Effect Modifications of Lipid-Lowering Therapy on Progression of Aortic Stenosis (from the Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] Study)

Anders M. Greve, Casper N. Bang, Kurt Boman, Kenneth Egstrup, Julie L. Forman, Y. Antero Kesäniemi, Simon Ray, Terje R. Pedersen, Patricia Best, Nalini M. Rajamannan, Kristian Wachtell

Research output: Contribution to journalArticle

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Abstract

Observational studies indicate that low-density lipoprotein (LDL) cholesterol acts as a primary contributor to an active process leading to aortic stenosis (AS) development. However, randomized clinical trials have failed to demonstrate an effect of lipid lowering on impeding AS progression. This study explored if pretreatment LDL levels and AS severity altered the efficacy of lipid-lowering therapy. The study goal was evaluated in the analysis of surviving patients with baseline data in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial of 1,873 asymptomatic patients with mild-to-moderate AS. Serially measured peak aortic jet velocity was the primary effect estimate. Linear mixed model analysis adjusted by baseline peak jet velocity and pretreatment LDL levels was used to assess effect modifications of treatment. Data were available in 1,579 (84%) patients. In adjusted analyses, lower baseline peak aortic jet velocity and higher pretreatment LDL levels increased the effect of randomized treatment (p = 0.04 for interaction). As such, treatment impeded progression of AS in the highest quartile of LDL among patients with mild AS at baseline (0.06 m/s per year slower progression vs placebo in peak aortic jet velocity, 95% confidence interval 0.01 to 0.11, p = 0.03), but not in the 3 other quartiles of LDL. Conversely, among patients with moderate AS, there was no detectable effect of treatment in any of the pretreatment LDL quartiles (all p ≥0.14). In conclusion, in a non–prespecified post hoc analysis, the efficacy of lipid-lowering therapy on impeding AS progression increased with higher pretreatment LDL and lower peak aortic jet velocity (SEAS study: NCT00092677).

Original languageEnglish (US)
Pages (from-to)739-745
Number of pages7
JournalAmerican Journal of Cardiology
Volume121
Issue number6
DOIs
StatePublished - Mar 15 2018

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Simvastatin
Aortic Valve Stenosis
LDL Lipoproteins
Lipids
Therapeutics
Ezetimibe
LDL Cholesterol
Observational Studies
Linear Models
Randomized Controlled Trials
Placebos
Confidence Intervals

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Effect Modifications of Lipid-Lowering Therapy on Progression of Aortic Stenosis (from the Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] Study). / Greve, Anders M.; Bang, Casper N.; Boman, Kurt; Egstrup, Kenneth; Forman, Julie L.; Kesäniemi, Y. Antero; Ray, Simon; Pedersen, Terje R.; Best, Patricia; Rajamannan, Nalini M.; Wachtell, Kristian.

In: American Journal of Cardiology, Vol. 121, No. 6, 15.03.2018, p. 739-745.

Research output: Contribution to journalArticle

Greve, AM, Bang, CN, Boman, K, Egstrup, K, Forman, JL, Kesäniemi, YA, Ray, S, Pedersen, TR, Best, P, Rajamannan, NM & Wachtell, K 2018, 'Effect Modifications of Lipid-Lowering Therapy on Progression of Aortic Stenosis (from the Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] Study)', American Journal of Cardiology, vol. 121, no. 6, pp. 739-745. https://doi.org/10.1016/j.amjcard.2017.12.011
Greve, Anders M. ; Bang, Casper N. ; Boman, Kurt ; Egstrup, Kenneth ; Forman, Julie L. ; Kesäniemi, Y. Antero ; Ray, Simon ; Pedersen, Terje R. ; Best, Patricia ; Rajamannan, Nalini M. ; Wachtell, Kristian. / Effect Modifications of Lipid-Lowering Therapy on Progression of Aortic Stenosis (from the Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] Study). In: American Journal of Cardiology. 2018 ; Vol. 121, No. 6. pp. 739-745.
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AU - Greve, Anders M.

AU - Bang, Casper N.

AU - Boman, Kurt

AU - Egstrup, Kenneth

AU - Forman, Julie L.

AU - Kesäniemi, Y. Antero

AU - Ray, Simon

AU - Pedersen, Terje R.

AU - Best, Patricia

AU - Rajamannan, Nalini M.

AU - Wachtell, Kristian

PY - 2018/3/15

Y1 - 2018/3/15

N2 - Observational studies indicate that low-density lipoprotein (LDL) cholesterol acts as a primary contributor to an active process leading to aortic stenosis (AS) development. However, randomized clinical trials have failed to demonstrate an effect of lipid lowering on impeding AS progression. This study explored if pretreatment LDL levels and AS severity altered the efficacy of lipid-lowering therapy. The study goal was evaluated in the analysis of surviving patients with baseline data in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial of 1,873 asymptomatic patients with mild-to-moderate AS. Serially measured peak aortic jet velocity was the primary effect estimate. Linear mixed model analysis adjusted by baseline peak jet velocity and pretreatment LDL levels was used to assess effect modifications of treatment. Data were available in 1,579 (84%) patients. In adjusted analyses, lower baseline peak aortic jet velocity and higher pretreatment LDL levels increased the effect of randomized treatment (p = 0.04 for interaction). As such, treatment impeded progression of AS in the highest quartile of LDL among patients with mild AS at baseline (0.06 m/s per year slower progression vs placebo in peak aortic jet velocity, 95% confidence interval 0.01 to 0.11, p = 0.03), but not in the 3 other quartiles of LDL. Conversely, among patients with moderate AS, there was no detectable effect of treatment in any of the pretreatment LDL quartiles (all p ≥0.14). In conclusion, in a non–prespecified post hoc analysis, the efficacy of lipid-lowering therapy on impeding AS progression increased with higher pretreatment LDL and lower peak aortic jet velocity (SEAS study: NCT00092677).

AB - Observational studies indicate that low-density lipoprotein (LDL) cholesterol acts as a primary contributor to an active process leading to aortic stenosis (AS) development. However, randomized clinical trials have failed to demonstrate an effect of lipid lowering on impeding AS progression. This study explored if pretreatment LDL levels and AS severity altered the efficacy of lipid-lowering therapy. The study goal was evaluated in the analysis of surviving patients with baseline data in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial of 1,873 asymptomatic patients with mild-to-moderate AS. Serially measured peak aortic jet velocity was the primary effect estimate. Linear mixed model analysis adjusted by baseline peak jet velocity and pretreatment LDL levels was used to assess effect modifications of treatment. Data were available in 1,579 (84%) patients. In adjusted analyses, lower baseline peak aortic jet velocity and higher pretreatment LDL levels increased the effect of randomized treatment (p = 0.04 for interaction). As such, treatment impeded progression of AS in the highest quartile of LDL among patients with mild AS at baseline (0.06 m/s per year slower progression vs placebo in peak aortic jet velocity, 95% confidence interval 0.01 to 0.11, p = 0.03), but not in the 3 other quartiles of LDL. Conversely, among patients with moderate AS, there was no detectable effect of treatment in any of the pretreatment LDL quartiles (all p ≥0.14). In conclusion, in a non–prespecified post hoc analysis, the efficacy of lipid-lowering therapy on impeding AS progression increased with higher pretreatment LDL and lower peak aortic jet velocity (SEAS study: NCT00092677).

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