Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis (TOPAS Study)

Aortic Valve Stenosis Clinical Trial

Official title:

Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis (TOPAS Study Phase III)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01835028
• Other study ID #: MOP-57745
• Status: Recruiting
• Start date: June 2002
• Est. completion date: January 2024

Study information

• Verified date: September 2021
• Source: Laval University
• Contact: Philippe Pibarot, DVM, PHD
• Phone: 418-656-8711
• Email: Philippe.Pibarot[@]med.ulaval.ca
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Low-flow, low-gradient (LF-LG) aortic stenosis (AS) may occur with depressed (i.e. Classical LF; CLF) or preserved (i.e. Paradoxical LF; PLF) LV ejection fraction (LVEF) and both situations are amongst the most challenging encountered in patients with valvular heart disease. Although, CLF-LG AS is recognized has an important clinical entity, current ACC/AHA-ESC guidelines however do not provide precise recommendations for clinical management of these patients . PLF-LG AS is a new entity recently described by our group, which is characterized by more pronounced LV concentric remodeling with smaller LV cavity size and a restrictive physiology leading to impaired LV filling, altered myocardial function, and a low-flow state. Up to recently, this entity was often misdiagnosed, leading to underestimation of AS severity and inappropriate delays for aortic valve replacement surgery (SAVR). The two main challenges in patients with CLF- or PLF- LG AS are to distinguish between a true-severe (TS) versus a pseudo-severe (PS) stenosis and to accurately quantify the extent of myocardial impairment. Unfortunately, the traditional resting and stress echocardiographic parameters currently used to assess the severity of valvular and myocardial dysfunction in patients with LF-LG AS are far from being optimal, and as a consequence, quantification of disease severity and therapeutic management may not be appropriate in a substantial proportion of these patients.

THE GENERAL OBJECTIVES of the TOPAS study are to develop and validate new parameters and biomarkers to improve the assessment of stenosis severity and myocardial impairment, the risk-stratification, and the clinical decision making in patients with LF-LG AS and to assess the impact of the different therapeutic strategies on patient outcomes.

Description:

Low-flow, low-gradient (LF-LG) aortic stenosis (AS) may occur with depressed (i.e. Classical LF; CLF) or preserved (i.e. Paradoxical LF; PLF) LV ejection fraction (LVEF) and both situations are amongst the most challenging encountered in patients with valvular heart disease. Although, CLF-LG AS is recognized has an important clinical entity, current ACC/AHA-ESC guidelines however do not provide precise recommendations for clinical management of these patients because there is an important lack of data on this condition. PLF-LG AS is a new entity recently described by our group, which is characterized by more pronounced LV concentric remodeling with smaller LV cavity size and a restrictive physiology leading to impaired LV filling, altered myocardial function, and a low-flow state. Up to recently, this entity was often misdiagnosed, leading to underestimation of AS severity and inappropriate delays for aortic valve replacement surgery (SAVR). The two main challenges in patients with CLF- or PLF- LG AS are to distinguish between a true-severe (TS) versus a pseudo-severe (PS) stenosis and to accurately quantify the extent of myocardial impairment. Unfortunately, the traditional resting and stress echocardiographic parameters currently used to assess the severity of valvular and myocardial dysfunction in patients with LF-LG AS are far from being optimal, and as a consequence, quantification of disease severity and therapeutic management may not be appropriate in a substantial proportion of these patients. Furthermore, it remains uncertain which is the optimal timing and mode of treatment (SAVR vs. Transcatheter Aortic Valve Implantation [TAVI] vs. Medical) for the different subsets of patients with LF-LG AS patients (CLF- vs. PLF- LG AS; TS vs. PS AS; absence vs. presence of myocardial contractile reserve etc.) THE GENERAL OBJECTIVES of the TOPAS study are to develop and validate new parameters and biomarkers to improve the assessment of stenosis severity and myocardial impairment, the risk-stratification, and the clinical decision making in patients with LF-LG AS and to assess the impact of the different therapeutic strategies on patient outcomes.

THE SPECIFIC AIMS of the phase III of the TOPAS study are: (1) To obtain and analyze the parameters of stenosis severity and LV functional impairment measured by stress echocardiography (SE), the degree of valvular calcification measured by multidetector computed tomography (CT), the extent of myocardial fibrosis measured by magnetic resonance imaging (MRI), the blood levels of natriuretic peptides and markers of extracellular matrix (ECM) turn-over, and the occurrence of clinical events in a series of 310 patients with CLF-LG AS (210 in TOPAS- I and II + 100 in TOPAS-III) and in a series of 380 patients with PLF-LG AS (80 in TOPAS II + 300 in TOPAS-III). (2) To measure the weight and calcification of the valves explanted from the patients who will undergo SAVR during follow-up in order to corroborate the actual severity of the stenosis. (3) To assess the usefulness of: i) the projected aortic valve area measured by SE to separate TS from PS AS and predict outcomes in PLF-LG AS; ii) the amount of valvular calcium measured by CT to separate TS from PS AS and predict outcomes in CLF- and PLF- LG AS; iii) the myocardial contractile reserve measured by SE, the extent of myocardial fibrosis measured by MRI, and the plasma levels of BNP and ECM biomarkers to predict operative (SAVR) / procedural (TAVI) risk as well as hemodynamic (LV function), functional (DASI and 6-min walk test distance), and clinical (morbidity-mortality) outcomes in CLF- and PLF- LG AS. (4) To compare the different modes of treatment (SAVR, TAVI, Medical), with respect to hemodynamic, functional, and clinical outcomes.

RELEVANCE OF THE STUDY: There have been very few prospective studies performed until now in patients with LF-LG AS and these studies have included a relatively small number of patients, have often used only one imaging modality (Doppler-echo) and a limited number of biomarkers, and they have generally not included the patients with PLF-LG AS. Our prospective study is the first of its kind, as it will use a complementary multimodality imaging approach and it will measure prospectively conventional parameters of disease severity as well as new emerging parameters and biomarkers developed by our team in large prospective series of patients with CLF- and PLF- LG AS. This study shall contribute to improve the diagnostic evaluation and clinical conduct in patients with LF-LG AS. This new knowledge will lead to the establishment of clinical guidelines for the management of these high-risk patients.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 320
• Est. completion date: January 2024
• Est. primary completion date: January 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 90 Years

Eligibility

Inclusion Criteria:

• LVEF= 40%

• Indexed aortic valve area (AVA) = 0.6 cm²/m²

• Mean transvalvular gradient < 40 mmHg

Exclusion criteria:

• Pregnant or lactating women

• advanced renal failure

• tumor with metastasis

Related Conditions & MeSH terms

• Aortic Valve Stenosis
• Constriction, Pathologic

Intervention

Other:
• Echocardiography
Observational Study using Imaging and Biomarkers
• Computed tomography
Observational Study using Imaging and Biomarkers
• Magnetic resonance imaging
Observational Study using Imaging and Biomarkers
• Blood biomarkers
Observational Study using Imaging and Biomarkers
• Stress echocardiography
Observational Study using Imaging and Biomarkers

Locations

Country	Name	City	State
Austria	Viena General Hospital	Vienna
Belgium	CHU Start Tilman	Liège
Canada	Ottawa Heart Institute University	Ottawa	Ontario
Canada	Institut Universitaire de Cardiologie et de Pneumologie de Québec	Québec
Canada	St Paul's Hospital, Vancouver	Vancouver
France	Hôpital La Timone	Marseille
France	Hôpital Bichat	Paris
France	CHU, Rennes	Rennes
Germany	University Hospital	Munster
United States	Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Laval University	University Hospital, Brest

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  France,  Germany, 

References & Publications (38)

Annabi MS, Clisson M, Clavel MA, Pibarot P. Workup and Management of Patients With Paradoxical Low-Flow, Low-Gradient Aortic Stenosis. Curr Treat Options Cardiovasc Med. 2018 May 2;20(6):49. doi: 10.1007/s11936-018-0642-y. Review. — View Citation

Annabi MS, Touboul E, Dahou A, Burwash IG, Bergler-Klein J, Enriquez-Sarano M, Orwat S, Baumgartner H, Mascherbauer J, Mundigler G, Cavalcante JL, Larose É, Pibarot P, Clavel MA. Dobutamine Stress Echocardiography for Management of Low-Flow, Low-Gradient Aortic Stenosis. J Am Coll Cardiol. 2018 Feb 6;71(5):475-485. doi: 10.1016/j.jacc.2017.11.052. — View Citation

Bergler-Klein J, Mundigler G, Pibarot P, Burwash IG, Dumesnil JG, Blais C, Fuchs C, Mohty D, Beanlands RS, Hachicha Z, Walter-Publig N, Rader F, Baumgartner H. B-type natriuretic peptide in low-flow, low-gradient aortic stenosis: relationship to hemodynam — View Citation

Blais C, Burwash IG, Mundigler G, Dumesnil JG, Loho N, Rader F, Baumgartner H, Beanlands RS, Chayer B, Kadem L, Garcia D, Durand LG, Pibarot P. Projected valve area at normal flow rate improves the assessment of stenosis severity in patients with low-flow — View Citation

Blais C, Dumesnil JG, Baillot R, Simard S, Doyle D, Pibarot P. Impact of valve prosthesis-patient mismatch on short-term mortality after aortic valve replacement. Circulation. 2003 Aug 26;108(8):983-8. Epub 2003 Aug 11. — View Citation

Burwash IG, Lortie M, Pibarot P, de Kemp RA, Graf S, Mundigler G, Khorsand A, Blais C, Baumgartner H, Dumesnil JG, Hachicha Z, DaSilva J, Beanlands RS. Myocardial blood flow in patients with low-flow, low-gradient aortic stenosis: differences between true — View Citation

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 Feb 24;65(7):645-53. doi: 10.1016/j.jacc.2014.11.047. — View Citation

Clavel MA, Burwash IG, Mundigler G, Dumesnil JG, Baumgartner H, Bergler-Klein J, Sénéchal M, Mathieu P, Couture C, Beanlands R, Pibarot P. 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 Apr;23(4):380-6. doi: 10.1016/j.echo.2010.02.002. — View Citation

Clavel MA, Côté N, Mathieu P, Dumesnil JG, Audet A, Pépin A, Couture C, Fournier D, Trahan S, Pagé S, Pibarot P. 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 Oct 7;35(38):2655-62. doi: 10.1093/eurheartj/ehu152. Epub 2014 Apr 21. — View Citation

Clavel MA, Dumesnil JG, Capoulade R, Mathieu P, Sénéchal M, Pibarot P. Outcome of patients with aortic stenosis, small valve area, and low-flow, low-gradient despite preserved left ventricular ejection fraction. J Am Coll Cardiol. 2012 Oct 2;60(14):1259-6 — View Citation

Clavel MA, Ennezat PV, Maréchaux S, Dumesnil JG, Capoulade R, Hachicha Z, Mathieu P, Bellouin A, Bergeron S, Meimoun P, Arsenault M, Le Tourneau T, Pasquet A, Couture C, Pibarot P. 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 Feb;6(2):175-83. doi: 10.1016/j.jcmg.2012.10.015. — View Citation

Clavel MA, Fuchs C, Burwash IG, Mundigler G, Dumesnil JG, Baumgartner H, Bergler-Klein J, Beanlands RS, Mathieu P, Magne J, Pibarot P. Predictors of outcomes in low-flow, low-gradient aortic stenosis: results of the multicenter TOPAS Study. Circulation. 2 — View Citation

Clavel MA, Rodés-Cabau J, Dumont É, Bagur R, Bergeron S, De Larochellière R, Doyle D, Larose E, Dumesnil JG, Pibarot P. Validation and characterization of transcatheter aortic valve effective orifice area measured by Doppler echocardiography. JACC Cardiov — View Citation

Clavel MA, Webb JG, Pibarot P, Altwegg L, Dumont E, Thompson C, De Larochellière R, Doyle D, Masson JB, Bergeron S, Bertrand OF, Rodés-Cabau J. Comparison of the hemodynamic performance of percutaneous and surgical bioprostheses for the treatment of sever — View Citation

Clavel MA, Webb JG, Rodés-Cabau J, Masson JB, Dumont E, De Larochellière R, Doyle D, Bergeron S, Baumgartner H, Burwash IG, Dumesnil JG, Mundigler G, Moss R, Kempny A, Bagur R, Bergler-Klein J, Gurvitch R, Mathieu P, Pibarot P. Comparison between transcat — View Citation

Dahou A, Bartko PE, Capoulade R, Clavel MA, Mundigler G, Grondin SL, Bergler-Klein J, Burwash I, Dumesnil JG, Sénéchal M, O'Connor K, Baumgartner H, Pibarot P. 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 Mar;8(3):e002117. doi: 10.1161/CIRCIMAGING.114.002117. — View Citation

Dahou A, Clavel MA, Capoulade R, Bartko PE, Magne J, Mundigler G, Bergler-Klein J, Burwash I, Mascherbauer J, Ribeiro HB, O'Connor K, Baumgartner H, Sénéchal M, Dumesnil JG, Rosenhek R, Mathieu P, Larose E, Rodés-Cabau J, Pibarot P. Right ventricular longitudinal strain for risk stratification in low-flow, low-gradient aortic stenosis with low ejection fraction. Heart. 2016 Apr;102(7):548-54. doi: 10.1136/heartjnl-2015-308309. Epub 2016 Jan 13. — View Citation

Dahou A, Clavel MA, Dumesnil JG, Capoulade R, Ribeiro HB, O'Connor K, Mathieu P, Beaudoin J, Larose É, Rodés-Cabau J, Pibarot P. Impact of AVR on LV Remodeling and Function in Paradoxical Low-Flow, Low-Gradient Aortic Stenosis With Preserved LVEF. JACC Cardiovasc Imaging. 2017 Jan;10(1):88-89. doi: 10.1016/j.jcmg.2016.07.009. Epub 2016 Nov 9. — View Citation

Dahou A, Magne J, Clavel MA, Capoulade R, Bartko PE, Bergler-Klein J, Sénéchal M, Mundigler G, Burwash I, Ribeiro HB, O'Connor K, Mathieu P, Baumgartner H, Dumesnil JG, Rosenhek R, Larose E, Rodés-Cabau J, Pibarot P. Tricuspid Regurgitation Is Associated With Increased Risk of Mortality in Patients With Low-Flow Low-Gradient Aortic Stenosis and Reduced Ejection Fraction: Results of the Multicenter TOPAS Study (True or Pseudo-Severe Aortic Stenosis). JACC Cardiovasc Interv. 2015 Apr 20;8(4):588-96. doi: 10.1016/j.jcin.2014.08.019. Epub 2015 Mar 26. — View Citation

Dahou A, Toubal O, Clavel MA, Beaudoin J, Magne J, Mathieu P, Philippon F, Dumesnil JG, Puri R, Ribeiro HB, Larose É, Rodés-Cabau J, Pibarot P. Relationship Between QT Interval and Outcome in Low-Flow Low-Gradient Aortic Stenosis With Low Left Ventricular Ejection Fraction. J Am Heart Assoc. 2016 Oct 20;5(10). pii: e003980. — View Citation

Dayan V, Vignolo G, Magne J, Clavel MA, Mohty D, Pibarot P. Outcome and Impact of Aortic Valve Replacement in Patients With Preserved LVEF and Low-Gradient Aortic Stenosis. J Am Coll Cardiol. 2015 Dec 15;66(23):2594-2603. doi: 10.1016/j.jacc.2015.09.076. — View Citation

Dumesnil JG, Pibarot P, Carabello B. Paradoxical low flow and/or low gradient severe aortic stenosis despite preserved left ventricular ejection fraction: implications for diagnosis and treatment. Eur Heart J. 2010 Feb;31(3):281-9. doi: 10.1093/eurheartj/ehp361. Epub 2009 Sep 8. Review. — View Citation

Dumesnil JG, Pibarot P. Evaluation of aortic stenosis severity: new challenges, new solutions. J Am Soc Echocardiogr. 2011 Sep;24(9):992-4. doi: 10.1016/j.echo.2011.07.011. — View Citation

Hachicha Z, Dumesnil JG, Bogaty P, Pibarot P. Paradoxical low-flow, low-gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival. Circulation. 2007 Jun 5;115(22):2856-64. Epub 2007 May 28. — View Citation

Hachicha Z, Dumesnil JG, Pibarot P. Usefulness of the valvuloarterial impedance to predict adverse outcome in asymptomatic aortic stenosis. J Am Coll Cardiol. 2009 Sep 8;54(11):1003-11. doi: 10.1016/j.jacc.2009.04.079. — View Citation

Le Ven F, Freeman M, Webb J, Clavel MA, Wheeler M, Dumont É, Thompson C, De Larochellière R, Moss R, Doyle D, Ribeiro HB, Urena M, Nombela-Franco L, Rodés-Cabau J, Pibarot P. Impact of low flow on the outcome of high-risk patients undergoing transcatheter aortic valve replacement. J Am Coll Cardiol. 2013 Aug 27;62(9):782-8. doi: 10.1016/j.jacc.2013.05.044. Epub 2013 Jun 12. — View Citation

Le Ven F, Thébault C, Dahou A, Ribeiro HB, Capoulade R, Mahjoub H, Urena M, Nombela-Franco L, Allende Carrera R, Clavel MA, Dumont É, Dumesnil J, De Larochellière R, Rodés-Cabau J, Pibarot P. Evolution and prognostic impact of low flow after transcatheter aortic valve replacement. Heart. 2015 Aug;101(15):1196-203. doi: 10.1136/heartjnl-2014-307067. Epub 2015 May 21. — View Citation

Mohty D, Boulogne C, Magne J, Pibarot P, Echahidi N, Cornu E, Dumesnil J, Laskar M, Virot P, Aboyans V. Prevalence and long-term outcome of aortic prosthesis-patient mismatch in patients with paradoxical low-flow severe aortic stenosis. Circulation. 2014 Sep 9;130(11 Suppl 1):S25-31. doi: 10.1161/CIRCULATIONAHA.113.007819. — View Citation

Mohty D, Dumesnil JG, Echahidi N, Mathieu P, Dagenais F, Voisine P, Pibarot P. Impact of prosthesis-patient mismatch on long-term survival after aortic valve replacement: influence of age, obesity, and left ventricular dysfunction. J Am Coll Cardiol. 2009 Jan 6;53(1):39-47. doi: 10.1016/j.jacc.2008.09.022. — View Citation

Mohty D, Magne J, Deltreuil M, Aboyans V, Echahidi N, Cassat C, Pibarot P, Laskar M, Virot P. Outcome and impact of surgery in paradoxical low-flow, low-gradient severe aortic stenosis and preserved left ventricular ejection fraction: a cardiac catheterization study. Circulation. 2013 Sep 10;128(11 Suppl 1):S235-42. doi: 10.1161/CIRCULATIONAHA.112.000031. — View Citation

Pibarot P, Dumesnil JG. Assessment of aortic stenosis severity: when the gradient does not fit with the valve area. Heart. 2010 Sep;96(18):1431-3. doi: 10.1136/hrt.2010.195149. — View Citation

Pibarot P, Dumesnil JG. Improving assessment of aortic stenosis. J Am Coll Cardiol. 2012 Jul 17;60(3):169-80. doi: 10.1016/j.jacc.2011.11.078. Review. — View Citation

Pibarot P, Dumesnil JG. Low-flow, low-gradient aortic stenosis with normal and depressed left ventricular ejection fraction. J Am Coll Cardiol. 2012 Nov 6;60(19):1845-53. doi: 10.1016/j.jacc.2012.06.051. Epub 2012 Oct 10. Review. — View Citation

Pibarot P, Dumesnil JG. Paradoxical low-flow, low-gradient aortic stenosis adding new pieces to the puzzle. J Am Coll Cardiol. 2011 Jul 19;58(4):413-5. doi: 10.1016/j.jacc.2011.01.057. — View Citation

Picano E, Pibarot P, Lancellotti P, Monin JL, Bonow RO. The emerging role of exercise testing and stress echocardiography in valvular heart disease. J Am Coll Cardiol. 2009 Dec 8;54(24):2251-60. doi: 10.1016/j.jacc.2009.07.046. — View Citation

Ribeiro HB, Lerakis S, Gilard M, Cavalcante JL, Makkar R, Herrmann HC, Windecker S, Enriquez-Sarano M, Cheema AN, Nombela-Franco L, Amat-Santos I, Muñoz-García AJ, Garcia Del Blanco B, Zajarias A, Lisko JC, Hayek S, Babaliaros V, Le Ven F, Gleason TG, Chakravarty T, Szeto WY, Clavel MA, de Agustin A, Serra V, Schindler JT, Dahou A, Puri R, Pelletier-Beaumont E, Côté M, Pibarot P, Rodés-Cabau J. Transcatheter Aortic Valve Replacement in Patients With Low-Flow, Low-Gradient Aortic Stenosis: The TOPAS-TAVI Registry. J Am Coll Cardiol. 2018 Mar 27;71(12):1297-1308. doi: 10.1016/j.jacc.2018.01.054. — View Citation

Rodriguez-Gabella T, Nombela-Franco L, Auffret V, Asmarats L, Islas F, Maes F, Ferreira-Neto AN, Paradis JM, Dumont E, Côté M, Jiménez-Quevedo P, Macaya C, Pibarot P, Rodés-Cabau J. Transcatheter Aortic Valve Implantation in Patients With Paradoxical Low-Flow, Low-Gradient Aortic Stenosis. Am J Cardiol. 2018 Aug 15;122(4):625-632. doi: 10.1016/j.amjcard.2018.04.044. Epub 2018 May 17. — View Citation

Williams TE, O'Day DM, Head WS, Robinson RD. Measurements of antifungal levels in corneal tissue: a simplified bioassay for amphotericin B. Graefes Arch Clin Exp Ophthalmol. 1990;228(6):538-40. — View Citation

* Note: There are 38 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	(1) Stenosis severity: We will use the weight and calcification of the valve explanted at the time of SAVR as a flow-independent marker of stenosis severity		Patients will be followed for 5 years, with an average of 3.5 years
Other	Hemodynamic (LV function) outcome: The outcome variables will be the changes during follow-up in resting and peak stress values of stroke volume, LVEF, longitudinal strain and plasma levels of BNP; LV flow reserve; LV contractile reserve		Patients will be followed for 5 years, with an average of 3.5 years
Other	Functional outcome: Another important objective of treatment is to improve the patient's functional status and quality of life. The outcome variables will be the changes in Duke Activity Score Index and the 6-min walk test distance during follow-up		Patients will be followed for 5 years, with an average of 3.5 years
Primary	all-cause mortality		Patients will be followed for 5 years, with an average of 3.5 years
Secondary	30-day mortality (for patients treated by SAVR or TAVR)		Patients will be followed for 5 years, with an average of 3.5 years
Secondary	cardiovascular mortality		Patients will be followed for 5 years, with an average of 3.5 years
Secondary	new major cardiovascular events as defined by VARC: myocardial infarction, stroke, vascular complications, and re-hospitalization for heart failure composite end-point of cardiovascular mortality and hospitalization for heart failure		Patients will be followed for 5 years, with an average of 3.5 years
Secondary	composite end-point of cardiovascular mortality and hospitalization for heart failure		Patients will be followed for 5 years, with an average of 3.5 years