As I first hinted here, yesterday afternoon, with my first link, some analysts -- Tim Anderson at Sanford Bernstein, most notably -- are suggesting that a small study due out in the Fall of 2008, called SEAS, will provide some vindication for Schering's Vytorin.
I. think. not. Here's why:
SEAS is a study not at all designed to measure Vytorin v. statins, or other actual therapies. No, it is a superiority non-inferiority study [Thanks go to commenter Marilyn, below!].
In fact, all SEAS "measures" is the effectiveness of the combo-pill, Vytorin, against a placebo. In other words, it seeks to provide the data that Vytorin should have shown, in order to be approved by the FDA, in the first place, as to effectiveness [but that, lax FDA approval processes, 2001-2004, is a topic for another day].
So, when all is said and done -- if SEAS returns a "positive" -- all we will know is that Schering's Vytorin does better than nothin' at all.
There will be no statistical way to tease out how much of the effect was due to the statin portion of the pill, and how much was due to the ezetimibe portion. [This point was very-cogently first made by one Marilyn Mann at Pharmalot's joint, yesterday.]
In fact, it might be fairly argued -- if we accept Tim Anderson's rather non-lucid analysis, and original premise -- that a "win" on SEAS simply declares that a statin -- the portion of the pill-combo that has been around forever, and been proven to work in improving outcomes -- was responsible.
So, IMO, this line of analysis is really clutching at straws.
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Confidential Sidebar: Isn't it possible that Schering has (once again!) acheived a "functional unblinding," (this is a superiority non-inferiority study, after-all) and "pre-"determined that Vytorin will show a positive outcome? I think so. Why else are we hearing about this, now?
Note -- IF Vytorin shows anything less than a VERY STRONG improvement over the PLACEBO -- it has NO BUSINESS being an approved drug -- none. It should be pulled by FDA, if it can't beat a placebo. This is especially true, if one considers that such a failure would mean that ezetimibe somehow dampens the known-effectiveness of statins. Wow.
To be clear -- I think Vytorin will show an improvement over "nothin' at all" -- but that is very cold comfort, for such a pricey drug.
Thursday, July 10, 2008
Of the "Generally-Goofy" Thoughts of Tim Anderson on SEAS. . . .
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6 comments:
[Ed -- Deleted in Error -- Reposted.]
I think you meant to say that SEAS is NOT a non-inferiority trial. It is a superiority trial.
Here is a description:
Aortic stenosis (AS) is an important health issue in the elderly, and many risk factors for
AS are common to cardiovascular disease (CVD). Lesions in aortic valves appear
histologically similar to atherosclerotic lesions, and prior studies suggest the level of
cholesterol may influence the progression of AS. SEAS investigates whether aggressive
cholesterol lowering in patients with moderate AS can slow progression of AS, reduce
number of valve replacements and reduce the incidence of CVD outcomes. It is an
event-driven, multicenter double blind, randomized (1:1), placebo (PBO)-controlled, 4-
year (median duration) outcomes study in patients with asymptomatic AS. AS is defined
as aortic valve thickening accompanied by a Doppler-measured peak flow velocity
across the valve of ³2.5 m/sec and £4.0 m/sec. The primary objective is to evaluate
whether treatment with ezetimibe (EZE)-10 mg + simvastatin (SIMVA)-40 mg
coadministered as a single tablet, compared to PBO, reduces the risk of a composite
endpoint of major cardiovascular events (MCEs) (cardiovascular death, aortic valve
replacement surgery, CHF as a result of progression of AS, nonfatal MI, CABG, PCI,
hospitalized unstable angina, and nonhemorrhagic stroke). Secondary objectives
include aortic valve events, echographic progression of AS and safety and tolerability of
~4-year exposure to EZE-10 mg + SIMVA-40 mg daily. Following a 4-week PBO/diet
run-in period, approximately 1400 eligible male and female patients (45 to 85 yr.; LDL-C
<6 mmol/L [232 mg/dL]; TG £4.5 mmol/L [398 mg/dL]) will be randomized to either
active- or PBO-treatment groups. The study ends after at least 464 patients have MCE
endpoints, confirmed by an external blinded adjudication committee. A Cox proportional
hazard model will be used to compare treatment groups for the primary endpoint.
I don't know much about aortic stenosis, so I don't know what the data indicate for statin treatment of people with AS.
Marilyn
Quite Right!
Thank-you! -- Now corrected!
I've been thinking about what you said about SEAS -- that ezetimibe should be taken off the market if eze/simva does not outperform placebo. My understanding is that the evidence for statins slowing progression of aortic stenosis is not as strong as the evidence related to prevention of heart attacks and strokes. The primary endpoint in SEAS is a composite of events related to CAD and events related to AS. Certainly, if there are not fewer strokes, heart attacks and deaths in the Vytorin group, that would be a very bad sign for ezetimibe. I'm not so sure about the implications if there is no effect on risk for valve replacement and the other AS-related endpoints.
Marilyn Mann
American Journal of Cardiology -- Articles in Press
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: 43-512-504-2276
Not sure if this study is relevant, but I'm posting it in case anyone is interested.
This is outstanding, [cough -- not so] Anonymous poster, immediately above!
And although nominally a disappointment for statins, I think it mostly tells us this disease/condition-state is far more complicated than we might have previously imagined -- a central theme of the object lesson contained in any truly-unbiased look at ENHANCE, and CASHMERE, to be sure. Great input!
Thanks! Do stop back.
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