Will The SEAS Trial Vindicate Vytorin?
13 CommentsBy Ed Silverman // July 9th, 2008 // 1:43 pm
The results of a clinical trial that Merck and Schering-Plough may report this coming November could provide the first glimpse of true clinical outcomes with Vytorin, at least among patients with aortic stenosis, which is a cardiac valve abnormality, writes Tim Anderson, a Sanford Bernstein analyst who follows pharma, in an investor report.
Theoretically, AS has a similar pathophysiology to ordinary coronary artery disease, he explains, and adds that a hypothesis exists that statins may benefit patients with AS, just like the use of statins benefits patients with coronary artery disease. Most retrospective analyses of AS have, in fact, supported that statins appear to have a beneficial effect, Anderson continues.
And the SEAS trial, he posits, “will represent the largest trial conducted evaluating whether cholesterol reducers have a beneficial impact on AS. It is easy to say that SEAS is not terribly relevant to the overall Vytorin/Zetia franchise given how the trial is designed and what is being measured. In reality, however, because of how the primary endpoint is constructed, SEAS will likely be the first time that some semblance of “true” clinical outcomes with Vytorin will be measured,” he writes.
“Some may be under the impression that SEAS only measures a direct impact on AS, which if true would not be as significant. In reality, the SEAS endpoint is a composite of aortic valve replacement and cardiovascular death, nonfatal myocardial infarction, and congestive heart failure,” he continues. “As such, the SEAS trial will provide the first glimpse of true clinical outcomes with Vytorin - at least in one subpopulation (those with AS) - well before IMPROVE-IT reports in 2012.”
“Predicting the outcome of SEAS is difficult, but our belief is that the trial could well yield neutral results (i.e. Vytorin shows no difference relative to placebo on the composite endpoint). The odds of this occurring are maybe 60 percent. This is based on our assessment of past clinical trials as well as the design of SEAS,” Anderson writes. He puts odds of a positive result (i.e. Vytorin is better than placebo) at 30 percent, and the odds that SEAS shows Vytorin is worse than placebo are maybe 10 percent.
CV MD
Now that’s really blowing smoke! This is an incredible stretch, just like the hoopla over CASHMERE, The analyst at SB is really under-informed concerning what this may mean to the prescription market. Aortic Stenosis is not that common a disease - it pales in comparison to the population of patients with hypercholseterolemia. In addition, the primary endpoint is a mix of AS-specific and ASCVD-general outcomes. Therfore, it would indicate little for the population as a whole. If by some miracle Vytorin has an impact on AS, all that will result from this is a publication. The folks at MSP and on the street are really hallucinating if they really think this will mean anything to prescribing habits. For more insight, they should consult some experts!
Former SP
MSP still doesn’t get it. It’s not the lack of positive results that sent their market down the tubes, it’s the way they behaved in handling the results of ENHANCE. The medical and scientific community is simply not ready to trust them and won’t be flocking back anytime soon. What may really help is if their executives are appropriately dealt with for their ill-advised actions.
Marilyn Mann
SEAS is a trial comparing Vytorin (ezetimibe/simvastatin) to placebo. Even if the results are positive, we will not know how much of the effect is due to simvastatin and how much is due to ezetimibe.
Neers87
Marilyn,
You read my mind.
Marilyn Mann
It is not really correct to say aortic stenosis and coronary artery disease have the same mechanism. In fact, the mechanism of aortic stenosis is not fully understood.
I don’t see how the comments of this analyst are worth a hill of beans, anyway.
Marilyn Mann
Here is what Tim Anderson said after the ENHANCE study was released January 14:
“It was comments like those that led to the anti-Merck and Schering ‘hysteria’ on Wall Street, according to Bernstein Research analyst Tim Anderson. ‘In isolation,’ Anderson says, ‘the results probably would have led to a share price rise for SGP and MRK, but largely due to negative comments from prominent cardiologist Steve Nissen, share prices declined.”
So Tim Anderson thought that the ENHANCE Trial was good news for Merck and Schering Plough . . . Either he has no clue, or he’s trying to curry favor with the companies.
Justice in MI
Brief question for Marilynn - You know much more about this than I do, but I believe there is recent research which suggests, at the least, strong correlation between aortic stenosis (and sclerosis, for that matter) and CAD. Mechanism is more complicated (for both?). As I understand it, some retrospective studies suggest that statin use can slow progression of both aortic stenosis and sclerosis, but this independent of LDL in some (interesting).
As I recall, Mayo views A sclerosis in people under 65 as red flag and independent risk factor.
Marilyn Mann
Dear Justice in Michigan,
You sound like you know as much as I do. AS and CAD share some of the same risk factors, and are both progressive diseases characterized by inflammation and lipid deposition.There is some evidence that statins slow progression of AS. As you suggest, this could be partly due to their antiinflammatory effects. That kind of thing is hard to quantify, though.
Stinky
I don’t fully understand this study or why it was done. There aren’t many folks that suffer from aortic stenosis, probably less than 1% of the population over 50? And the majority of those with it are likely already on a statin. My guess is this was a quick and dirty way to get outcomes based on the high degree of mortality in AS patients. Study probably won’t be long enough to show anything though.
Marilyn Mann
Articles in Press — American Journal of Cardiology
Prognosis and Risk Factors in Patients With Asymptomatic Aortic Stenosis and Their Modulation by Atorvastatin (20 mg)
Wolfgang Dichtl, MD, PhDa, Hannes Franz Alber, MDa, Gudrun Maria Feuchtner, MDb, Florian Hintringer, MDa, Markus Reinthaler, MDa, Thomas Bartel, MDa, Alois Süssenbacher, MDa, Wilhelm Grander, MDa, Hanno Ulmer, PhDc, Otmar Pachinger, MDa, Silvana Müller, MDa
Received 2 March 2008; received in revised form 26 April 2008; accepted 26 April 2008. published online 07 July 2008.
Corrected Proof
The aim of the prospective, randomized, placebo-controlled Tyrolean Aortic Stenosis Study (TASS) was to characterize the natural history and risk factors and their possible modulation by new-onset atorvastatin treatment (20 mg/day vs placebo) in patients with asymptomatic calcified aortic stenosis. Forty-seven patients without previous lipid-lowering therapy or indications for it according to guidelines at study entry were randomized to atorvastatin treatment or placebo and prospectively followed for a mean study period of 2.3 ± 1.2 years. Patients’ prognoses were worse than expected, with 24 (51%) experiencing major adverse clinical events, in most cases the new onset of symptoms followed by aortic valve replacement. In multivariate regression analysis, independent risk factors for worse clinical outcomes were aortic valve calcification, as assessed by multidetector computed tomography, and plasma levels of C-reactive protein. In univariate analysis, mean systolic pressure gradient or an increased N-terminal–pro-B-type natriuretic peptide plasma level allowed the prediction of major adverse clinical events as well, whereas concomitant coronary calcification, age, and the initiation of atorvastatin treatment had no significant prognostic implication. As shown in a subgroup of 35 patients (19 randomly assigned to atorvastatin and 16 to placebo), annular progression in aortic valve calcification and hemodynamic deterioration were similar in both treatment groups. In conclusion, TASS could demonstrate a poor clinical outcome in patients with asymptomatic calcified aortic stenosis which can be predicted by new risk factors such as strong AVC or increased plasma levels of CRP or NT-proBNP. The study does not support the concept that treatment with a HMG-CoA reductase inhibitor (20 mg atorvastatin once daily) halts the progression of calcified aortic stenosis.
a Clinical Department of Cardiology, Medical University Innsbruck, Innsbruck, Austria
b Clinical Department of Radiology, Medical University Innsbruck, Innsbruck, Austria
c Department of Medical Statistics, Informatics and Health Economics, Medical University Innsbruck, Innsbruck, Austria
Corresponding author: Tel: 43-512-504-81307; fax: 43-512-504-22767
* * *
I don’t know if this study is relevant, but I’m posting it in case anyone is interested.
Marilyn
Marilyn Mann
Anderson says there is a 60 percent chance that Vytorin is no better than placebo. I would call that a negative result, not a neutral one.
Justice in MI
Hi Marilynn - Commented on the TASS study on newer thread on SEAS. Does the N seem small to you? I have no idea of relevant stats.
Large Marge
Can you tell me the hoopla that surrounded CASHMERE? It was pretty buried if you ask me.
Crazy stuff.