Valvular heart disease
Observed and Predicted Reduction of Ischemic Cardiovascular Events in the Simvastatin and Ezetimibe in Aortic Stenosis Trial

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In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, combined ezetimibe (10 mg) and simvastatin (40 mg) decreased low-density lipoprotein cholesterol levels by 50% and ischemic cardiovascular event (ICE) risk by 22% compared to placebo. A larger decrease in ICE risk might have been expected for the degree of lipid-lowering observed. This analysis investigated relations between changes in lipoprotein components (LCs), and ICE risk decrease in the SEAS trial in all patients, by severity of aortic stenosis (AS), and compared to results of other clinical trials. A total of 1,570 patients with baseline aortic jet velocity (JV) data, baseline and 1-year low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B, and no ICEs during the first year were included in the analysis. Relations between on-treatment measurements of 1-year LCs and time-to-ICE occurrence were assessed in all patients and in JV tertiles (<2.8, 2.8 to 3.3, and >3.3 m/s). Observed and predicted ICE risk decreases were compared by Cox model. Decreases in LCs after 1 year of ezetimibe plus simvastatin were associated with decreased ICE risk in all patients and in the 2 lower JV tertiles (p <0.05 to <0.001) but not in tertile 3. In JV tertiles 1 and 2, ICE risk decreased by 47% and 36%, respectively, was reasonably well predicted by all LCs, and was consistent with findings from meta-regression analyses in other populations. In conclusion, the degree of lipid lowering by ezetimibe plus simvastatin may predict the extent of ICE risk decrease in patients with mild AS, but ICE risk prediction in patients with more severe AS is confounded by AS-associated cardiovascular events and a shorter interval of exposure to lipid lowering.

Section snippets

Methods

The SEAS study design and main outcome have been published.1, 2 In short, men and women (45 to 85 years of age) with asymptomatic mild-to-moderate AS (Doppler measured JV ≥2.5 and ≤4.0 m/s) and the absence of heart conditions requiring therapy at baseline were included. Patients with known coronary, cerebral, or peripheral arterial disease, diabetes mellitus, endocrine disorders, or active liver disease or patients taking/deemed to require lipid-lowering therapy to decrease atherosclerotic

Results

A total of 1,570 patients in the SEAS trial who had complete data for baseline JV, baseline and 1-year low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B measurements, and no ICEs during the first year were included in the main analyses. A special analysis with time-varying covariates was also performed in those 1,763 patients who had a valid baseline assessment of peak aortic JV measured at the core laboratory. Patient baseline characteristics were

Discussion

The present analysis demonstrates that ICE risk decreases in SEAS were greater in patients with less severe AS, as reflected by lower baseline JV, and were associated with changes in LCs. In contrast, ICE risk was not related to LC changes in patients with more severe AS. ICE risk decreases were also well predicted by changes in all LCs in patients with less severe AS. Compared to the CTT meta-analysis,3 a decrease in ICE risk of approximately 43% was predicted for an average decrease in

Acknowledgment

Thomas Musliner, MD, Jean-Louis Marchal, PhD, Joanne Tomassini, PhD, and Nigel Dodd, MSc, are gratefully acknowledged for contributing helpful comments, assistance in writing this report, and/or statistical support.

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This work was supported by Merck/Schering-Plough Pharmaceuticals, Inc., North Wales, Pennsylvania.

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