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: 54.42). 10/2008; DOI: 10.1056/NEJMoa0804602
Source: PubMed

ABSTRACT 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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    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. · 6.18 Impact Factor
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    ABSTRACT: Objectives: Recent data shows a relationship between aortic valve (AV) inflammation and calcification. However, direct evidence linking early valve inflammation (prior to hemodynamic compromise) to subsequent calcium (Ca) deposition is lacking in humans. We sought to test the hypothesis whether local AV inflammation predisposes to subsequent AV Ca deposition. Methods: We identified 111 individuals (age 60[49, 68], 50.5% male) without active cancer or aortic stenosis who underwent 2 PET/CT studies 1-5 years apart for cancer surveillance. AV inflammation was determined by measuring FDG uptake (maximum standardized uptake value, SUVmax) within the AV on baseline PET/CT. Subsequent deposition of AV Ca was determined by comparing baseline and follow-up CT scans, determined as an increase in AV Ca volume score (CaVS). Patients were classified as "non-progressors" or "progressors" based on Square Root difference in CaVS (using a pre-determined cut-off value of 2.5). CT and PET measurements were conducted by 2 mutually blinded laboratories. Results: During follow-up, AV Ca increased in 23 patients (20.2%) classified as "progressors", of whom 9 (9.2%) demonstrated subsequent 'incident' AV Ca. The AV SUVmax (mean ± SD) was higher in progressors vs. non-progressors (2.03 ± 0.52 vs.1.74 ± 0.36, p = 0.02) and especially in patients with-vs. without-incident AV Ca (2.28 ± 0.42 vs. 1.73 ± 0.36, p < 0.001). Moreover, AV inflammation (AV SUVmax) independently predicted subsequent calcification after adjusting for cardiovascular risk factors [OR (95%CI): 4.99 (1.30-19.15), p = 0.02]. Conclusion: The findings suggest that early AV inflammation may predispose to AV sclerosis. The evaluation of valvular metabolic activity may prove useful for developing a better understanding of calcific valve disease. Copyright © 2014. Published by Elsevier Ireland Ltd.
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    ABSTRACT: Valvular aortic stenosis (AS) is a progressive disease that affects 2% of the population aged 65 years or older. The major cause of valvular AS in adults is calcification and fibrosis of a previously normal tricuspid valve or a congenital bicuspid valve, with rheumatic AS being rare in the United States. Once established, the rate of progression of valvular AS is quite variable and impossible to predict for any particular patient. Symptoms of AS are generally insidious at onset, though development of any of the three cardinal symptoms of angina, syncope, or heart failure portends a poor prognosis. Management of symptomatic AS remains primarily surgical, though transcatheter aortic valve replacement (TAVR) is becoming an accepted alternative to surgical aortic valve replacement (SAVR) for patients at high or prohibitive operative risk.
    Clinical Medicine Insights. Cardiology. 01/2014; 8(Suppl 1):15-24.

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