Simvastatin and ezetimibe combination does not reduce the rate of progression of aortic valve disease in the SEAS trial

July 22, 2008 By Vijayalakshmi Kunadian MBBS MD MRCP [mailto:vkunadian@perfuse.org]

London, UK: A press release yesterday on the SEAS trial suggests that intensive cholesterol reduction with simvastatin and ezetimibe combination among patients with mild-moderate aortic stenosis (AS) does not reduce the rate of progression of AS but does appear to reduce the risk of coronary artery disease events.

The SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial is a randomized multinational study which determined the effects of intensive lipid (LDL cholesterol) lowering among patients with mild to moderate aortic stenosis. This study which was initiated and designed by investigators in Scandinavia consisted of 1873 patients with mild to moderate aortic stenosis (AS) from Germany, United Kingdom and Ireland in addition to the Scandinavian countries (173 centers in total). These patients were not considered to have a clear indication for therapy with lipid lowering agents. This study commenced in 2001 with data lock towards the end of June 2008. Patients in this trial were randomized to receive simvastatin (40 mg once daily) and ezetimibe (10 mg once daily) combination or matching placebo.

The primary endpoint of this study consisted of major cardiovascular events (composite of events associated with aortic valve disease and atherosclerotic disease). The secondary endpoints consisted of events related to aortic valve disease (surgical aortic valve replacement, hospitalization due to heart failure and cardiovascular death) and atherosclerotic coronary artery disease events (non-fatal myocardial infarction, CABG, percutaneous coronary intervention, hospitalization due to unstable angina, non-hemorrhagic stroke and cardiovascular death) assessed independently. Other analysis also consisted of assessment of progression of aortic valve disease measured on echocardiography.

The mean age of study patients was 68 years and the mean baseline LDL-cholesterol level was 140 mg/dl. Simvastatin and ezetimibe therapy reduced LDL-cholesterol by 61%. There was no significant difference in the occurrence of primary endpoint between the treatment and the placebo groups (333 patients vs. 355 patients: HR 0.96; 95% confidence interval 0.83 to 1.12, p=NS). There was also no significant difference in the occurrence of aortic valve disease events alone (308 patients vs. 326 patients: HR 0.97; 95% CI 0.83 to 1.14, p=NS) between treatment and placebo groups. However, the combination therapy did reduce the occurrence of atherosclerotic coronary artery disease events by 22% (148 patients vs. 187 patients: 95% CI 3% to 37%, p=0.02).

Interestingly in the safety analysis, a total of 93 patients (9.9%) in the combination group compared with 65 patients (7.0%) in the placebo group had suffered serious adverse events that were attributed to malignancy (unadjusted p value =0.03) with slightly more cancer deaths in the treatment group [39 (4.1%) vs. 23 (2.5%), unadjusted p=0.05). No particular type of cancer was observed more frequently.

Dr. Terje R. Pedersen, Professor of Medicine, Head of the Centre for Preventive Medicine and Chairman of the SEAS trial Steering Committee, Ulleval University Hospital, Oslo, Norway who released the results of the SEAS trial concluded that the combination therapy with simvastatin and ezetimibe did not reduce the rate of progression of aortic valve disease but did appear to reduce the risk of atherosclerotic coronary artery disease events among patients with mild to moderate aortic stenosis. He also noted that the combination therapy with simvastatin and ezetimibe was generally well tolerated and safe.

The increased cancer events in the SEAS trial prompted an immediate evaluation of the two ongoing large trials (SHARP and IMPROVE-IT) that utilizes the simvastatin and ezetimibe combination by the University of Oxford Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU). The SHARP (Study of Heart and Renal Protection) study conducted by Duke University evaluates the efficacy of simvastatin and ezetimibe in 9400 patients with chronic renal disease and IMPROVE-IT (Improved Reduction of Outcomes: VYTORIN Efficacy International Trial) conducted by Harvard University evaluates the benefit of simvastatin and ezetimibe combination compared with simvastatin alone among 18,000 patients with acute coronary syndrome.

The CTSU analysis demonstrated that there was no increase in cancer events in the treatment (n=313, 97 fatal cases) and placebo (n=326, 72 fatal cases) groups in a combined analysis of the ongoing SHARP and IMPROVE-IT trials. This analysis was performed independent of the source of funding by CTSU. Dr Peto from Oxford University who conducted this analysis suggested that he used the SEAS trial for hypothesis generating and the latter two trials for hypothesis testing. He suggests that the increase in the cancer events in SEAS might be a chance finding given there was no trend for a particular type of cancer in this population.

Given the fact that there was no increase in cancer events in the SHARP and IMPROVE-IT trials, these trials continue to enroll patients and will be closely monitored.

Sources of Funding
The press release reports that the SEAS and SHARP studies are funded by Merck Sharp and Dohme (MSD) and Schering-Plough pharmaceutical companies.

Source

 * 1) http://www.newswire.ca/en/releases/archive/July2008/21/c6253.html;%20accessed%2007/21/2008
 * 2) http://www.marketwatch.com/news/story/independent-analyses-seas-sharp-improve-studies/story.aspx?guid=%7BE3D87514-4BB3-47F8-8361-A2DF5D83A66A%7D&dist=hppr