Aortic stenosis: Vytorin does not slow progression of aortic valve disease

The SEAS ( Simvastatin and Ezetimibe in Aortic Stenosis ) study has investigated the effects of intensive cholesterol lowering with the combination of Simvastatin ( 40 dmg daily ) and Ezetimibe ( 10 mg daily ) ( Inegy, Vytorin ) in patients with aortic stenosis.

Aortic stenosis is a relatively common disease among older people in Western populations. Left untreated, it can progress to death from heart failure or cardiac arrest. Aortic valve replacement for severe symptoms is the second most frequent type of heart surgery. Apart from surgery, there is no medical therapy known to prevent or heal this condition.
Population studies and other scientific research indicate that a high blood level of LDL-cholesterol is a risk factor for developing aortic stenosis and may be involved in the pathological process.

The SEAS study is the first large-scale randomised trial to assess the effects of lowering LDL-cholesterol in patients with aortic stenosis. The study was initiated and designed by academic researchers in Scandinavia, and carried out at 173 clinical centres in Norway, Denmark, Sweden, Finland, Germany, UK and Ireland. It included 1873 patients with mild to moderate aortic stenosis without symptoms who were not considered to have a clear indication for treatment with cholesterol-lowering drugs.

Patients were randomly assigned to receive either intensive cholesterol lowering with the combination of Simvastatin ( 40 mg daily ) and Ezetimibe ( 10 mg daily ) or matching placebo.
The first patient was included in 2001. The study was completed according to the study plan when the last patient included had been followed for 4 years ( March 2008 ).
Vital status at the end of the study was established for all patients. All data have been checked for completeness and the data file for analysis was closed on 30 June 2008.

The primary endpoint of the SEAS study was major cardiovascular events, which is the composite of events associated with aortic valve disease and with atherosclerotic disease.
The secondary endpoints were the two separate components of the primary endpoint: aortic valve disease events ( surgical valve replacement, hospitalization because of heart failure, and cardiovascular death ); and atherosclerotic disease events ( non-fatal myocardial infarction, coronary artery bypass surgery or percutaneous coronary intervention, hospitalization because of unstable angina pectoris, non-haemorrhagic stroke and cardiovascular death ).

Compared with placebo, the combination of Simvastatin and Ezetimibe reduced LDL-cholesterol by an average of 61%, corresponding to a reduction of about 2 mmol/L ( 76 mg/dl ), and this effect was sustained throughout the study.
688 patients had one or more primary endpoint events. No significant difference was observed between the treatment groups for the combined primary endpoint ( 333 patients with an event on LDL-lowering treatment versus 355 on placebo; hazard ratio (HR) 0.96 ).

Nor was there a significant difference for the secondary endpoint of aortic valve disease events alone ( 308 versus 326; HR 0.97 ).

The combination of Simvastatin and Ezetimibe did, however, produce a statistically significant 22% ( p=0.02 ) proportional reduction in the secondary endpoint of atherosclerotic events alone: 148 ( 15.7% ) in the Simvastatin plus Ezetimibe group versus 187 ( 20.1% ) in the placebo group.

The study therapy was generally well tolerated, with no significant differences between the treatment groups in the proportions of patients who stopped taking study treatment.

In the subsidiary safety analyses, a total of 158 patients were recorded with a serious adverse event attributed to cancer. More of these events were observed among patients assigned the combination of Simvastatin and Ezetimibe than among those assigned placebo ( 9.9% versus 7.0%; unadjusted p=0.03 ), and there were also slightly more cancer deaths ( 4.1% versus 2.5%; unadjusted p=0.05 ). These apparent differences were not related to any particular type of cancer and did not become significantly larger with more prolonged treatment.

The observed differences in cancer in the SEAS study are based on small numbers and could have occurred as a result of chance.

In conclusion, the SEAS study has found that intensive LDL-cholesterol lowering with the combination of Simvastatin and Ezetimibe in patients with mild to moderate aortic stenosis does appear to reduce the risk of coronary artery disease events but not the rate of progression of aortic valve disease.

Source: Ulleval University Hospital, 2008


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