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Original Article| Volume 18, ISSUE 5, P343-346, October 2009

At Sea with SEAS: The First Clinical Endpoint Trial for Ezetimibe, Treatment of Patients with Mild to Moderate Aortic Stenosis, Ends with Mixed Results and More Controversy

DOI:https://doi.org/10.1016/j.hlc.2009.02.007
At Sea with SEAS: The First Clinical Endpoint Trial for Ezetimibe, Treatment of Patients with Mild to Moderate Aortic Stenosis, Ends with Mixed Results and More Controversy
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      SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) hypothesised that aggressive lipid lowering with simvastatin/ezetimibe reduced cardiovascular disease (CVD) risk and the need for aortic valve replacement (AVR) in patients with asymptomatic aortic stenosis (AS). The study enrolled from 173 centres in seven European countries 1873 elderly non-diabetics with mild to moderate AS (mean aortic-valve area 1.28 ± 0.47 cm2), who had no indication for lipid-lowering therapy. Patients were randomised to treatment with either simvastatin/ezetimibe 40/10 mg daily or matching placebo after a four-week diet/placebo run-in period. Compared with placebo, LDL cholesterol was reduced by 61% (2.0 mmol/l). There was no difference in the primary endpoint (a combination of AVR, CV death, non-fatal MI, congestive heart failure from AS progression, coronary revascularisation, hospitalised unstable angina and non-haemorrhagic stroke). Compared with placebo, CVD events were reduced by 4.4% from 20.1% to 15.7% in the simvastatin/ezetimibe group (p = 0.02). Cancer incidence and cancer deaths were more frequent in the simvastatin/ezetimibe group (9.9% vs. 7.0%, p = 0.03 and 4.1% vs. 2.5%, p = 0.05, respectively). These differences were not related to any form of cancer and did not increase with increased duration of therapy.

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      References

        • Rossebo A.B.
        • Pedersen T.R.
        • Allen C.
        • Boman K.
        • Chambers J.
        • Egstrup K.
        • Gerdts E.
        • Gohlke-Bärwolf C.
        • Holme I.
        • Kesäniemi V.A.
        • Malbecq W.
        • Nienaber C.
        • Ray S.
        • Skjaerpe T.
        • Wachtell K.
        • Willenheimer R.
        Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study.
        Am J Cardiol. 2007; 99: 970-973
        View in Article
        • Rossebo A.B.
        • Pedersen T.R.
        • Boman K.
        • Brudi P.
        • Chambers J.B.
        • Egstrup K.
        • Gerdts E.
        • Gohlke-Bärwolf C.
        • Holme I.
        • Kesäniemi Y.A.
        • Malbecq W.
        • Nienaber C.A.
        • Ray S.
        • Skjaerpe T.
        • Wachtell K.
        • Willenheimer R.
        • SEAS Investigators
        Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.
        N Engl J Med. 2008; 359 (accessed July 24, 2008)https://doi.org/10.1056/NEJMoa0804602
        View in Article
        • Kastelein J.J.
        • Akdim F.
        • Stroes E.S.
        • Zwinderman A.H.
        • Bots M.L.
        • Stalenhoef A.F.
        • Visseren F.L.
        • Sijbrands E.J.
        • Trip M.D.
        • Stein E.A.
        • Gaudet D.
        • Duivenvoorden R.
        • Veltri E.P.
        • Marais A.D.
        • de Groot E.
        • ENHANCE Investigators
        Simvastatin with or without ezetimibe in familial hypercholesterolemia.
        N Engl J Med. 2008; 358: 1431-1443
        View in Article
        • Baigent C.
        • Keech A.
        • Kearney P.M.
        • Blackwell L.
        • Buck G.
        • Pollicino C.
        • Kirby A.
        • Sourjina T.
        • Peto R.
        • Collins R.
        • Simes R.
        • Cholesterol Treatment Trialists’ (CTT) Collaborators
        Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
        Lancet. 2005; 366 (Erratum in: Lancet 2005;366(9494):1358. Lancet 2008;371(9630):2084): 1267-1278
        View in Article
        • Takasu J.
        • Shavelle D.M.
        • O’Brien K.D.
        • Babaei A.
        • Rosales J.
        • Mao S.
        • Fischer H.
        • Budoff M.J.
        Association between progression of aortic valve calcification and coronary calcification: assessment by electron beam tomography.
        Acad Radiol. 2005; 12: 298-304
        View in Article
        • Zhao X.Q.
        • Yuan C.
        • Hatsukami T.S.
        • Frechette E.H.
        • Kang X.J.
        • Maravilla K.R.
        • Brown B.G.
        Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case-control study.
        Arterioscler Thromb Vasc Biol. 2001; 1: 1623-1629
        View in Article
        • Steinberg D.
        Thematic review series: the pathogenesis of atherosclerosis: an interpretive history of the cholesterol controversy. Part III. Mechanistically defining the role of hyperlipidemia.
        J Lipid Res. 2005; 46: 2037-2051
        View in Article
        • Hamilton-Craig I.R.
        After ENHANCE, the lipid hypothesis is alive and well.
        Med J Aust. 2008; 189: 303
        View in Article
        • Afilalo J.
        • Duque G.
        • Steele R.
        • Jukema J.W.
        • de Craen A.J.
        • Eisenberg M.J.
        Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis.
        J Am Coll Cardiol. 2008; 51: 37-45
        View in Article
        • Peto R.
        • Emberson J.
        • Landray M.
        • Baigent C.
        • Collins R.
        • Clare R.
        • Califf R.
        Analyses of cancer data from three ezetimibe trials.
        N Engl J Med. 2008; 359: 1357-1366
        View in Article

      11. Stein EA. After ENHANCE–is more LDL cholesterol lowering still better? Clin Chem 2008, April 10; published as doi:10.1373/clinchem.2008.104893 (accessed August 2, 2008).

        View in Article

      12. IMPROVE-IT Trial. http://clinicaltrials.gov/ct2/show/NCT00202878?term=IMPROVE-IT&rank=1 (accessed August 2, 2008).

        View in Article
        • Peto R.
        • Emberson J.
        • Landray M.
        • Baigent C.
        • Collins R.
        • Clare R.
        • Califf R.
        Analyses of cancer data for three ezetimibe trials.
        N Engl J Med. 2008; 359 ([Epub 2008 Sep 2]): 1357-1366
        View in Article
        • Rosenhek R.
        • Rader F.
        • Loho N.
        • Gabriel H.
        • Heger M.
        • Klaar U.
        • Schemper M.
        • Binder T.
        • Maurer G.
        • Baumgartner H.
        Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis.
        Circulation. 2004; 110: 1291-1295
        View in Article
        • Mohler 3rd, E.R.
        • Wang H.
        • Medenilla E.
        • Scott C.
        Effect of statin treatment on aortic valve and coronary artery calcification.
        J Heart Valve Dis. 2007; 16: 378-386
        View in Article
        • Cowell S.J.
        • Newby D.E.
        • Prescott R.J.
        • Bloomfield P.
        • Reid J.
        • Northridge D.B.
        • Boon N.A.
        • Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) Investigators
        A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis.
        N Engl J Med. 2005; 352: 2389-2397
        View in Article
        • Moura L.M.
        • Ramos S.F.
        • Zamorano J.L.
        • Barros I.M.
        • Azevedo L.F.
        • Rocha-Gonçalves F.
        • Rajamannan N.M.
        Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis.
        J Am Coll Cardiol. 2007; 49: 554-561
        View in Article
        • Rosenhek R.
        • Baumgartner H.
        Aortic sclerosis, aortic stenosis and lipid-lowering therapy.
        Expert Rev Cardiovasc Ther. 2008; 6: 385-390
        View in Article
        • Chan K.L.
        • Teo K.
        • Tam J.
        • Dumesnil J.G.
        • Astronomer Investigators
        Rationale, design, and baseline characteristics of a randomized trial to assess the effect of cholesterol lowering in the progression of aortic stenosis: the Aortic Stenosis Progression Observation: measuring Effects of Rosuvastatin (ASTRONOMER) trial.
        Am Heart J. 2007; 153: 925-931
        View in Article
        • Pedersen T.R.
        Overview of clinical trials on calcific aortic stenosis.
        Eur Heart J Suppl. 2008; 10: E31-E40
        View in Article
        • Clark I.M.
        • Swingler T.E.
        • Sampieri C.L.
        • Edwards D.R.
        The regulation of matrix metalloproteinases and their inhibitors.
        Int J Biochem Cell Biol. 2008; 40: 1362-1378
        View in Article

      22. Drazen, JM, D’Agostino RB, Ware JH, Morrissey S, Curfman GD. Ezetimibe and cancer—an uncertain association. N Engl J Med 2008; published online at www.nejm.org (article 10.1056/NEJMe0807200) accessed November 24, 2008.

        View in Article

      Article info

      Publication history

      Accepted: February 17, 2009
      Received in revised form: December 15, 2008
      Received: October 2, 2008

      Footnotes

      ☆The SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study is a double first: the first clinical outcomes trial for ezetimibe, and the first pre-specified clinical outcomes trial of statin therapy for patients with aortic stenosis (AS), in this case simvastatin in combination with ezetimibe [Rossebo AB, PedersenTR, Allen C, et al. Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. Am J Cardiol 2007;99:970–73; Rossebo AB, PedersenTR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359, doi: 10.1056/NEJMoa0804602 (accessed November 24, 2008)].

      ☆☆SEAS enrolled 1873 elderly non-diabetic patients with mild to moderate AS, who had no definite indication for cholesterol-lowering therapy. It follows the ENHANCE study, in which patients with familial hypercholesterolaemia were treated with simvastatin alone or simvastatin plus ezetimibe [The ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431–43].

      Identification

      DOI: https://doi.org/10.1016/j.hlc.2009.02.007

      Copyright

      © 2009 Published by Elsevier Inc.

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