Another Vytorin® Vexation: Merck's SHARP Study | Blunted*, Or "SHARP-ened"?

I am willing to accept the principal investigator's assessment at face value^*: SHARP was likely to show the effects of confusing variables -- and thus, a potential for a "false negative" outcome. So the PI is refocusing the statistical emphasis, after the sponsor (New Merck) declined to change the primary endpoint.

What this overnight HeartWire report means, then -- is that if the "refocused" SHARP study does not show a clear benefit for the Vytorin^® arm, then there can be almost no other explanation than that Vytorin. . . Simply. Doesn't. Work. Do go read it all, but here is a bit:

. . . .The evaluation of the efficacy of lipid-lowering therapy with ezetimibe/simvastatin (Vytorin, Merck) in the Study of Heart and Renal Protection (SHARP) trial will no longer focus on the primary end point of major vascular events but instead will emphasize the effect on major atherosclerotic events, defined as the combination of coronary death, MI, ischemic stroke, or any revascularization procedure.

The change in emphasis, according to investigators, is to reduce the possibility of a "false-negative" trial, where the potential benefit of LDL-lowering therapy on atherosclerotic outcomes in patients with chronic kidney disease is diluted by nonatherosclerotic events. . . .

As part of their regular statistical checks on the trial, SHARP investigators noted that the primary end point of major vascular events was 4.3% per year, slightly higher than anticipated, and that 33% of these events were noncoronary cardiac deaths and hemorrhagic strokes, two outcomes known to not be affected by reductions in LDL cholesterol. In addition, blinded review showed that reductions in LDL cholesterol were smaller than expected among the simvastatin/ezetimibe-treated patients: 33 mg/dL vs an expected 39-mg/dL reduction.

As a result of the discrepancy with their underlying assumptions, the SHARP steering committee, still blinded to the effects of study treatment, decided in October 2009 to change the primary outcome to major atherosclerotic events and approached the sponsor, as required in the contract, to seek approval for the change. Merck, however, declined to approve the changes. Unable to change the trial's primary end point, the investigators changed the study's statistical analysis plan, focusing instead on major atherosclerotic events.

Baigent stressed that investigators are still blinded to the treatment effects, and the change in statistical analysis has been published prior to the introduction of the study's results, so as to refute any accusations of possible bias. . . .

Still, it seems Vytorin is showing a lower than expected benefit (even in surrogate LDL reduction measures), after the first year of therapy. Not a good thing, as we wait -- perhaps until 2014 -- for the definitive answer from IMPROVE-IT: Does Vytorin actually work to reduce cardiac events? Of course, by then, it will have been sold to millions of patients, for perhaps a total of $25 billion. And that's not the way health care ought to work.

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* _{Of course, the honest truth is that the darker angels of my nature wonder whether this statistical refocusing will make it more likely that no clear outcome may be discerned from SHARP -- and thus, Merck may keep on touting and selling Vyotrin -- until 2014, and IMPROVE-IT is published.}