Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis

The authors' affiliations are listed in the Appendix. This article (10.1056/NEJMoa0804602) was published at on September 2, 2008. It will appear in the September 25 issue of the Journal.
New England Journal of Medicine (Impact Factor: 55.87). 10/2008; 359(13). DOI: 10.1056/NEJMoa0804602
Source: PubMed


BACKGROUND: Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results. METHODS: We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events. RESULTS: During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin-ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97). Fewer patients had ischemic cardiovascular events in the simvastatin-ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs. 70, P=0.01). CONCLUSIONS: Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic-valve events and ischemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. ( number, NCT00092677.) Copyright 2008 Massachusetts Medical Society.

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    • "The Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study was a multicenter, randomized , double-blind, placebo-controlled study, investigating whether intensive lipid lowering with simvastatin/ezetimibe combination vs. placebo could reduce the need for AVR and risk of cardiovascular morbidity and mortality in 1873 patients, aged 45 to 85 years, with asymptomatic mild-to-moderate AS (defined as echocardiographic aortic valve thickening accompanied by Doppler-measured aortic peak flow velocity ≥2.5 and ≤4.0 m/s and normal systolic LV function). The main outcomes including study design, organization , clinical measures, exclusion criteria (most important systolic heart failure, diabetes and clinically apparent cardiovascular atherosclerosis), baseline characteristics and main outcome have been published previously [16] [17]. All SEAS patients were automatically enrolled in the SEAS ECG substudy. "
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    ABSTRACT: An elevated resting heart rate (RHR) may be an early sign of cardiac failure, but its prognostic value during watchful waiting in asymptomatic aortic stenosis (AS) is largely unknown. RHR was determined by annual ECGs in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study of asymptomatic mild-to-moderate AS patients. Primary endpoint in this substudy was major cardiovascular events (MCEs) and secondary outcomes its individual components. Multivariable Cox-models using serially-measured RHR were used to examine the prognostic impact of RHR per se. 1563 patients were followed for a mean of 4.3years (6751 patient-years of follow-up), 553 (35%) MCEs occurred, 10% (n=151) died, including 75 cardiovascular deaths. In multivariable analysis, baseline RHR was independently associated with MCEs (HR 1.1 per 10min(-1) faster, 95% CI: 1.0-1.3) and cardiovascular mortality (HR 1.3 per 10min(-1) faster, 95% CI: 1.0-1.7, both p≤0.03). Updating RHR with annual in-study reexaminations, time-varying RHR was highly associated with excess MCEs (HR 1.1 per 10min(-1) faster, 95% CI: 1.1-1.3) and cardiovascular mortality (HR 1.4 per 10min(-1) faster, 95% CI: 1.2-1.7, both p≤0.006). The association of RHR with MCEs and cardiovascular mortality was not dependent on atrial fibrillation status (both p≥0.06 for interaction). RHR is independently associated with MCEs and cardiovascular death in asymptomatic AS (; unique identifier NCT00092677). Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    International Journal of Cardiology 11/2014; 180C:122-128. DOI:10.1016/j.ijcard.2014.11.181 · 4.04 Impact Factor
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    • "The standardized echocardiography protocol of the SEAS study was previously published [14], [15]. All images were recorded and sent for central, blinded interpretation by qualified technicians at the SEAS echocardiography core laboratory at the Haukeland University Hospital in Bergen, Norway. "
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    ABSTRACT: Background Fibulin-1, a circulating extracellular matrix glycoprotein, has been associated with arterial disease and elevated N-terminal prohormone B-type natriuretic peptide (NT-proBNP) in diabetes. Soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation, has been associated with subclinical atherosclerosis. Therefore, we aimed to explore the interplay between these biomarkers and mild to moderate aortic valve stenosis (AS). Methods In 374 patients with mild to moderate AS, we investigated the relationship of fibulin-1 with NT-proBNP, levels of suPAR and the degree of AS at baseline and after one and four years of treatment with Simvastatin 40 mg and Ezetimibe 10 mg or placebo. Results During treatment, fibulin-1 became more closely associated with NT-proBNP (βyear0 = 0.10, p = 0.08, βyear1 = 0.16, p = 0.005, βyear4 = 0.22, p<0.001) and suPAR (βyear0 = 0.05, p = 0.34, βyear1 = 0.16, p = 0.006, βyear4 = 0.13, p = 0.03) at the expense of the association to aortic valve area index (AVAI) (βyear0 = −0.14, p = 0.005, βyear1 = −0.08, p = 0.11, βyear4 = −0.06, p = 0.22) independently of age, gender, creatinine, and serum aspartate aminotransferase (Adj.Ryear02 = 0.19, Adj.Ryear12 = 0.22, Adj.Ryear42 = 0.27). Fibulin-1 was unrelated to aortic regurgitation, left ventricular mass, and ejection fraction. In patients with baseline AVAI<0.58 cm2/m2 (median value), fibulin-1 was more closely associated to NT-proBNP (βyear0 = 0.25, βyear1 = 0.21, βyear4 = 0.22, all p<0.01), and suPAR (βyear0 = 0.09, p = 0.26, βyear1 = 0.23, βyear4 = 0.21, both p<0.01) independently of age, gender, AST and treatment allocation. Conclusions Increased levels of fibulin-1 were independently associated with higher levels of suPAR and NT-proBNP especially in patients with lower AVAI, suggesting that fibulin-1 may be an early marker of AS as well as cardiac fibrosis secondarily to elevated left ventricular hemodynamic load.
    PLoS ONE 07/2014; 9(7):e101522. DOI:10.1371/journal.pone.0101522 · 3.23 Impact Factor
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    • "The effects of combined therapy of statin and ezetimibe on the surrogate markers of cardiovascular diseases were disappointing.14)20)21)22)23) The combined therapy reduced LDL-C comparable to or even more than the effects of higher dose of statin therapy or statin plus niacin. "
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    ABSTRACT: Background and Objectives The inhibition of cholesterol absorption by ezetimibe increases cholesterol synthesis. The effect of inhibition of cholesterol synthesis on cholesterol absorption is controversial. The influence of these interactions on cholesterol levels is unknown. We investigated on the extent to which cholesterol levels were affected by the reaction of one pathway to the inhibition of the other pathway. Subjects and Methods This case-controlled study enrolled 198 patients who needed cholesterol-lowering drugs. Ezetimibe (10 mg) was administered to the patients with (n=58) and without on-going statin therapy (n=58). Simvastatin (20 mg) was administered to the patients treated with (n=41) and without ezetimibe (n=41). Results Ezetimibe without statin lowered the total cholesterol by 13.3±8.8% (p<0.001) and the low density lipoprotein-cholesterol (LDL-C) by 18.7±15.3% (p<0.001). Ezetimibe added to statin decreased the total cholesterol by 21.1±7.7% (p<0.001) and the LDL-C by 29.9±12.6% (p<0.001). The total cholesterol and LDL-C were reduced more by ezetimibe in patients with statin therapy than in those without statin therapy (p<0.001 and p<0.001, respectively). The differences in the effect of simvastatin on total cholesterol and LDL-C between the patients with and without ezetimibe showed borderline significance (p=0.10 and p=0.055, respectively). Conclusion A prior inhibition of cholesterol synthesis by statin enhanced the effect of ezetimibe on total cholesterol and LDL-C by 7.8% and 11.2%, respectively. This finding suggests that ezetimibe increased cholesterol synthesis, resulting in a significant elevation of cholesterol levels.
    Korean Circulation Journal 07/2014; 44(4):227-32. DOI:10.4070/kcj.2014.44.4.227 · 0.75 Impact Factor
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