Merck's Massive "Head-to-Head" IMPROVE-IT Study May Never Reach A Meaningful Endpoint

Given the outstanding quality of my anonymous commenter audience of late, I probably ought to just let my commenters write this blog -- as they are far more adept at pointing these things out, and succinctly so, than I -- very nice work, "Anonymous" [BTW, the image at right is a letter, from the Congressional investigations begun last year into these matters -- click it to get all the background on other arguable cholesterol-study shenanigans, circa Summer of 2008]:

. . . .Mark these words: IMPROVE-IT will be at the very best a neutral study -- it will show no definitive difference at all between Vytorin and generic simvastatin. Given the number of events recorded to date (~2,300) in 15,000 patients enrolled and with enrollment having started in October of 2005, the PIs retained by Merck actually should have enough statistical power to detect a clinically meaningful difference in events. [Editor's Note: Remember here also that the PIs unblinded the IMPROVE-IT data, to an independent safety panel, immediately after the SEAS cancer signal -- and then the IMPROVE-IT study size was increased. Interesting, no? -- But back to the main story, now.]

The problem is, they haven't, and this is mainly due to two arguably errant assumptions by Merck's study designers:

(1) all LDL-C lowering is not equal in terms of its association with event reduction, and

(2) Merck's assumed relationship between LDL-C reduction and cardiovascular event risk is not linear.

On the latter point, Merck believes that for every 1.6 mg/dL decrease in LDL-C, cardiovascular event risk is reduced by a relative 1%. What Whitehouse Station is too blind to see is that this relationship does not hold true at the LDL-C values expected in this study (baseline ~100 mg/dL, and on-Rx values in the 50-65 range. In fact, this relationship is actually curvilinear, and the cardiovascular event reduction gets progressively smaller and smaller as LDL-C declines below 100. The "joke" will be on New Merck. It would be funny if it weren't for the tens of millions of patients that will get Zetia/Vytorin instead of a more beneficial therapy (niacin, anyone?) at an aggregated spend of $4 billion/year until we find that out.

-- Anonymous, November 18, 2009 10:15 PM. . . .

I think that has it just about perfectly right. For its part, New Merck is supposed to release a newly revised/projected end-date for IMPROVE-IT in the coming weeks, according to on-the-record remarks made by the study PIs, at AHA in Orlando, this week. Will the new date be in 2013? 2014? Or later? We'll see -- but my money's on the above analysis, regardless of what Merck "forecasts" (or guess-timates, more pointedly) here, as 2009 draws to a close.