A prospective, double-blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor Ramipril In Aortic Stenosis (RIAS trial)

Sacha Bull, Margaret Loudon, Jane M Francis, Jubin Joseph, Stephen Gerry, Theodoros D Karamitsos, Bernard D Prendergast, Adrian P Banning, Stefan Neubauer, Saul G Myerson, Sacha Bull, Margaret Loudon, Jane M Francis, Jubin Joseph, Stephen Gerry, Theodoros D Karamitsos, Bernard D Prendergast, Adrian P Banning, Stefan Neubauer, Saul G Myerson

Abstract

Aims: Angiotensin-converting enzyme (ACE) inhibitors improve left ventricular (LV) remodelling and outcome in heart failure and hypertensive heart disease. They may be similarly beneficial in patients with aortic stenosis (AS), but historical safety concerns have limited their use, and no prospective clinical trials exist.

Methods and results: We conducted a prospective, randomized, double-blind, placebo-controlled trial in 100 patients with moderate or severe asymptomatic AS to examine the physiological effects of ramipril, particularly LV mass (LVM) regression. Subjects were randomized to ramipril 10 mg daily (n = 50) or placebo (n = 50) for 1 year, and underwent cardiac magnetic resonance, echocardiography, and exercise testing at 0, 6, and 12 months, with follow-up data available in 77 patients. There was a modest but progressive reduction in LVM (the primary end point) in the ramipril group vs. the placebo group (mean change -3.9 vs. +4.5 g, respectively, P = 0.0057). There were also trends towards improvements in myocardial physiology: the ramipril group showed preserved tissue Doppler systolic velocity compared with placebo (+0.0 vs. -0.5 cm/s, P = 0.04), and a slower rate of progression of the AS (valve area 0.0 cm(2) in the ramipril group vs. -0.2 cm(2) in the placebo arm, P = 0.067). There were no significant differences in major adverse cardiac events.

Conclusion: ACE inhibition leads to a modest, but progressive reduction in LVM in asymptomatic patients with moderate-severe AS compared with placebo, with trends towards improvements in myocardial physiology and slower progression of valvular stenosis. A larger clinical outcome trial to confirm these findings and explore their clinical relevance is required.

Keywords: ACE inhibition; aortic stenosis; myocardium; valve disease.

© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1
Figure 1
Study design and flow chart.
Figure 2
Figure 2
CONSORT flow chart—numbers of subjects randomized and allocated to each treatment.
Figure 3
Figure 3
Changes in LV mass with ramipril 10 mg daily or placebo over a 12-month period.

References

    1. Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, et al. Clinical factors associated with calcific aortic valve disease. J Am Coll Cardiol 1997;29:630–4.
    1. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–96.
    1. Dell'Amore A, Aquino TM, Pagliaro M, Lamarra M, Zussa C. Aortic valve replacement with and without combined coronary bypass grafts in very elderly patients: early and long-term results. Eur J Cardiothorac Surg 2012;41:491–8.
    1. Assmann A, Minol JP, Mehdiani A, Akhyari P, Boeken U, Lichtenberg A. Cardiac surgery in nonagenarians: not only feasible, but also reasonable? Interact Cardiovasc Thorac Surg 2013;17:340–4.
    1. Rosenhek R, Rader F, Loho N, Gabriel H, Heger M, Klaar U, et al. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004;110:1291–5.
    1. Novaro GM, Tiong IY, Pearce GL, Lauer MS, Sprecher DL, Griffin BP. Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis. Circulation 2001;104:2205–9.
    1. Rossebo AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343–56.
    1. Cowell SJ, Newby DE, Prescott RJ, Bloomfield P, Reid J, Northridge DB, et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389–97.
    1. Chan KL, Teo K, Dumesnil JG, Ni A, Tam J. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010;121:306–14.
    1. Dweck MR, Boon NA, Newby DE. Calcific aortic stenosis: a disease of the valve and the myocardium. J Am Coll Cardiol 2012;60:1854–63.
    1. Otto CM, Burwash IG, Legget ME, Munt BI, Fujioka M, Healy NL, et al. Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95:2262–70.
    1. Cioffi G, Faggiano P, Vizzardi E, Tarantini L, Cramariuc D, Gerdts E, et al. Prognostic effect of inappropriately high left ventricular mass in asymptomatic severe aortic stenosis. Heart 2011;97:301–7.
    1. Dweck MR, Joshi S, Murigu T, Alpendurada F, Jabbour A, Melina G, et al. Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis. J Am Coll Cardiol 2011;58:1271–9.
    1. Kearney LG, Lu K, Ord M, Patel SK, Profitis K, Matalanis G, et al. Global longitudinal strain is a strong independent predictor of all-cause mortality in patients with aortic stenosis. Eur Heart J Cardiovasc Imaging 2012;13:827–33.
    1. Schunkert H, Jackson B, Tang SS, Schoen FJ, Smits JF, Apstein CS, et al. Distribution and functional significance of cardiac angiotensin converting enzyme in hypertrophied rat hearts. Circulation 1993;87:1328–39.
    1. Fielitz J, Hein S, Mitrovic V, Pregla R, Zurbrugg HR, Warnecke C, et al. Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease. J Am Coll Cardiol 2001;37:1443–9.
    1. Fujisaka T, Hoshiga M, Hotchi J, Takeda Y, Jin D, Takai S, et al. Angiotensin II promotes aortic valve thickening independent of elevated blood pressure in apolipoprotein-E deficient mice. Atherosclerosis 2013;226:82–7.
    1. Dahlof B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients. A metaanalysis of 109 treatment studies. Am J Hypertens 1992;5:95–110.
    1. Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, Martinez Ubago JL. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 2002;105:2512–7.
    1. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429–35.
    1. Greenberg B, Quinones MA, Koilpillai C, Limacher M, Shindler D, Benedict C, et al. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiography substudy. Circulation 1995;91:2573–81.
    1. Martinez Sanchez C, Henne O, Arceo A, Pena M, Gonzalez H, Chuquiure E, et al. Hemodynamic effects of oral captopril in patients with critical aortic stenosis. Arch Inst Cardiol Mex 1996;66:322–30.
    1. O'Brien KD, Zhao XQ, Shavelle DM, Caulfield MT, Letterer RA, Kapadia SR, et al. Hemodynamic effects of the angiotensin-converting enzyme inhibitor, ramipril, in patients with mild to moderate aortic stenosis and preserved left ventricular function. J Investig Med 2004;52:185–91.
    1. Chockalingam A, Venkatesan S, Subramaniam T, Jagannathan V, Elangovan S, Alagesan R, et al. Safety and efficacy of angiotensin-converting enzyme inhibitors in symptomatic severe aortic stenosis: Symptomatic Cardiac Obstruction-Pilot Study of Enalapril in Aortic Stenosis (SCOPE-AS). Am Heart J 2004;147:E19.
    1. Nadir MA, Wei L, Elder DH, Libianto R, Lim TK, Pauriah M, et al. Impact of renin-angiotensin system blockade therapy on outcome in aortic stenosis. J Am Coll Cardiol 2011;58:570–6.
    1. Wakabayashi K, Tsujino T, Naito Y, Ezumi A, Lee-Kawabata M, Nakao S, et al. Administration of angiotensin-converting enzyme inhibitors is associated with slow progression of mild aortic stenosis in Japanese patients. Heart Vessels 2011;26:252–7.
    1. Bull S, Loudon M, Francis J, Joseph J, Gerry S, Karamitsos T, et al. A prospective, double-blind, randomised controlled trial of the angiotensin converting enzyme inhibitor Ramipril In Asymptomatic Aortic Stenosis (RIAS trial): Trial Protocol. J Clin Trials 2014;4:151–7.
    1. Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E. Standardized cardiovascular magnetic resonance imaging (CMR) protocols, society for cardiovascular magnetic resonance: board of trustees task force on standardized protocols. J Cardiovasc Magn Reson 2008;10:35.
    1. Axel L, Dougherty L. MR imaging of motion with spatial modulation of magnetization. Radiology 1989;171:841–5.
    1. Bull S, White SK, Piechnik SK, Flett AS, Ferreira VM, Loudon M, et al. Human non-contrast T1 values and correlation with histology in diffuse fibrosis. Heart 2013;99:932–7.
    1. Piechnik SK, Ferreira VM, Dall'Armellina E, Cochlin LE, Greiser A, Neubauer S, et al. Shortened Modified Look-Locker Inversion recovery (ShMOLLI) for clinical myocardial T1-mapping at 1.5 and 3 T within a 9 heartbeat breathhold. J Cardiovasc Magn Reson 2010;12:69.
    1. Simonetti OP, Kim RJ, Fieno DS, Hillenbrand HB, Wu E, Bundy JM, et al. An improved MR imaging technique for the visualization of myocardial infarction. Radiology 2001;218:215–23.
    1. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539–42.
    1. Selvanayagam JB, Jerosch-Herold M, Porto I, Sheridan D, Cheng AS, Petersen SE, et al. Resting myocardial blood flow is impaired in hibernating myocardium: a magnetic resonance study of quantitative perfusion assessment. Circulation 2005;112:3289–96.
    1. Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:167–84.
    1. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009;22:107–33.
    1. Naughton J, Sevelius G, Balke B. Physiological responses of normal and pathological subjects to a modified work capacity test. J Sports Med Phys Fitness 1963;44:201–7.
    1. Rajappan K, Melina G, Bellenger NG, Amrani M, Khaghani A, Pennell DJ, et al. Evaluation of left ventricular function and mass after Medtronic Freestyle versus homograft aortic root replacement using cardiovascular magnetic resonance. J Heart Valve Dis 2002;11:60–5; discussion 66.
    1. Lievre M, Gueret P, Gayet C, Roudaut R, Haugh MC, Delair S, et al. Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individuals. HYCAR Study Group. Hypertension 1995;25:92–7.
    1. Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi Q, et al. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation 2001;104:1615–21.
    1. Varo N, Iraburu MJ, Varela M, Lopez B, Etayo JC, Diez J. Chronic AT(1) blockade stimulates extracellular collagen type I degradation and reverses myocardial fibrosis in spontaneously hypertensive rats. Hypertension 2000;35:1197–202.
    1. Flett AS, Sado DM, Quarta G, Mirabel M, Pellerin D, Herrey AS, et al. Diffuse myocardial fibrosis in severe aortic stenosis: an equilibrium contrast cardiovascular magnetic resonance study. Eur Heart J Cardiovasc Imaging 2012;13:819–26.
    1. Steadman CD, Jerosch-Herold M, Grundy B, Rafelt S, Ng LL, Squire IB, et al. Determinants and functional significance of myocardial perfusion reserve in severe aortic stenosis. JACC Cardiovasc Imaging 2012;5:182–9.
    1. O'Brien KD, Shavelle DM, Caulfield MT, McDonald TO, Olin-Lewis K, Otto CM, et al. Association of angiotensin-converting enzyme with low-density lipoprotein in aortic valvular lesions and in human plasma. Circulation 2002;106:2224–30.
    1. Helske S, Lindstedt KA, Laine M, Mayranpaa M, Werkkala K, Lommi J, et al. Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol 2004;44:1859–66.
    1. Cote N, Couture C, Pibarot P, Despres JP, Mathieu P. Angiotensin receptor blockers are associated with a lower remodelling score of stenotic aortic valves. Eur J Clin Invest 2011;41:1172–9.
    1. O'Brien KD, Probstfield JL, Caulfield MT, Nasir K, Takasu J, Shavelle DM, et al. Angiotensin-converting enzyme inhibitors and change in aortic valve calcium. Arch Intern Med 2005;165:858–62.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever