weighted numbers at risk are simulated and thus not shown (see Figure S1 for the weights' distributions). The adjusted weighted HRs are adjusted for residual differences after IPTW (Table S3). PSAS indicates pseudo‐severe AS; and TSAS, true‐severe AS.
Figure 2. Survival benefit of surgical aortic…
Figure 2. Survival benefit of surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) in low‐flow, low‐gradient aortic stenosis (LFLG AS) and pooled analysis of the different treatment modalities.
Standard Kaplan‐Meier survival curves for the 3 treatment modalities (A) and after splitting the TAVR group into trans femoral and alternative access subgroups (B). C, Adjusted Survival Curves for the Cox proportional hazards model. See Data S1 for details about multivariate analysis. HR indicates hazard ratio.
Figure 3. Survival benefit of surgical aortic…
Figure 3. Survival benefit of surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) in low‐flow, low‐gradient aortic stenosis (LFLG AS) using inverse probability of treatment weighting (IPTW).
Pairwise treatment comparison using inverse probability weighting. A, SAVR vs conservative management (ConsRx). B, TAVR vs ConsRx. C, SAVR vs TAVR. D, SAVR vs TAVR, subdivided into trans femoral and alternative access groups. The survival curves are adjusted using IPTW. The weighted numbers at risk are simulated and are, thus, not shown (see Figure S1 for the weights). Adjusted weighted hazard ratio (HR): adjusted for baseline differences that remained significant despite IPTW (Tables S4, S5 and S6).

References

    1. Minners J, Allgeier M, Gohlke‐Baerwolf C, Kienzle RP, Neumann FJ, Jander N. Inconsistent grading of aortic valve stenosis by current guidelines: haemodynamic studies in patients with apparently normal left ventricular function. Heart. 2010;96:1463–1468.
    1. Minners J, Allgeier M, Gohlke‐Baerwolf C, Kienzle RP, Neumann FJ, Jander N. Inconsistencies of echocardiographic criteria for the grading of aortic valve stenosis. Eur Heart J. 2008;29:1043–1048.
    1. Clavel MA, Magne J, Pibarot P. Low‐gradient aortic stenosis. Eur Heart J. 2016;37:2645–2657.
    1. Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Munoz DR, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease: the Task Force for the management of valvular heart disease of the European Society of Cardiology (ESC) and the European Association for Cardio‐Thoracic Surgery (EACTS). Eur Heart J. 2017;38:2739–2791.
    1. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP III, Fleisher LA, Jneid H, Mack MJ, McLeod CJ, O'Gara PT, 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. J Am Coll Cardiol. 2017;70:252–289.
    1. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP III, Fleisher LA, Jneid H, Mack MJ, McLeod CJ, O'Gara PT, 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:e1159–e1195.
    1. Annabi MS, Touboul E, Dahou A, Burwash IG, Bergler‐Klein J, Enriquez‐Sarano M, Orwat S, Baumgartner H, Mascherbauer J, Mundigler G, et al. Dobutamine stress echocardiography for management of low‐flow, low‐gradient aortic stenosis. J Am Coll Cardiol. 2018;71:475–485.
    1. Clavel MA, Messika‐Zeitoun D, Pibarot P, Aggarwal S, Malouf J, Araoz P, Michelena H, Cueff C, Larose É, Capoulade R, et al. The complex nature of discordant severe calcified aortic valve disease grading: new insights from combined doppler‐echocardiographic and computed tomographic study. J Am Coll Cardiol. 2013;62:2329–2338.
    1. Fischer‐Rasokat U, Renker M, Liebetrau C, van Linden A, Arsalan M, Weferling M, Rolf A, Doss M, Mollmann H, Walther T, et al. 1‐Year survival after TAVR of patients with low‐flow, low‐gradient and high‐gradient aortic valve stenosis in matched study populations. JACC Cardiovasc Interv. 2019;12:752–763.
    1. van Gils L, Clavel MA, Vollema EM, Hahn RT, Spitzer E, Delgado V, Nazif T, De Jaegere PP, Geleijnse ML, Ben‐Yehuda O, et al. Prognostic implications of moderate aortic stenosis in patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2017;69:2383–2392.
    1. Samad Z, Vora AN, Dunning A, Schulte PJ, Shaw LK, Al‐Enezi F, Ersboll M, McGarrah RW III, Vavalle JP, Shah SH, et al. Aortic valve surgery and survival in patients with moderate or severe aortic stenosis and left ventricular dysfunction. Eur Heart J. 2016;37:2276–2286.
    1. Blais C, Burwash IG, Mundigler G, Dumesnil JG, Loho N, Rader F, Baumgartner H, Beanlands RS, Chayer B, Kadem L, et al. Projected valve area at normal flow rate improves the assessment of stenosis severity in patients with low flow, low‐gradient aortic stenosis: the multicenter TOPAS (truly or pseudo severe aortic stenosis) study. Circulation. 2006;113:711–721.
    1. Clavel MA, Fuchs C, Burwash IG, Mundigler G, Dumesnil JG, Baumgartner H, Bergler‐Klein J, Beanlands RS, Mathieu P, Magne J, et al. Predictors of outcomes in low‐flow, low‐gradient aortic stenosis: results of the multicenter TOPAS Study. Circulation. 2008;118:S234–S242.
    1. Dahou A, Bartko PE, Capoulade R, Clavel MA, Mundigler G, Grondin SL, Bergler‐Klein J, Burwash I, Dumesnil JG, Senechal M, et al. Usefulness of global left ventricular longitudinal strain for risk stratification in low ejection fraction, low‐gradient aortic stenosis: results from the multicenter true or pseudo‐severe aortic stenosis study. Circ Cardiovasc Imaging. 2015;8:e002117. DOI: 10.1161/CIRCIMAGING.114.002117.
    1. 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. J Am Soc Echocardiogr. 2009;22:1–23.
    1. Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu BA, Tribouilloy C, Hagendorff A, Monin JL, Badano L, Zamorano JL. European Association of Echocardiography recommendations for the assessment of valvular regurgitation, part 2: mitral and tricuspid regurgitation (native valve disease). Eur J Echocardiogr. 2010;11:307–332.
    1. Lancellotti P, Tribouilloy C, Hagendorff A, Moura L, Popescu BA, Agricola E, Monin JL, Pierard LA, Badano L, Zamorano JL. European Association of Echocardiography recommendations for the assessment of valvular regurgitation, part 1: aortic and pulmonary regurgitation (native valve disease). Eur J Echocardiogr. 2010;11:223–244.
    1. Pawade T, Clavel MA, Tribouilloy C, Dreyfus J, Mathieu T, Tastet L, Renard C, Gun M, Jenkins WSA, Macron L, et al. Computed tomography aortic valve calcium scoring in patients with aortic stenosis. Circ Cardiovasc Imaging. 2018;11:e007146. DOI: 10.1161/CIRCIMAGING.117.007146.
    1. Clavel MA, Burwash IG, Mundigler G, Dumesnil JG, Baumgartner H, Bergler‐Klein J, Sénéchal M, Mathieu P, Couture C, Beanlands R, et al. Validation of conventional and simplified methods to calculate projected valve area at normal flow rate in patients with low flow, low gradient aortic stenosis: the multicenter TOPAS (true or pseudo severe aortic stenosis) study. J Am Soc Echocardiogr. 2010;23:380–386.
    1. Clavel MA, Côté N, Mathieu P, Dumesnil JG, Audet A, Pépin A, Couture C, Fournier D, Trahan S, Pagé S, et al. Paradoxical low‐flow, low‐gradient aortic stenosis despite preserved left ventricular ejection fraction: new insights from weights of operatively excised aortic valves. Eur Heart J. 2014;35:2655–2662.
    1. Cole SR, Hernan MA. Adjusted survival curves with inverse probability weights. Comput Methods Programs Biomed. 2004;75:45–49.
    1. Pibarot P, Messika‐Zeitoun D, Ben‐Yehuda O, Hahn RT, Burwash IG, Van Mieghem NM, Spitzer E, Leon MB, Bax J, Otto CM. Moderate aortic stenosis and heart failure with reduced ejection fraction: can imaging guide us to therapy? JACC Cardiovasc Imaging. 2019;12:172–184.
    1. Clavel MA, Ennezat PV, Maréchaux S, Dumesnil JG, Capoulade R, Hachicha Z, Mathieu P, Bellouin A, Bergeron S, Meimoun P, et al. Stress echocardiography to assess stenosis severity and predict outcome in patients with paradoxical low‐flow, low‐gradient aortic stenosis and preserved LVEF. JACC Cardiovasc Imaging. 2013;6:175–183.
    1. Sato K, Sankaramangalam K, Kandregula K, Bullen J, Kapadia SR, Krishnaswamy A, Mick S, Rodriguez L, Grimm RA, Menon V, et al. Contemporary outcomes in low‐gradient aortic stenosis patients who underwent dobutamine stress echocardiography. J Am Heart Assoc. 2019;8:e011168. DOI: 10.1161/JAHA.118.011168.
    1. Spitzer E, Van Mieghem NM, Pibarot P, Hahn RT, Kodali S, Maurer MS, Nazif TM, Rodés‐Cabau J, Paradis JM, Kappetein AP, et al. Rationale and design of the transcatheter aortic valve replacement to unload the left ventricle in patients with advanced heart failure (TAVR UNLOAD) trial. Am Heart J. 2016;182:80–88.
    1. Monin JL, Quere JP, Monchi M, Petit H, Baleynaud S, Chauvel C, Pop C, Ohlmann P, Lelguen C, Dehant P, et al. Low‐gradient aortic stenosis: operative risk stratification and predictors for long‐term outcome: a multicenter study using dobutamine stress hemodynamics. Circulation. 2003;108:319–324.
    1. Tribouilloy C, Levy F, Rusinaru D, Gueret P, Petit‐Eisenmann H, Baleynaud S, Jobic Y, Adams C, Lelong B, Pasquet A, et al. Outcome after aortic valve replacement for low‐flow/low‐gradient aortic stenosis without contractile reserve on dobutamine stress echocardiography. J Am Coll Cardiol. 2009;53:1865–1873.
    1. Clavel MA, Berthelot‐Richer M, Le Ven F, Capoulade R, Dahou A, Dumesnil JG, Mathieu P, Pibarot P. Impact of classic and paradoxical low flow on survival after aortic valve replacement for severe aortic stenosis. J Am Coll Cardiol. 2015;65:645–653.
    1. Vahanian A, Iung B. The new ESC/EACTS guidelines on the management of valvular heart disease. Arch Cardiovasc Dis. 2012;105:465–467.
    1. Dayan V, Vignolo G, Magne J, Clavel MA, Mohty D, Pibarot P. Outcome and impact of aortic valve replacement in patients with preserved LV ejection fraction and low gradient aortic stenosis: a meta‐analysis. J Am Coll Cardiol. 2015;66:2594–2603.
    1. Herrmann HC, Pibarot P, Hueter I, Gertz ZM, Stewart WJ, Kapadia S, Tuczu EM, Babaliaros V, Thourani V, Szeto WY, et al. Predictors of mortality and outcomes of therapy in low flow severe aortic stenosis: a PARTNER trial analysis. Circulation. 2013;127:2316–2326.
    1. Ribeiro HB, Lerakis S, Gilard M, Cavalcante JL, Makkar R, Herrmann HC, Windecker S, Enriquez‐Sarano M, Cheema AN, Nombela‐Franco L, et al. Transcatheter aortic valve replacement in patients with low‐flow, low‐gradient aortic stenosis: the TOPAS‐TAVI Registry. J Am Coll Cardiol. 2018;71:1297–1308.
    1. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011;46:399–424.
    1. Austin PC. The performance of different propensity‐score methods for estimating differences in proportions (risk differences or absolute risk reductions) in observational studies. Stat Med. 2010;29:2137–2148.
    1. Afilalo J, Kim S, O'Brien S, Brennan JM, Edwards FH, Mack MJ, McClurken JB, Cleveland JC Jr, Smith PK, Shahian DM, et al. Gait speed and operative mortality in older adults following cardiac surgery. JAMA Cardiol. 2016;1:314–321.
    1. Lang RM, Badano LP, Mor‐Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28:1–39.
    1. Baumgartner H, Hung J, Bermejo J, Chambers JB, Edvardsen T, Goldstein S, Lancellotti P, LeFevre M, Miller F, Otto CM. Recommendations on the echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr. 2017;30:372–392.
    1. Concato J, Peduzzi P, Holford TR, Feinstein AR. Importance of events per independent variable in proportional hazards analysis, I: background, goals, and general strategy. J Clin Epidemiol. 1995;48:1495–1501.

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