Here’s a note from my good friend, Thomas Dayspring, M.D., written for physicians (but, others are welcome to look on). Tom is one of the world’s most respected lipidologists (doctors who specializes in cholesterol problems):
Although CNN has already spoken: “Vytorin fails and should not be used and also causes cancer,” I’d like to offer my opinion so as to stop the nonsense that will be spewed over the airwaves by other no-brain media types and no doubt others.
Here is what you need to know about the results of SEAS, a study designed to test the efficacy of simvastatin plus ezetimibe (Vytorin) vs placebo in reducing CV endpoints in patients with aortic stenosis (AS) with a baseline LDL-C of 140 mg/dL.
As a secondary endpoints they looked at:
(1) complications of AS (CHF, death, valve replacements) and
(2) ischemic events (non-fatal myocardial infarction, coronary artery bypass surgery or percutaneous coronary intervention, hospitalization because of unstable angina pectoris, non-hemorrhagic stroke and cardiovascular death).
The primary endpoint is both (1 and 2) combined.
The numbers are reported in detail below, but in essence Vytorin vs placebo failed (null) in the primary endpoint and also failed (null) for the secondary endpoints related to AS.
But it did reduce ischemic event outcomes in patients with AS (22%): FANTASTIC.
Reducing ischemic (atherosclerotic) events is the reason we treat lipids so aggressively and now we have Level 2 evidence that Vytorin (statin plus ezetimibe) does what we had hoped for: reduce ischemic events. The therapy was quite safe and lowered LDL-C > 60%.
One might say, statins reduce events by 20-35% which would be very similar to the 22% so why add ezetimibe to a statin?
Anyone who says that would be wrong.
We have no knowledge what statin monotherapy does to ischemic events in people with AS, for the simple reason that no one ever did such a study.
AS certainly contributes to CV events.
We still have no knowledge what statin/ezetimibe would do to event reduction in people without AS: that is being tested in (the) IMPROVE IT (study). So it is not scientifically correct and indeed it is disingenuous to extrapolate that either statin monotherapy or anything else would have done the same or better than Vytorin did in this very special population.
In most primary care practices it would be unusual to have more than 1-2% of your patients with AS. But if you are a cardiologist who likely has lots of patients with AS, you finally have a product that can reduce ischemic events in those persons.
If you are evidenced based, one could argue would not be proper to use statin monotherapy over Vytorin to prevent ischemic related events in such patients as there is no data.
There has never ever been ANY drug that has helped people with AS, including statin monotherapy. We now know Vytorin does not help these people with their AS complications: it is unfortunate but we are right back where we have always been.
Earlier this year Crestor failed in a big outcome trial looking at the primary endpoint in persons with CHF. So what? No other statin helps these people and we do not write statins to treat CHF endpoints.
But with respect to secondary outcomes Crestor reduced MIs. That was reassuring and those of us who use Crestor did not throw Crestor out because it did not help CHF endpoints. I hope no one will stop considering Zetia added to their statin because you cannot help reduce AS related events using medication.
The benefit on ischemic events should finally put the ENHANCE study to rest (a carotid IMT trial). IMT changes are an unproven surrogate of event reduction. Vytorin did nothing (good or bad) to IMT in persons with relatively normal carotids, but yet we now know Vytorin reduces ischemic events in persons with AS who have a baseline LDL-C of 140. One can remain optimistic about IMPROVEIT (Vytorins’s big outcome trial, now underway).
I will not even comment on the cancers as it is silly and it is dealt with below.
Results From the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) Study
LONDON, July 21, 2008 /PRNewswire via COMTEX/ — The SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study has investigated the effects of intensive cholesterol lowering with the combination of simvastatin (40 mg daily) and ezetimibe (10 mg daily) in patients with aortic stenosis.
Aortic stenosis (which involves partial blockage of the aortic valve in the heart) 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 (so called “bad cholesterol) is a risk factor for developing aortic stenosis and may be involved in the pathological process. Treatment to lower LDL-cholesterol in many other types of patient has been shown to produce substantial reductions in the rates of heart attacks, strokes and other adverse outcomes.
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 scientific leadership of the study was a Steering Committee consisting of 14 academic representatives of centres in each of the participating countries and two members (a statistician and a coordinator) representing the funders. The SEAS study is funded by the pharmaceutical companies Merck Sharp & Dohme (MSD) and Schering-Plough who market the drugs being tested. All clinical endpoint events were adjudicated by an independent committee that was blinded to the study treatment allocation. The study was monitored by an independent Data Safety and Monitoring Board. Data collection was performed by MSD, and the data were analyzed by statisticians at Ulleval University Hospital in Oslo, Norway, and at MSD.
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). Subsidiary outcomes included echocardiographic evidence of aortic stenosis progression and safety.
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; 95% confidence interval [CI] 0.83 to 1.12). Nor was there a significant difference for the secondary endpoint of aortic valve disease events alone (308 versus 326; HR 0.97; 95% CI 0.83 to 1.14). The combination of simvastatin and ezetimibe did, however, produce a statistically significant 22% (95% CI 3% to 37%; 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 (irrespective of whether it was active or placebo). 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 (93 [9.9%] versus 65 [7.0%]; unadjusted p=0.03), and there were also slightly more cancer deaths (39 [4.1%] versus 23 [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 order to assess their relevance, the SEAS data have been provided to an independent academic group for combined analysis with data on cancer from the two other large trials of simvastatin and ezetimibe, which are still in progress. The SHARP (Study of Heart and Renal Protection) study is a randomized placebo-controlled trial of simvastatin and ezetimibe in 9400 patients with chronic kidney disease. The IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) study is a randomized double-blind trial of simvastatin and ezetimibe compared to simvastatin alone which has recruited 12,000 of a planned 18,000 patients with acute coronary disease. In combination, the SHARP and IMPROVE-IT studies involve about 4 times as many cancers as in the SEAS study. The analysis of SHARP and IMPROVE-IT does not support the suggestion of an increase in cancer that was raised by the subsidiary analyses of the relatively small numbers of cancers in the SEAS study. Independent analysis of these data was initiated and has been conducted and interpreted by the Clinical Trial Service Unit (CTSU) at the University of Oxford, UK. The CTSU also designed and is conducting the SHARP trial, which is funded by a research grant to the University of Oxford from MSD and Schering-Plough academic. Both the SHARP study and the analyses of cancer data have been conducted by the CTSU independently of the pharmaceutical companies. Please, refer to the press release issued by the CTSU today.
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 (as has been shown for many other types of patient in previous trials) but not the rate of progression of aortic valve disease. The use of simvastatin and ezetimibe in such patients was generally well tolerated and safe.
SOURCE ; Prof Terje Pedersen, SEAS Study Principal Investigator & Head of Steering Committee