Right now, Merck (NYSE: MRK) and Schering-Plough (NYSE: SGP) probably wish that the Enhance study had lived up to its name. The drugmakers certainly hoped data from the study would enhance the value and status of their blockbuster cholesterol-fighting drugs Zetia and Vytorin -- but its results did quite the opposite.

The controversial study got a thorough examination this weekend from the cardiologists gathered at the annual American College of Cardiology meeting, and it was further dissected in four papers concurrently published by the New England Journal of Medicine (NEJM).

As previously discussed, patients in the Enhance trial with very high cholesterol levels were given Vytorin tablets (combining Zetia and Zocor) or Zocor alone. The study gained notoriety when a House Committee demanded information about the study after a delay in the results' publication.

Zetia blocks the uptake of foodborne cholesterol from the digestive tract, thus lowering LDL (the "bad" cholesterol that clogs arteries). The well-studied Zocor, like other statins such as Pfizer's (NYSE: PFE) Lipitor and AstraZeneca's (NYSE: AZN) Crestor, works on receptors in the liver to lower cholesterol levels. Zocor is now available as less-expensive generic simvastatin, sold by companies such as generic drug behemoth Teva (Nasdaq: TEVA).

Because Vytorin lowers cholesterol levels more effectively than other cholesterol drugs, and because heart patients with lower cholesterol levels tend to do better in clinical trials, many cardiologists felt that Vytorin was an excellent medication for patients with heart disease. Sales of Zetia, approved in 2002, and Vytorin, approved in 2004, total $5 billion annually, making them one of the world's best-selling drug families.

Where things went wrong
The Enhance trial did show that Vytorin did a much better job of lowering total cholesterol, lowering LDL cholesterol, and lowering CRP levels, a marker of inflammation associated with developing heart disease. From these results, one would guess that combination Vytorin would work better than Zocor alone.

But the primary endpoint of the Enhance study involved measuring the thickness of subjects' carotid arteries via ultrasound to see how much plaque was present. Investigators expected that Vytorin would outperform Zocor in reducing the artery's thickness. The study proved them resoundingly wrong.

Its authors offered three explanations for this paradoxical finding. First, and most unlikely, the technique of measuring the arteries may not have been accurate enough to show changes in the amount of atherosclerosis. Second, the patients studied had previously been treated with statins, so the previous treatment may have already cleared out their carotid arteries. Third, the study may simply reveal that Zetia does not reduce the progression of atherosclerosis, despite lowering LDL and CRP levels. As you might guess, that last question has become the study's major concern.

Less than ideal results
In light of the results, physician leaders seemed uniformly unenthusiastic about prescribing Zetia or Vytorin for most patients with elevated cholesterol levels, preferring to increase the dose of a statin or add other cholesterol-lowering medications.

Quoting one of the NEJM editorials:

Until such data are available, it seems prudent to encourage patients whose LDL cholesterol levels remain elevated despite treatment with an optimal dose of a statin to redouble their efforts at dietary control and regular exercise. Niacin, fibrates, and resins should be considered when diet, exercise, and a statin have failed to achieve the target, with ezetimibe (Zetia) reserved for patients who cannot tolerate these agents.

Adding insult to injury, Merck and Schering-Plough couldn't even get help from their competitors. AstraZeneca announced this week that a study involving Crestor would be stopped early because subjects taking the drug showed such a significantly lower frequency of cardiac events.

In light of the Enhance study's high-profile flop, expect sales of Crestor, Lipitor, generic statins, and newly FDA-approved Simcor, a combination of simvastatin and Abbott Laboratories' (NYSE: ABT) non-statin Niaspan, to increase in the coming months.

Sales of Vytorin and Zetia, on the other hand, should be anything but enhanced.

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Fool contributor Michael Cecil is a cardiologist and an avid college hoops fan. Dr. Cecil does not own any of the stocks mentioned in the article. The Fool's disclosure policy blames its high cholesterol on its Uncle Will.