Different River

”You can never step in the same river twice.” –Heraclitus

February 18, 2005

Blogging hiatus

Filed under: — Different River @ 11:22 am

I’ll be out of town with limited Internet access until Tuesday, so blogging will be limited or nonexistent until then.

Have a great weekend, and Happy Birthday George W.!

(The “W.” is for Washington … who did you think I meant? ;-) )

Vioxx may come back

Filed under: — Different River @ 1:33 am

When drugs are withdrawn from the market, it is almost always due to a small risk of a serious adverse reaction. If the drug posed a large risk of such a reaction, the risk would have been detected in clinical trials, and the drug would never have made it to the market in the first place. Worse, the benefits of the drug to the rest of the patient population seems rarely to be considered.

Such is the case with Vioxx, which was withdrawn from the market on Sept. 30, 2004, due to a small risk of heart attack. The benefit of Vioxx was basically, treatment of severe arthritis without causing bleeding ulcers or other gastrointestinal side effects of previously existing treatments. Basically, the primary treatment for severe arthritis is to take, daily and sometimes in large doses, non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or naproxen (aspirin is also sort of in this category). These drugs work by inhibiting an enzyme called cyclooxegenase (COX). It turns out there are (at least) two forms of this enzyme — cyclooxegenase-1 (COX-1) has a role in protecting the digestive tract, and cyclooxegenase-2 (COX-2) has a role in transmitting pain and producing inflammation. Traditional NSAIDs like ibuprofen and naproxen inhibit both types of COX, which means they stop the inflammation, but also have the potential to irritate or damage the digestive tract. In some patients, this can cause severe and potentially fatal gastrointestinal side effects (such as bleeding ulcers), which makes the drug essentially unusable for those patients.

Vioxx is one of a new class of drugs that inhibit COX-2 but leave COX-1 mostly unaffected (hence the name “COX-2 inhibitors” — the NSAIDs are basically non-selective COX-1 and -2 inhibitors). These drugs — the others on the market are Celebrex and Bextra — are basically ibuprofen and naproxen without the gastrointestinal side effects.

Needless to say, this was a fantastic development for people with severe arthritis who could not take NSAIDs due to the gastrointestinal side effects. It turned out, however, that in some patients, there was also an increased risk of heart attacks that was statistically related to taking Vioxx instead of an NSAID. Now it also turns out that one of the beneficial side effects of NSAIDs is that they prevent heart attacks. This is related to the cardiac benefits of aspirin — if you’ve heard of the notion of taking an dose aspirin a day to ward off heart attacks, you are familiar with this effect; other NSAIDs have the same effect but to a lesser extent. My first question upon hearing this is, do COX-2 inhibitors cause heart attacks, or do they merely fail to protect against them the way non-selective NSAIDs do? I haven’t seen the actual research papers — it appears they haven’t yet been published — so I can’t make a judgement about this, but the consensus seems to be the former — that Vioxx actually does increase the risk of heart attacks.

So, Vioxx was pulled from the market due to this possibility of harm. The problem with this is, in order to avoid a small increase in the risk of a heart attack, thousands of patients are going to be left with the choice of (a) returning to being essentially disabled by severe arthritis, or (b) risk severe illness and possible death due to the gastrointestinal side effects of NSAIDS. This is not a good choice to have to make, and it should be easy to see why some people might choose to risk taking Vioxx instead of risking taking NSAIDs or living with severe arthritis. It might be the right medical decision for a lot of people.

Normally, when a drug gets taken off the market, that’s it — patients who were depending on it go back to suffering or dying, even though they will not die of side effects from that particular drug. THere is a cost-benefit trade-off to be made, but patients and their doctors are not usually given the choice of how to make that trade-off. However, in the case of Vioxx, patients appear to be fighting back. According to this story, Vioxx might even come back:

WASHINGTON – Vioxx could go back on sale if the government finds that heart and stroke problems linked to arthritis drug are not unique to the painkiller and that the medication’s benefits outweigh the risks, a company executive suggested Thursday.

“When we withdrew the drug it was based on the information available at the time,” said Peter S. Kim, president of Merck Research Laboratories.

Vioxx was pulled from the market on Sept. 30. Since then new information has indicated that those medical problems may be associated with an entire class of painkillers known as Cox-2 inhibitors, Kim told a Food and Drug Advisory panel that is assessing the safety of those drugs, which include Vioxx, Celebrex and Bextra.

If the committee and the agency conclude that the benefits of this class of drugs outweigh the risks for some patients, “then we would have to consider the implications of these new data” for Vioxx, Kim said.

Earlier Thursday, an Army physician argued that some popular pain relievers “are essential to the global war on terrorism” and should be kept on the market despite their potentially dangerous side effects.

Without them, he said, the military cannot keep as many soldiers functioning on the battlefield.

Dr. Christopher Grubb told the FDA advisory committees that the military carries Cox-2 drugs into battle. They are needed, he said, because of concerns about excess bleeding that can be caused by more traditional pain relievers such as aspirin.

Other witnesses cited the drugs’ painkilling value.

“Vioxx gave me my life back,” Dimitra Poulos said. “I have 40 Vioxx left, I have 40 days left before my life will be altered.”

Dr. David Graham, a medical officer at the FDA’s Center for Drug Evaluation and Research, said Vioxx could cause hundreds to thousands of additional heart attacks. He said he believes there is a heart hazard from using Celebrex at high doses, and the problem may cover the whole class of drugs.

Other speakers at the session included:

  • Judith Fogel of Ithaca, N.Y., a longtime arthritis sufferer who started taking Celebrex three years ago. “On most days I feel better than I did 30 years ago,” she said.
  • Dr. Mark Einstein of New York, a specialist in gynecological cancer who said the Cox-2 drugs show promise for possible treatment of endometrial and cervical cancer. He complained that trials to test the drugs have been stopped.
  • Diana Zuckerman of the National Research Center for Women and Families, who said Americans “don’t expect to have to weigh the risks and benefits. They expect medications approved by FDA to be safe and effective.”

Graham discussed two studies – both preliminary and not officially published – that cast doubts on the safety of Vioxx because they showed an increased risk of heart attack for the drug’s users.

“We’re talking about small levels of risk that turn out, at the population level, to be enormously important,” Graham said.

He said various studies indicate a range of increased heart attack risk that translates to as few as 400 or as many as 10,800 additional heart attacks per million men age 65 to 74 at low doses of the drug, and up to 40,000 at higher doses.

Merck said in a statement that Graham’s estimates were speculative and that determining the cause of a patient’s heart attack or stroke must be done case by case.

Also Thursday, the European Medicines Agency said it would require stronger warnings about the cardiovascular risks posed by Cox-2 inhibitors.

(Boldface added.)

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