And so the much-anticipated presentation at the American College of Cardiology of the controversial Enhance trial of Vytorin fails to solve the mystery. As the investigators write in the study, which is now available in the New England Journal of Medicine, “the reduction of LDL cholesterol by the addition of (Vytorin) to (Zocor) did not reduce intima–media thickness of the carotid-artery wall in patients with familial hypercholesterolemia in our study. The reason for the failure to observe an incremental effect on (this) thickness despite a reduction in levels of LDL cholesterol remains unknown.”

This leaves us wondering whether the surrogate endpoint used - the measurement of that particular artery - is a helpful gauge. Another uncertainty surrounds the characteristics of the patients studied, since they had an inherited form of high cholesterol and may have received extensive treatment in the past. Of course, the other key unanswered question is whether Vytorin - which combines Merck’s Zocor and Schering-Plough’s Zetia - has any clinical benefit. And that leaves the drugmakers vulnerable to further criticism and lost sales, especially since Vytorin is expensive and has been widely promoted.

“That possibility, which is the elephant, in the parlor deserves serious consideration in any discussions of results of this study,” write Greg Brown and Allen Taylor in an accompany editorial. “Further answers to these questions, as well as results of the trials that are under way, will clarify findings of the Enhance study, which, after all, are based on a surrogate, although seemingly useful, end point. For now, the study’s findings are a red flag, but not a black box.” Both are consultant to Merck, by the way.

Meanwhile, a separate study published in the NEJM of Vytorin use in the US and Canada from 2002 through 2006 found that the US pattern increased overall cost, but the effect on clinical outcomes is uncertain. The study noted that at daily doses having a similar effect in reducing LDL cholesterol, the cost of Vytorin 10 or 20 mg is more than three times that of 80 mg of Zocor, which is now available generically in the US. In Canada, you may recall, DTC advertising is not permitted.

Seventeen cardiologists reviewed the NEJM studies for Forbes, and 14 expect Vytorin and Zetia usage will decline following the release of the studies. “The willingness of US physicians to so rapidly adopt an unproven therapy is worrisome,” Paul Ridker, a cardiologist at the Brigham & Woman’s Hospital in Boston, tells the mag. “The questions patients with high cholesterol should ask their physicians is simple: Will the drug you are giving me lower my risk of heart attack or stroke? If not, why are you prescribing it?”

Not surprisingly, the drugmakers are on the defensive. “What we do not agree with is that it should be used as a second- or third-line therapy,” Enrico Veltri, the Schering-Plough vp in charge of heart disease drugs, tells Forbes. “We don’t think it needs to be a last resort.” In a statement issued by both drugmakers, Tom Musliner, who heads Merck’s cardiovascular disease research, attributed Vytorin’s failure on extensive treatments given the study patients. And he argues that the Enhance study “was not designed nor powered to evaluate cardiovascular clinical events,” and points to the ongoing Improve-It study, although that is now being delayed.

Here is Kastelein’s slide presentation made at the ACC today.