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More head-scratching with latest Zetia study

You can’t feel hypertension or atherosclerosis, but a blood pressure cuff around the arm will give you a fairly accurate measure of the pressure your blood vessels are under.

You can’t feel hypertension or atherosclerosis, but a blood pressure cuff around the arm will give you a fairly accurate measure of the pressure your blood vessels are under. Monitoring the process of atherosclerosis — the scarring and narrowing of arteries — is a little trickier, but we’ve come to rely on cholesterol levels as a surrogate marker.
A recent study evaluating the cholesterol-lowering medication ezetimibe (Zetia) calls that practice into question. And this week’s news coming out of the American College of Cardiology reinforces it.

The head-scratching began this January when the manufacturer of Zetia, Merck/Schering-Plough, released preliminary results from its ENHANCE trial. The study took several hundred patients with very high cholesterol and treated them with simvastatin (Zocor) or simvastatin plus ezetimibe (Zetia). Zetia lowers cholesterol via a different mechanism from statins like Zocor, and the two have been marketed as a combination pill called Vytorin.

When it came to lowering cholesterol, the study showed that indeed, two are better than one. Both groups had significant decreases in their LDL, the so-called “bad” cholesterol, but those on combination therapy with Zocor and Zetia had LDL levels that were 27 percent lower than those achieved with Zocor alone.

Then things got confusing. When researchers used ultrasound to follow the buildup of atherosclerosis within the inner lining of the blood vessels, Zetia’s extra “kick” in lowering LDL didn’t make any difference. The rate of thickening over the two-year study was the same. This contradicted what has become gospel in preventive cardiology: Lower LDLs mean less atherosclerosis.

Everyone remain calm, even if confused
Merck/SP’s release of the preliminary data garnered furrowed brows from investors, physicians, and most importantly, from the millions of people taking the drug (34 million prescriptions were filled in 2006). 

A statement from the American College of Cardiology (ACC) mirrored the general response from the medical community: No need to panic — everyone remain calm. “The ACC recommends that Zetia remains a reasonable option for patients who are currently on a high dose statin but have not reached their goal. The ACC also notes that Zetia is a reasonable option for patients who cannot tolerate statins or can only tolerate a low-dose statin.”

The full details of the ENHANCE trial were so highly anticipated that the authors of the study presented their findings as the “torch-lighting” equivalent for Sunday’s opening session of the ACC’s national meeting in Chicago. The study and several editorials analyzing it also garnered marquee positions in this week’s New England Journal of Medicine.

The authors of the study offer three explanations for why Zetia’s power to lower LDL didn’t translate into any visible atherosclerotic benefit.

Starting with the obvious: Zetia doesn’t work. Yes, it lowers cholesterol, but it doesn’t affect the atherosclerotic process, as we know the statins (Zocor, Lipitor etc.) do. The statins’ proven clinical benefit is thought to be the result of a combination of LDL-lowering effects and what are called “pleiotropic effects”: anti-inflammatory actions that soothe achy, sore, irritated blood vessels. Blood vessels start out inflamed, and the resultant scarring is what we know as atherosclerosis.

The second explanation seemed like kind of a shot in the dark. Their ultrasound technology didn’t work — it didn’t “accurately reflect changes in atherosclerotic burden.”

The third explanation was that the patients selected for the study were at too low a risk to show a benefit. Yes, the patients selected for the study had sky-high cholesterol levels, but 80 percent had already been on a drug like Zocor before the study. And because they were already treated, and the cholesterol buildup had had time to shrink or at least stabilize, there wasn’t a lot more benefit to be had. The thought was that the last 10 percent of any cleanup job is always the hardest.
So what’s a patient to do?
According to the study and the comments in the accompanying editorials, it appears that the fully vetted version of the trial doesn’t look substantially different from the preliminary information released in January. It’s like Howard Dean’s fall from favor after his whinny in Iowa. The facts don’t seem to be any different, but the mood has changed. The cautious tones of mid-January have been replaced by dark skepticism.

A review in Journal Watch Cardiology, published by the NEJM, says, “From a practical perspective, the findings push ezetimibe to the back of the of the line of cholesterol-lowering drugs, and perhaps, for some people, out of line altogether.”

One of the New England Journal editorials accompanying the ENHANCE study report says, “For now the study findings are a red flag but not a black box,” and recommends a “reasonably cautious strategy.” That means maximizing the benefits of exercise, dietary control and statin drugs like Zocor, and adding in older cholesterol-lowering medications like niacin, etc., if needed. Zetia can remain a last option.

Good news travels fast; bad news slower
One thing is clear: Merck/Schering-Plough wasn’t pleased with the results or it would have published them sooner. The study ended in April 2006, and Merck/Schering-Plough’s January press release was issued under duress generated by media pressure in the fall of 2007. A “Dear Health Care Professional” letter I received from Merck/Schering-Plough explained the delay in this way: “The study analysis required meticulous examination of over 30,000 images of IMT [ultrasound imaging] of the carotid and femoral arteries. This process was time consuming and took longer than anticipated. The decision was made to release the results of the primary end point because of the growing level of scientific interest with the results.”

Certainly, physicians and the patients who are counting on Zetia to ward off a heart attack have a scientific interest. But there was also a lot of financial interest in the trial. Annual sales of the drug (as Zetia and Vytorin) reached $5.2 billion last year, and the company spent a cool $200 million in 2006 trying to persuade you to ask me if Vytorin might be right for you.

Paying for proof
The company’s delay in releasing the results of the ENHANCE trial raises a recurring question: How healthy is it for our country to have so much of our health-care research in the hands of for-profit companies whose motives are, in part and by necessity, financial?

For a nation going gray and staggering under the burden of runaway health-care costs, perhaps the greatest question raised by the results of the trial is this: Should drugs be approved by the Food and Drug Administration based solely on their effect on surrogate markers (in this case, cholesterol), without any proof of clinical benefit?

Take the case of the drug torcetrapib. On paper it was a real cholesterol slayer, strongly boosting good cholesterol (HDL) and lowering LDL. But in December 2006, development of the drug was halted after a trial being done as part of the FDA approval process showed that taking torcetrapib increased mortality. Who wants their vigorously low LDL carved into their tombstone?

In the meantime we’ve anteed up billions of dollars for Zetia (and Vytorin) with no proof that the drug actually lowers the risk of heart attack and stroke. We have good reasons to believe they will, and they might — but we don’t know yet. Several large trials involving Zetia are under way, and they are designed to answer just that question: Does Zetia improve patients’ cholesterol level, or their cardiovascular health, or both?