News:Ezetimibe and Simvastatin Combination in the SEAS Trial does Reduce Coronary Artery Events but Not the Progression of Aortic Stenosis

September 2, 2008 By Vijayalakshmi Kunadian MBBS MD MRCP [mailto:vkunadian@perfuse.org]

The results of the SEAS trial were presented by Dr. Terje R. Pedersen of Oslo Norway at the European Society of Cardiology Congress 2008 in Munich, Germany today. This study is simultaneously published in the New England Journal of Medicine today.

Elevated cholesterol levels have been linked with stenosis of the aortic valve. Whether cholesterol lowering drugs would halt the progression of the aortic valve disease was evaluated in the SEAS trial (Simvastatin and Ezetimibe in Aortic Stenosis).

This study was double-blinded and randomized consisting of 1873 patients with mild to moderate aortic stenosis from 173 clinical centers in Norway, Denmark, Sweden, Finland, United Kingdom and Ireland. These patients were not identified to have a clear indication for the administration of a lipid-lowering agent. Patients were randomized to receive either 40 mg of simvastatin plus 10 mg ezetimibe (n=944) or a placebo (n=929) once daily. The study terminated in March 2008 following its initial recruitment that began in 2001.

The primary endpoint of this trial consisted of a composite of major adverse cardiovascular events including death from cardiovascular causes, aortic valve replacement, non-fatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary artery bypass surgery, percutaneous coronary intervention and non-hemorrhagic stroke. The secondary endpoints consisted of events relating to aortic stenosis and ischemic cardiovascular events.

The median follow-up duration for this study was 52.2 months. During the whole follow-up period there was a significant reduction in the LDL cholesterol in the treatment group of 53.8% compared to 3.8% in the placebo group (p<0.001). The primary endpoint occurred in 333 patients in the simvastatin-ezetimibe group and 355 patients in the placebo group [35.3% vs. 38.2%; Hazard Ratio (HR) 0.96, 95% confidence interval (CI) 0.83 to 1.12, p=0.59]. There was no significant difference in the incidence of secondary outcomes between the treatment and placebo groups [HR 0.97; 95% CI 0.83 to 1.14, p=0.73]. Aortic valve replacement was performed in equal proportions of patients in the treatment and placebo groups [267 (28.3%) vs. 278 (29.9%); HR 1.00, 95% CI 0.84 to 1.18, p=0.97). Furthermore, fewer patients in the treatment group underwent coronary artery bypass surgery compared to the placebo [69 (7.3%) vs. 100 (10.8%); HR 0.68, 95% CI 0.50 to 0.93, p=0.02] which was associated with a significant reduction in the occurrence of ischemic cardiovascular events in the treatment group compared to placebo [148 (15.7%) vs. 187 (20.1%); HR 0.78, 95% CI 0.63 to 0.97, p=0.02). There were no differences in the predefined key echocardiographic measures for the evaluation of progression of aortic stenosis including peak aortic jet velocity and mean pressure gradient between the two groups.

There was no difference in the overall mortality rates and death due to non-cardiovascular causes (5.9%-treatment vs. 44%-placebo, p=0.26) between the two groups. The treatment group was also associated with increased occurrence of new malignancies compared to the placebo group [105 (11%) vs. 70 (7.5%), p=0.01]. This included patients who developed cancer 2 weeks following withdrawal from the study and patients with recurrent cancer. The incidence of fatal cancer was greater among the treatment group compared with the placebo group [39 (4.1%) vs. 23 (2.5%); HR 1.67, 95% CI 1.00 to 2.79, p=0.05). The occurrence of cancer was not clustered at any particular site and was not associated with the degree of LDL-C lowering.

The investigators of the SEAS trial concluded that although intensive lowering of LDL cholesterol utilizing ezetimibe-simvastatin combination reduced the occurrence of ischemic events it did not reduce the progression of aortic valve disease among patients with mild to moderate aortic stenosis. The greater risk of incident cancer will require further prospective evaluation in the ongoing SHARP and IMPROVE-IT trials.

In an accompanying special article in the NEJM, Peto and coworkers combined the three trials (SEAS, SHARP and IMPROVE-IT) and demonstrated that there was no increase in the incidence of cancer with ezetimibe [313-active treatment vs. 326-placebo; risk ratio 0.96, 95% CI 0.82 to 1.12, p=0.61) and no significant excess at any particular site. There was, however, an excess of fatal cancer when the three trials are combined (p=0.007).

While the cancer data from SEAS can be viewed as hypothesis generating, the prospective data from the ongoing SHARP and IMPROVE-IT trials did not confirm that vytorin is associated with an increased risk of new or incident cancer. However, in the validation cohort of SHARP and IMPROVE-IT, there was a trend towards a higher risk of fatal cancer (p=0.07). It should be noted that this p-value is a two-sided p-value testing whether there was either an increase or decrease in fatal cancer associated with Vytorin. If a one-sided test is applied to determine if there was an increased risk of cancer, the p-value would be statistically significant.

Reviewed by C. Michael Gibson, M.S., M.D.

Source of funding
The SEAS trial was funded by Merck Sharp and Dohme and Schering-Plough pharmaceutical companies.

Source

 * 1) http://content.nejm.org/cgi/reprint/NEJMoa0804602v1.pdf
 * 2) http://content.nejm.org/cgi/reprint/NEJMsa0806603v1.pdf