Tuesday, April 01, 2008

First Do No Harm & Profiting From Death

April 1, 2008, 2:00 p.m.

This is No 'April Fools' -- Drug Companies Profit from Death

Quite appropriately, the History of Medicine Division of the National Library of Medicine of the National Institutes of Health provides a translation from the Greek, of what is known in medicine as "The Hippocratic Oath" along with a snapshot of the original. (Thought to have been written in the Fourth Century, this version was a 1595 translation from Frankfurt.)

As the accompanying NIH text explains, "One of the best known prohibitions is, to 'do no harm'
(epi dhlhsei de kai adikihi eirxein)."

This remains a consideration of no little consequence still today, some 15 or more centuries later. "Iatrogenic" (literally "physician-induced") disease -- conditions that a patient would not be suffering had they not visited a doctor or hospital -- are said by some to be the third leading cause of death in the United States (195,000 deaths a year, creating an extra $6 billion in costs -- out of a total cost from iatrogenic errors of $29 billion). And of course not all errors result in death. As the American Iatrogenic Association reports, "The Centers for Disease Control and Prevention estimates that 2 million people annually acquire infections while hospitalized and 90,000 people die from those infections."

In fairness to the medical profession, and hospital administrators, they are making efforts to reduce these preventable injuries, diseases and death. There may be some hospitals that increase their profits somewhat by not doing all they might with regard to cleanliness. But none, to my knowledge, is otherwise engaged in deliberately increasing patient harm.

Alas, this cannot be said for the pharmaceutical industry.

Now before I get too far into this story let me concede that (a) I am not trained as a doctor or a pharmacist (I don't even "play one on TV"), and (b) I am relying on a New York Times report rather than original source material. Alex Berenson, "Study Reveals Doubt on Drug for Cholesterol," New York Times, January 15, 2008 (the source of all quotes that follow).

Over the last weekend I heard references to Zetia in some newscasts. The impression I got from them was that Zetia might actually increase rather than decrease the formation of plaque.

The stories got my attention because I take Zetia, my supply had run out, and I was going to pay a visit to my pharmacist for a re-supply.

Frankly, I like pharmacists. In my experience they are well informed and communicative when it comes to prescribed drugs -- as one might hope, given their professional training.

So I inquired about the news stories I'd heard, but was reassured by a couple of them that while they were aware of some Zetia studies, and while it might be possible that it would not reduce plaque as much as some other drugs, they didn't see how it could possibly increase plaque.

And why is plaque important? Isn't it cholesterol we're trying to reduce? Yes and no. (And this is now medically uninformed and uneducated "Dr. Nick" speaking.) Cholesterol, qua cholesterol, is not the problem; it helps create the problem; the problem is the deposits of fatty plaque in the carotid arteries ("atherosclerosis") that can contribute to the blood clots and blockages that can cause strokes and "heart attacks."

Merely reducing cholesterol without reducing the formation of plaque deposits -- let alone actually increasing them -- does little to reduce cardiovascular deaths.

At least that's how I understand it.

Actually, there are two or more stories here, not just one. I have numbered [in brackets] the paragraphs that relate to each.

[1] Combining Zetia with a statin (such as Zocor, or the more popular Lipitor) does reduce cholesterol more than the statin alone -- something to which I can personally attest. And that is the result from the Merck and Schering-Plough product Vytorin -- which contains both. That's not disputed so far as I know. The issue is whether Zetia alone, or in combination with a statin, fails to reduce -- or actually increases -- deposits of plaque more than if the patient was taking a statin alone. And that appears to be the case. Zetia alone "seemed to contribute," though by only "a small amount," more plaque formation; in patients taking Zetia in combination with a statin "the plaque actually grew almost twice as fast."

[2] These results were known in 2006, should have been revealed immediately by the two drug companies, and yet were withheld from the medical profession, media and public until 2008.

[3] There is speculation that their $5 billion in sales of Zetia and Vytorin contributed to their delay.

[4] Congress is investigating the matter -- an investigation that apparently was what finally pressured the companies to release their findings.

A clinical trial of a widely used cholesterol drug has raised questions both about the medicine’s effectiveness and about the behavior of the pharmaceutical companies that conducted the study, cardiologists said Monday [Jan. 14, 2008].

[1] Merck and Schering-Plough, which make the drug, Zetia, and a pill that contains it, Vytorin, said Monday morning that Zetia had failed to benefit patients in a two-year trial that ended in April 2006.

[2] Merck and Schering repeatedly missed their own deadlines for reporting the results, leading cardiologists around the world to wonder what the study would show. At the same time, millions of patients have continued taking Zetia and Vytorin.

The drug companies blamed the complexity of the data for the delay. Now, barely a month after news articles noted the delay and Congress pressured the companies to disclose the study’s findings, the results are out.

[1] In a press release, Merck and Schering said that not only did Zetia fail to slow the accumulation of fatty plaque in the arteries, it actually seemed to contribute to plaque formation — although by such a small amount that the finding could have been a result of chance.

Dr. Steven E. Nissen, the chairman of cardiology at the Cleveland Clinic, said the results were “shocking.”

“This is as bad a result for the drug as anybody could have feared,” said Dr. Nissen, a widely published researcher and senior consulting editor to the Journal of the American College of Cardiology. Millions of patients may be taking a drug that does not benefit them, raising their risk of heart attacks and exposing them to potential side effects, he said. Patients should not be given prescriptions for Zetia unless all other cholesterol drugs have failed, he said.

[3] Both companies’ shares fell Monday. Sales of the two drugs were $5 billion in 2007, and they are important contributors to Merck’s and Schering’s profits.

[4] The House Energy and Commerce Committee, which is investigating the delay, said in a statement Monday that the negative results added to suspicions that the companies had deliberately sat on their findings from the study, which was known as Enhance.

[2] “In light of today’s results, which were released nearly two years after the Enhance trial ended, it is easy to conclude that Merck and Schering-Plough intentionally sought to delay the release of this data,” Representative Bart Stupak, Democrat of Michigan, said in the statement. Mr. Stupak is chairman of the committee’s Subcommittee on Oversight and Investigations.

Dr. Harlan M. Krumholz, a cardiologist at Yale, said drug companies had a responsibility to release all their trial findings, positive or negative, as quickly as possible — even if the results might hurt sales.

* * *

[1] Statins like Zocor and Lipitor have been shown to lower cholesterol by 35 to 60 percent in most patients and have also been proved to reduce heart attacks. Zetia, which works by a different mechanism, reduces cholesterol 15 to 20 percent, but it has never been proved to reduce heart attacks.

The Enhance trial was meant to prove that Vytorin’s combination of Zetia and Zocor would reduce the growth of fatty plaque in the arteries more than Zocor alone. Instead, the plaque actually grew almost twice as fast in patients taking the combination.

Reducing plaque growth is crucial, because plaque formation — known as atherosclerosis — can lead to the blockages and blood clots that cause heart attacks and strokes, said Dr. Howard N. Hodis, a cardiologist at the University of Southern California. That is why the trial’s finding is worrisome, Dr. Hodis said.

“Clearly, progression of atherosclerosis is the only way you get events,” Dr. Hodis said. “If you don’t treat progression, then you get events.”

* * *

[3] Merck and Schering share profits from their joint marketing of Zetia and Vytorin. The drugs are important contributors to both companies’ profits, but more so to Schering, which is smaller and less profitable than Merck. Analysts estimate that about 70 percent of Schering’s earnings depend on Zetia and Vytorin .

Merrill Lynch on Monday reduced its rating on Schering’s stock from buy to neutral, warning that some doctors might move away from Zetia. Schering’s share price fell 8 percent , while Merck’s dipped 1.3 percent.

[1] Because Zetia reduces cholesterol in a different way from statins like Lipitor and Zocor, doctors often prescribe it as an additional therapy for patients whose cholesterol remains high even after they are already taking statins.

But even before Zetia was introduced in 2002, some cardiologists argued that statins have positive cardiovascular effects that go beyond their ability to reduce cholesterol, and that Zetia lacks those effects.

* * *

Over the two years of the trial, patients who took Zocor alone reduced their LDL by 41 percent on average, while patients who took Vytorin reduced their cholesterol by 58 percent. Yet despite the larger cholesterol reduction, patients taking Vytorin actually had more growth of fatty plaque in their carotid arteries than those on Zocor.
Well, that's the story.

The very same pharmaceutical companies that underwrite the campaign costs of the members of our U.S. Senate and House have now been caught knowingly continuing to promote the sale of of a drug after it's known to at best provide no benefit (in terms of reduction of "events" -- doctor speak for "death") and at worst "do harm" -- the very thing Hippocrates said doctors should take an oath to avoid -- all for $5 billion in annual sales.

Oh, I almost forgot. The day I was going to pick up my Zetia refill I got a letter from my pharmacy. It was the first time they'd ever written me. According to the letter, "This program is provided by financial support from Merck/Schering-Plough Pharmaceuticals, the maker of ZETIA." Personally addressed to me by name, it was encouraging me to refill my Zetia prescription.

Odd, I thought. Could it have been a coincidence? Or was it, perhaps, sent in anticipation of the bad publicity they feared might come to my attention? (And, not incidentally, is it standard practice for pharmacies to mail encouragement to customers to buy prescription drugs -- essentially turning over access to the private medical records of customers (names, addresses and prescribed drugs) to drug companies -- especially when the printing and mailing are paid for by a drug company that stands to profit from the refill of the prescription for the drug in question?)

Needless to say, I read it carefully to see what mention they might make of the study revealing this very serious "side effect" (namely, the worsening, rather than the relieving, of the condition for which the drug is sold). Nothing. Nada.

There were warnings about pregnancy. Warnings about muscle pain. Warnings about liver problems.

But not only was there no warning that, taken with statins, Zetia might actually increase, rather than decrease, the deposits of fatty plaque that might bring on a heart attack -- there was actually the comforting, though dangerously inaccurate, reassurance that, "ZETIA can be taken alone or with a statin."

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