TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial

Dylan R Morris, Margaret A Cunningham, Anna A Ahimastos, Bronwyn A Kingwell, Elise Pappas, Michael Bourke, Christopher M Reid, Theo Stijnen, Ronald L Dalman, Oliver O Aalami, Jan H Lindeman, Paul E Norman, Philip J Walker, Robert Fitridge, Bernie Bourke, Anthony E Dear, Jenna Pinchbeck, Rene Jaeggi, Jonathan Golledge, Dylan R Morris, Margaret A Cunningham, Anna A Ahimastos, Bronwyn A Kingwell, Elise Pappas, Michael Bourke, Christopher M Reid, Theo Stijnen, Ronald L Dalman, Oliver O Aalami, Jan H Lindeman, Paul E Norman, Philip J Walker, Robert Fitridge, Bernie Bourke, Anthony E Dear, Jenna Pinchbeck, Rene Jaeggi, Jonathan Golledge

Abstract

Background: Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm.

Methods/design: Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands.

Discussion: Currently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms.

Trial registration: Australian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976 , registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084 , registered on 5 September 2012.

Figures

Fig. 1
Fig. 1
Design of the Telmisartan in the management of abdominal aortic aneurysm (TEDY) Trial

References

    1. Hoyert DL, Xu JQ. Deaths: preliminary data for 2011. National vital statistics reports; vol 61 no 6. Hyattsville, MD: National Center for Health Statistics; 2012.
    1. Agency for Healthcare Research and Quality . Hospital cost and utilization project: nationwide inpatient sample data set. Rockville, MD: Agency for Healthcare Research and Quality; 2006.
    1. Buxton MJ. Screening for abdominal aortic aneurysm. BMJ. 2009;338:b2185. doi: 10.1136/bmj.b2185.
    1. United Kingdom ETI, Greenhalgh RM, Brown LC, Powell JT, Thompson SG, Epstein D, et al. Endovascular versus open repair of abdominal aortic aneurysm. N Engl J Med. 2010;362:1863–71. doi: 10.1056/NEJMoa0909305.
    1. Ashton HA, Buxton MJ, Day NE, Kim LG, Marteau TM, Scott RA, et al. The multicentre aneurysm screening study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial. Lancet. 2002;360:1531–9. doi: 10.1016/S0140-6736(02)11522-4.
    1. Norman PE, Jamrozik K, Lawrence-Brown MM, Le MT, Spencer CA, Tuohy RJ, et al. Population based randomised controlled trial on impact of screening on mortality from abdominal aortic aneurysm. BMJ. 2004;329:1259. doi: 10.1136/bmj.38272.478438.55.
    1. Filardo G, Powell JT, Martinez MA, Ballard DJ. Surgery for small asymptomatic abdominal aortic aneurysms. Cochrane Database Syst Rev. 2012;3:CD001835.
    1. Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the american college of cardiology foundation/american heart association task force on practice guidelines. J Am Coll Cardiol. 2011;58:2020–45. doi: 10.1016/j.jacc.2011.08.023.
    1. Lederle FA, Wilson SE, Johnson GR, Reinke DB, Littooy FN, Acher CW, et al. Immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med. 2002;346:1437–44. doi: 10.1056/NEJMoa012573.
    1. United Kingdom Small Aneurysm Trial P Long-term outcomes of immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med. 2002;346:1445–52. doi: 10.1056/NEJMoa013527.
    1. Powell JT, Sweeting MJ, Brown LC, Gotensparre SM, Fowkes FG, Thompson SG. Systematic review and meta-analysis of growth rates of small abdominal aortic aneurysms. Br J Surg. 2011;98:609–18. doi: 10.1002/bjs.7465.
    1. Small UK. Aneurysm trial participants. Health service costs and quality of life for early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. Lancet. 1998;352:1656–60. doi: 10.1016/S0140-6736(98)10284-2.
    1. Brady AR, Thompson SG, Fowkes FG, Greenhalgh RM, Powell JT. UK small aneurysm trial participants. Abdominal aortic aneurysm expansion: risk factors and time intervals for surveillance. Circulation. 2004;110:16–21. doi: 10.1161/01.CIR.0000133279.07468.9F.
    1. Powell JT, Brown LC, Forbes JF, Fowkes FG, Greenhalgh RM, Ruckley CV, et al. Final 12-year follow-up of surgery versus surveillance in the UK Small Aneurysm Trial. Br J Surg. 2007;94:702–8. doi: 10.1002/bjs.5778.
    1. Rughani G, Robertson L, Clarke M. Medical treatment for small abdominal aortic aneurysms. Cochrane Database Syst Rev. 2012;9:CD009536.
    1. Golledge J, Norman PE. Current status of medical management for abdominal aortic aneurysm. Atherosclerosis. 2011;217:57–63. doi: 10.1016/j.atherosclerosis.2011.03.006.
    1. Propanolol Aneurysm Trial I Propranolol for small abdominal aortic aneurysms: results of a randomized trial. J Vasc Surg. 2002;35:72–9. doi: 10.1067/mva.2002.121308.
    1. Meijer CA, Stijnen T, Wasser MN, Hamming JF, van Bockel JH, Lindeman JH, et al. Doxycycline for stabilization of abdominal aortic aneurysms: a randomized trial. Ann Intern Med. 2013;159:815–23.
    1. Golledge J, Muller J, Daugherty A, Norman P. Abdominal aortic aneurysm: pathogenesis and implications for management. Arterioscler Thromb Vasc Biol. 2006;26:2605–13. doi: 10.1161/01.ATV.0000245819.32762.cb.
    1. Schouten O, van Laanen JH, Boersma E, Vidakovic R, Feringa HH, Dunkelgrun M, et al. Statins are associated with a reduced infrarenal abdominal aortic aneurysm growth. Eur J Vasc Endovasc Surg. 2006;32:21–6. doi: 10.1016/j.ejvs.2005.12.024.
    1. Mosorin M, Juvonen J, Biancari F, Satta J, Surcel HM, Leinonen M, et al. Use of doxycycline to decrease the growth rate of abdominal aortic aneurysms: a randomized, double-blind, placebo-controlled pilot study. J Vasc Surg. 2001;34:606–10. doi: 10.1067/mva.2001.117891.
    1. Walton LJ, Franklin IJ, Bayston T, Brown LC, Greenhalgh RM, Taylor GW, et al. Inhibition of prostaglandin E2 synthesis in abdominal aortic aneurysms: implications for smooth muscle cell viability, inflammatory processes, and the expansion of abdominal aortic aneurysms. Circulation. 1999;100:48–54. doi: 10.1161/01.CIR.100.1.48.
    1. Yoshimura K, Aoki H, Ikeda Y, Fujii K, Akiyama N, Furutani A, et al. Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase. Nat Med. 2005;11:1330–8. doi: 10.1038/nm1335.
    1. Heart Protection Study Collaborative Group MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22. doi: 10.1016/S0140-6736(02)09327-3.
    1. Ferguson CD, Clancy P, Bourke B, Walker PJ, Dear A, Buckenham T, et al. Association of statin prescription with small abdominal aortic aneurysm progression. Am Heart J. 2010;159:307–13. doi: 10.1016/j.ahj.2009.11.016.
    1. Daugherty A, Cassis L. Angiotensin II and abdominal aortic aneurysms. Curr Hypertens Rep. 2004;6:442–6. doi: 10.1007/s11906-004-0038-0.
    1. Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest. 2000;105:1605–12. doi: 10.1172/JCI7818.
    1. Rush C, Nyara M, Moxon JV, Trollope A, Cullen B, Golledge J. Whole genome expression analysis within the angiotensin II-apolipoprotein E deficient mouse model of abdominal aortic aneurysm. BMC Genomics. 2009;10:298. doi: 10.1186/1471-2164-10-298.
    1. Campos AH, Zhao Y, Pollman MJ, Gibbons GH. DNA microarray profiling to identify angiotensin-responsive genes in vascular smooth muscle cells: potential mediators of vascular disease. Circ Res. 2003;92:111–8. doi: 10.1161/01.RES.0000049100.22673.F6.
    1. Habashi JP, Doyle JJ, Holm TM, Aziz H, Schoenhoff F, Bedja D, et al. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science. 2011;332:361–5. doi: 10.1126/science.1192152.
    1. Golledge J, Muller J, Shephard N, Clancy P, Smallwood L, Moran C, et al. Association between osteopontin and human abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 2007;27:655–60. doi: 10.1161/01.ATV.0000255560.49503.4e.
    1. Ahimastos AA, Aggarwal A, D‘Orsa KM, Formosa MF, White AJ, Savarirayan R, et al. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial. JAMA. 2007;298:1539–47. doi: 10.1001/jama.298.13.1539.
    1. Ahimastos AA, Dart AM, Kingwell BA. Angiotensin II blockade in Marfan’s syndrome. N Eng J Med. 2008;359:1732. doi: 10.1056/NEJMc081528.
    1. Imayama I, Ichiki T, Inanaga K, Ohtsubo H, Fukuyama K, Ono H, et al. Telmisartan downregulates angiotensin II type 1 receptor through activation of peroxisome proliferator-activated receptor gamma. Cardiovasc Res. 2006;72:184–90. doi: 10.1016/j.cardiores.2006.07.014.
    1. Sharma AM. Telmisartan: the ACE of ARBs? Hypertension. 2006;47:822–3. doi: 10.1161/01.HYP.0000215184.00915.62.
    1. Jones A, Deb R, Torsney E, Howe F, Dunkley M, Gnaneswaran Y, et al. Rosiglitazone reduces the development and rupture of experimental aortic aneurysms. Circulation. 2009;119:3125–32. doi: 10.1161/CIRCULATIONAHA.109.852467.
    1. Moran CS, Clancy P, Biros E, Blanco-Martin B, McCaskie P, Palmer LJ, et al. Association of PPARgamma allelic variation, osteoprotegerin and abdominal aortic aneurysm. Clin Endocrinol. 2010;72:128–32. doi: 10.1111/j.1365-2265.2009.03615.x.
    1. Golledge J, Cullen B, Rush C, Moran CS, Secomb E, Wood F, et al. Peroxisome proliferator-activated receptor ligands reduce aortic dilatation in a mouse model of aortic aneurysm. Atherosclerosis. 2010;210:51–6. doi: 10.1016/j.atherosclerosis.2009.10.027.
    1. Moran CS, Cullen B, Campbell JH, Golledge J. Interaction between angiotensin II, osteoprotegerin, and peroxisome proliferator-activated receptor-gamma in abdominal aortic aneurysm. J Vasc Res. 2009;46:209–17. doi: 10.1159/000163019.
    1. Krishna SM, Seto SW, Moxon JV, Rush C, Walker PJ, Norman PE, et al. Fenofibrate increases high-density lipoprotein and sphingosine 1 phosphate concentrations limiting abdominal aortic aneurysm progression in a mouse model. Am J Pathol. 2012;181:706–18. doi: 10.1016/j.ajpath.2012.04.015.
    1. Nishimoto M, Takai S, Fukumoto H, Tsunemi K, Yuda A, Sawada Y, et al. Increased local angiotensin II formation in aneurysmal aorta. Life Sci. 2002;71:2195–205. doi: 10.1016/S0024-3205(02)01998-7.
    1. Furubayashi K, Takai S, Jin D, Muramatsu M, Ibaraki T, Nishimoto M, et al. The significance of chymase in the progression of abdominal aortic aneurysms in dogs. Hypertens Res. 2007;30:349–57. doi: 10.1291/hypres.30.349.
    1. Cruden NL, Witherow FN, Webb DJ, Fox KA, Newby DE. Bradykinin contributes to the systemic hemodynamic effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure. Arterioscler Thromb Vasc Biol. 2004;24:1043–8. doi: 10.1161/01.ATV.0000129331.21092.1d.
    1. Messerli FH, Bangalore S, Ram VS. Telmisartan, ramipril, or both in patients at high risk of vascular events. N Eng J Med. 2008;359:426–7. doi: 10.1056/NEJMc081065.
    1. Iida Y, Xu B, Schultz GM, Chow V, White JJ, Sulaimon S, et al. Efficacy and mechanism of angiotensin II receptor blocker treatment in experimental abdominal aortic aneurysms. PLoS One. 2012;7:e49642. doi: 10.1371/journal.pone.0049642.
    1. Matsumoto S, Kamide K, Banno F, Inoue N, Mochizuki N, Kawano Y, et al. Impact of RGS2 deficiency on the therapeutic effect of telmisartan in angiotensin II-induced aortic aneurysm. Hypertens Res. 2010;33:1244–9. doi: 10.1038/hr.2010.184.
    1. Kaschina E, Schrader F, Sommerfeld M, Kemnitz UR, Grzesiak A, Krikov M, et al. Telmisartan prevents aneurysm progression in the rat by inhibiting proteolysis, apoptosis and inflammation. J Hypertens. 2008;26:2361–73. doi: 10.1097/HJH.0b013e328313e547.
    1. Thompson A, Cooper JA, Fabricius M, Humphries SE, Ashton HA, Hafez H. An analysis of drug modulation of abdominal aortic aneurysm growth through 25 years of surveillance. J Vasc Surg. 2010;52:55–61. doi: 10.1016/j.jvs.2010.02.012.
    1. Parr A, Jayaratne C, Buttner P, Golledge J. Comparison of volume and diameter measurement in assessing small abdominal aortic aneurysm expansion examined using computed tomographic angiography. Eur J Radiol. 2011;79:42–7. doi: 10.1016/j.ejrad.2009.12.018.
    1. Moxon JV, Parr A, Emeto TI, Walker P, Norman PE, Golledge J. Diagnosis and monitoring of abdominal aortic aneurysm: current status and future prospects. Curr Probl Cardiol. 2010;35:512–48. doi: 10.1016/j.cpcardiol.2010.08.004.
    1. Golledge J, Muller R, Clancy P, McCann M, Norman PE. Evaluation of the diagnostic and prognostic value of plasma D-dimer for abdominal aortic aneurysm. Eur Heart J. 2011;32:354–64. doi: 10.1093/eurheartj/ehq171.
    1. Sturm JW, Osborne RH, Dewey HM, Donnan GA, Macdonell RAL, Thrift AG. Brief comprehensive quality of life assessment after stroke: the assessment of quality of life instrument in the north East melbourne stroke incidence study (NEMESIS) Stroke. 2002;33:2888–94. doi: 10.1161/01.STR.0000040407.44712.C7.
    1. Hawthorne G, Richardson J, Osborne R. The assessment of quality of life (AQoL) instrument: a psychometric measure of health-related quality of life. Qual Life Res. 1999;8:209–24. doi: 10.1023/A:1008815005736.
    1. Golledge J, Karan M, Moran CS, Muller J, Clancy P, Dear AE, et al. Reduced expansion rate of abdominal aortic aneurysms in patients with diabetes may be related to aberrant monocyte-matrix interactions. Eur Heart J. 2008;29:665–72. doi: 10.1093/eurheartj/ehm557.
    1. Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, et al Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372:1174–83. doi: 10.1016/S0140-6736(08)61242-8.
    1. Mann JFE, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547–53. doi: 10.1016/S0140-6736(08)61236-2.
    1. DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med. 1994;13:1341–52. doi: 10.1002/sim.4780131308.
    1. Imperial College London, Imperial Clinical Trials Unit. (accessed 24 December 2012).
    1. Hackam DG, Thiruchelvam D, Redelmeier DA. Angiotensin-converting enzyme inhibitors and aortic rupture: a population-based case–control study. Lancet. 2006;368:659–65. doi: 10.1016/S0140-6736(06)69250-7.
    1. Sweeting MJ, Thompson SG, Brown LC, Greenhalgh RM, Powell JT. Use of angiotensin converting enzyme inhibitors is associated with increased growth rate of abdominal aortic aneurysms. J Vasc Surg. 2010;52:1–4. doi: 10.1016/j.jvs.2010.02.264.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere