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AVARIJN Study


- candidate number4236
- NTR NumberNTR1496
- ISRCTNISRCTN wordt niet meer aangevraagd
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR17-okt-2008
- Secondary IDsMEC 2006-066 
- Public TitleAVARIJN Study
- Scientific TitleAVARIJN (Aortic VAlve RIJNmond) study about severe aortic stenosis: incidence, treatment and prognosis. A hospital-based multi-center prospective cohort study.
- ACRONYMAVARIJN (Aortic VAlve RIJNmond)
- hypothesisWe hypothesize that a significant proportion of patients with severe aortic stenosis is not referred for surgical treatment because of co-morbidities and/or old age, or is operated late in the course of the disease due to underestimation of disease severity and progression. NtproBNP, tissue Doppler imaging and strain measurement may predict the onset of symptoms in asymptomatic patients and may predict outcome in symptomatic patients.
- Healt Condition(s) or Problem(s) studiedAortic valve stenosis
- Inclusion criteria1. Adult patients with severe aortic valve stenosis, presented in the Erasmus medical Center or outpatient Cardiology clinic in the wider Rotterdam area.
2. Written informed consent.
- Exclusion criteria1. Patients with previous aortic valve surgery or balloon dilatation.
2. Patients mentally disabled and/or suspect for senile dementia.
- mec approval receivedyes
- multicenter trialyes
- randomisedno
- group[default]
- TypeSingle arm
- Studytypeintervention
- planned startdate 1-mei-2006
- planned closingdate1-mei-2011
- Target number of participants342
- InterventionsWe establish patient characteristics, treatment strategy, functional status, quality of life, Doppler echocardiography, ECG and Nt-proBNP at baseline. After 6, 12 and 24 months, we repeat the echocardiography, ECG and Nt-proBNP and related that to the functional score and quality of life at that particular time point.
If the patient underwent aortic valve replacement, we repeat these assessments one year after AVR.
- Primary outcome- Death
- Secondary outcome- Aortic valve replacement
- Quality of life.
- TimepointsAccrual time: May 1 2006 - May 1 2009.
Study end: May 1 2010.
- Trial web siteN/A
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESMD. Helena J. Heuvelman
- CONTACT for SCIENTIFIC QUERIESMD. Helena J. Heuvelman
- Sponsor/Initiator Erasmus Medical Center, Department of Cardio-thoracic Surgery
- Funding
(Source(s) of Monetary or Material Support)
Erasmus Medical Center, Department of Cardio-thoracic Surgery
- PublicationsN/A
- Brief summaryBackground
Aortic stenosis is the most common valvular heart disease in developed countries. The cause is mostly degenerative 1, other causes are rheumatic aortic valve disease, congenital malformations, (bicuspid valve or malformed leaflets) and endocarditis. The genetic background is largely unclear although some involved genes have been identified. While aortic valve calcification increases with age the prevalence of severe aortic stenosis increases concomitantly. Estimates range from 1-2% in people aged 75 years to nearly 6% in people who are a decade older 2,3. Aortic stenosis is becoming an increasingly important health problem in developed countries as the life expectancy of the population continues to rise. Agreement on treatment exists in symptomatic patients with severe aortic stenosis 4; these should be treated aggressively to prevent sudden death and deterioration of left ventricular function. Prognosis of these patients is poor when treated conservatively 5. Surgical replacement by a mechanical or biological prosthetic valve offers excellent long-term results. Other less invasive treatment modalities are balloon valvuloplasty, which can temporarily relief symptoms, and new techniques as percutaneous aortic valve replacement 6-9. However, a significant proportion of symptomatic patients are denied AVR because of severe co-morbidities or due to underestimation of disease severity 10,11.
For asymptomatic patients the optimal treatment strategy is uncertain. Truly asymptomatic patients have a much better prognosis compared to symptomatic patients, with an incidence of sudden death of only 0,4% 4. These patients should not be confronted with the risks associated with AVR since these are considerably higher than the risks of conservative treatment: operative mortality varies from 1% in young patients up to 11% in octogenarians 12-17, and prosthetic valve-related morbidity and mortality occurs in 3-4% per year 4. However, according an European observational study, a significant proportion (up to 37%) of the patients who claim to be asymptomatic, are found to be symptomatic when an exercise test is performed 18. In The Netherlands this propotion is not yet established. Therefore the number of patients who could benefit from an aortic valve replacement is probably underestimated. Furthermore echocardiographic findings have shown rapid progression of pressure gradients and decrease of aortic valve area in some patients 19-21. This may be accompanied by a rapid progression from an asymptomatic into a symptomatic stage; 3% of the patients die within 3-6 months after the onset of symptoms 22. Often, when symptoms occur disease is more advanced, and left ventricular dysfunction is present. It would therefore be useful to have a better indicator of disease-severity, to be able to select those who are at risk of clinical deterioration, and to determine the threshold when surgery is indicated. Ideally this cut-off point would be just before LV dysfunction and symptoms occur. At present biomarkers are not routinely used for diagnosis and evaluation of patients with (asymptomatic) aortic stenosis. Recent studies have demonstrated several natriuretic peptides to be predictive of left ventricular failure. BNP is secreted mostly in the left ventricle, ANP mainly in the atria, in reaction on increased intra-ventricular and intra-atrial pressure or stretch. BNP is useful in discriminating cardiac versus non-cardiac dyspnea 23, it is accurate in discriminating symptomatic and asymptomatic patients, and it is associated with outcome in both patient categories 24. Asymptomatic patients with high Nt-proBNP at baseline have a much higher risk of developing symptoms during follow-up than those whose levels are normal 25. Nt-proBNP is the N-terminal end of proBNP, the precursor of BNP, and is biologically more stable than BNP 26. Therefore Nt-proBNP is a more practical marker in clinical practice. Measurement of elevated plasma Nt-proBNP could be predictive for symptom development in asymptomatic patients, and poor outcome in both symptomatic and asymptomatic patients 24,25,27.
In this regard Tissue Doppler Imaging is a new emerging ultrasound techniques that provides a measure of left ventricular wall motion 28. Instead of high-frequency low-amplitude signals from moving blood cells in conventional echocardiography, it quantifies high-amplitude, low-velocity signals of myocardial tissue motion 29. Thereby it provides objective means to quantify global and regional left and right ventricular function even before the occurrence of (subjective) symptoms and improves accuracy and reproducibility of conventional echocardiography studies 28,30.

Hypothesis
We hypothesize that a significant proportion of patients with severe aortic stenosis is not referred for surgical treatment because of co-morbidities and/or old age, or is operated late in the course of the disease due to underestimation of disease severity and progression. Nt-proBNP, TDI and strain measurement may predict the onset of symptoms in asymptomatic patients and may predict outcome in symptomatic patients.

Study objectives
The goals of this prospective observational cohort study are:
1. To assess in patients who are echocardiographically diagnosed with severe aortic stenosis if they are truly asymptomatic or not, to document the selected treatment strategy, to investigate potential determinants of prognosis, and to measure 1 and 2-year survival, functional status and quality of life.
2. To investigate if Nt-proBNP, Tissue Doppler Imaging and measurement of strain can predict the course of the disease in symptomatic patients, and to investigate if they are of additive prognostic value in asymptomatic or suspected symptomatic patients.

Study design
Hospital-based prospective cohort study in the wider Rotterdam area (Rijnmond) in The Netherlands (including Erasmus MC and all referring hospitals in the Rotterdam area).

Methods
From May 2006, all adult patients who visit the Erasmus Medical Center or an outpatient Cardiology clinic in the wider Rotterdam area and are diagnosed with severe aortic stenosis will be provided with study information, and invited to the Erasmus Medical Center or the participating center to participate in the proposed study. Written informed consent will be obtained prior to participation. Patients with previous aortic valve surgery or balloon dilatation will be excluded.
Echocardiographic inclusion criteria are (minimal 1):
1. Peak aortic velocity 4,0 m/s 4
2. Aortic valve area 1,0 cm2
3. Aortic valve area adjusted for body surface area 0,6 cm2/m2 31
4. LVOT/AoV TVI ratio 0,25
Patient characteristics, functional status, quality of life and treatment strategy will be established at baseline. Also Nt-proBNP will be measured, and a Doppler echocardiography, including Tissue Doppler Imaging, will be performed. Additional to Nt-proBNP measurement, serum will be saved in order to be able to assess possible Nt-proBNP influencing factors such as renal function or to assess future biomarkers. Also DNA will be saved for gene research. In case of asymptomatic severe aortic stenosis, an exercise test will be done according to recommendations in recent literature 1,31. Follow-up will be at 6 months, 1 and 2 years if conservatively treated. If the patient underwent AVR during this follow-up, one year after AVR is the final follow-up. At these time points echocardiography (Tissue Doppler Imaging, strain, strainrate) and Nt-proBNP assessment will be repeated, and related to functional status and quality of life at that particular time. Endpoints are death or AVR. Total duration of the study will be 3-4 years. Approximately 215 patients are operated for aortic stenosis in Erasmus MC each year. A significant proportion (33% up to 68%) of elderly patients do not receive surgery although they have severe aortic stenosis 11,32. We estimate this proportion to be approximately 50%. Based on these assumptions we estimate it should theoretically be possible to include approximately 430 patients during the period of 1 year.

Innovative aspects
Better timing of intervention and earlier detection of patients who might benefit from surgical treatment are the key innovative goals of this study. Nt-proBNP measurements, Tissue Doppler Imaging and strain measurements are not routinely performed but can prove to be of significant value to cardiovascular medicine in the near future. To our knowledge there are no previous or ongoing studies on this subject. Furthermore the proposed study will provide important new insights into the characteristics of the substantial number of patients who require valve replacement but are currently rejected for surgery. This will be of value to determine which patients may benefit from less invasive techniques to replace the aortic valve that are currently under development but may prove to be a realistic alternative treatment option.

References
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2. Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol 1993;21:1220-5.
3. Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 1997;29:630-4.
4. Bonow RO, Carabello B, de Leon AC, Edmunds LH, Jr., Fedderly BJ, Freed MD, Gaasch WH, McKay CR, Nishimura RA, O'Gara PT, O'Rourke RA, Rahimtoola SH, Ritchie JL, Cheitlin MD, Eagle KA, Gardner TJ, Garson A, Jr., Gibbons RJ, Russell RO, Ryan TJ, Smith SC, Jr. ACC/AHA Guidelines for the Management of Patients With Valvular Heart Disease. Executive Summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Valvular Heart Disease). J Heart Valve Dis 1998;7:672-707.
5. Horstkotte D, Loogen F. The natural history of aortic valve stenosis. Eur Heart J 1988;9 Suppl E:57-64.
6. Cribier A, Eltchaninoff H, Bash A, Borenstein N, Tron C, Bauer F, Derumeaux G, Anselme F, Laborde F, Leon MB. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002;106:3006-8.
7. Cribier A, Eltchaninoff H, Tron C, Bauer F, Agatiello C, Sebagh L, Bash A, Nusimovici D, Litzler PY, Bessou JP, Leon MB. Early experience with percutaneous transcatheter implantation of heart valve prosthesis for the treatment of end-stage inoperable patients with calcific aortic stenosis. J Am Coll Cardiol 2004;43:698-703.
8. Boudjemline Y, Bonhoeffer P. Steps toward percutaneous aortic valve replacement. Circulation 2002;105:775-8.
9. Grube E, Laborde JC, Zickmann B, Gerckens U, Felderhoff T, Sauren B, Bootsveld A, Buellesfeld L, Iversen S. First report on a human percutaneous transluminal implantation of a self-expanding valve prosthesis for interventional treatment of aortic valve stenosis. Catheter Cardiovasc Interv 2005;66:465-9.
10. Bouma BJ, van der Meulen JH, van den Brink RB, Arnold AE, Smidts A, Teunter LH, Lie KI, Tijssen JG. Variability in treatment advice for elderly patients with aortic stenosis: a nationwide survey in The Netherlands. Heart 2001;85:196-201.
11. Iung B, Cachier A, Baron G, Messika-Zeitoun D, Delahaye F, Tornos P, Gohlke-Barwolf C, Boersma E, Ravaud P, Vahanian A. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur Heart J 2005;26:2714-20.
12. Roques F, Nashef SA, Michel P, Gauducheau E, de Vincentiis C, Baudet E, Cortina J, David M, Faichney A, Gabrielle F, Gams E, Harjula A, Jones MT, Pintor PP, Salamon R, Thulin L. Risk factors and outcome in European cardiac surgery: analysis of the EuroSCORE multinational database of 19030 patients. Eur J Cardiothorac Surg 1999;15:816-22; discussion 822-3.
13. Edwards FH, Peterson ED, Coombs LP, DeLong ER, Jamieson WR, Shroyer ALW, Grover FL. Prediction of operative mortality after valve replacement surgery. J Am Coll Cardiol 2001;37:885-92.
14. Freeman WK, Schaff HV, O'Brien PC, Orszulak TA, Naessens JM, Tajik AJ. Cardiac surgery in the octogenarian: perioperative outcome and clinical follow-up. J Am Coll Cardiol 1991;18:29-35.
15. Craver JM, Puskas JD, Weintraub WW, Shen Y, Guyton RA, Gott JP, Jones EL. 601 octogenarians undergoing cardiac surgery: outcome and comparison with younger age groups. Ann Thorac Surg 1999;67:1104-10.
16. Akins CW, Daggett WM, Vlahakes GJ, Hilgenberg AD, Torchiana DF, Madsen JC, Buckley MJ. Cardiac operations in patients 80 years old and older. Ann Thorac Surg 1997;64:606-14; discussion 614-5.
17. Sundt TM, Bailey MS, Moon MR, Mendeloff EN, Huddleston CB, Pasque MK, Barner HB, Gay WA, Jr. Quality of life after aortic valve replacement at the age of >80 years. Circulation 2000;102:III70-4.
18. Das P, Rimington H, Chambers J. Exercise testing to stratify risk in aortic stenosis. Eur Heart J 2005;26:1309-13.
19. Otto CM, Pearlman AS, Gardner CL. Hemodynamic progression of aortic stenosis in adults assessed by Doppler echocardiography. J Am Coll Cardiol 1989;13:545-50.
20. 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;95:2262-70.
21. Faggiano P, Ghizzoni G, Sorgato A, Sabatini T, Simoncelli U, Gardini A, Rusconi C. Rate of progression of valvular aortic stenosis in adults. Am J Cardiol 1992;70:229-33.
22. Pellikka PA, Nishimura RA, Bailey KR, Tajik AJ. The natural history of adults with asymptomatic, hemodynamically significant aortic stenosis. J Am Coll Cardiol 1990;15:1012-7.
23. Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol 2002;39:202-9.
24. Lim P, Monin JL, Monchi M, Garot J, Pasquet A, Hittinger L, Vanoverschelde JL, Carayon A, Gueret P. Predictors of outcome in patients with severe aortic stenosis and normal left ventricular function: role of B-type natriuretic peptide. Eur Heart J 2004;25:2048-53.
25. Gerber IL, Legget ME, West TM, Richards AM, Stewart RA. Usefulness of serial measurement of N-terminal pro-brain natriuretic peptide plasma levels in asymptomatic patients with aortic stenosis to predict symptomatic deterioration. Am J Cardiol 2005;95:898-901.
26. Sullivan DR, West M, Jeremy R. Utility of brain natriuretic peptide (BNP) measurement in cardiovascular disease. Heart Lung Circ 2005;14:78-84.
27. Bergler-Klein J, Klaar U, Heger M, Rosenhek R, Mundigler G, Gabriel H, Binder T, Pacher R, Maurer G, Baumgartner H. Natriuretic peptides predict symptom-free survival and postoperative outcome in severe aortic stenosis. Circulation 2004;109:2302-8.
28. Pellerin D, Sharma R, Elliott P, Veyrat C. Tissue Doppler, strain, and strain rate echocardiography for the assessment of left and right systolic ventricular function. Heart 2003;89 Suppl 3:iii9-17.
29. Ho CY, Solomon SD. A clinician's guide to tissue Doppler imaging. Circulation 2006;113:e396-8.
30. Greenberg NL, Firstenberg MS, Castro PL, Main M, Travaglini A, Odabashian JA, Drinko JK, Rodriguez LL, Thomas JD, Garcia MJ. Doppler-derived myocardial systolic strain rate is a strong index of left ventricular contractility. Circulation 2002;105:99-105.
31. Iung B, Gohlke-Barwolf C, Tornos P, Tribouilloy C, Hall R, Butchart E, Vahanian A. Recommendations on the management of the asymptomatic patient with valvular heart disease. Eur Heart J 2002;23:1252-66.
32. Kapoor N. VP, Pai R.G. Survival patterns in conservatively treated patients with severe aortic stenosis: prognostic variables in 457 patients. Abstract presented at Scientific session AHA 11-09-2004 2004.
- Main changes (audit trail)
- RECORD17-okt-2008 - 31-okt-2008


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