Merck pulls Vioxx off the market

Merck Pulls Vioxx Painkiller From Market, and Stock Plunges [NYT]:

Merck & Company announced today that it was immediately pulling its arthritis and acute pain medication Vioxx from the worldwide market after data from a clinical trial showed that the drug produced an increased risk for heart attacks and strokes.[...]

Merck's shares plunged by more than $12 to as low as $32.46 when trading opened on the New York Stock Exchange this morning, and the stock remained down by about 25 percent in early trading — reducing the company's market capitalization by about $26 billion.[...]

Serves them right. Now, why don't we have better science journalism? The real question is why Merck acted so precipitously? Vioxx was one of their best selling drugs. I think it's because they're afraid of lawsuits. Merck has know about the CV risk of Vioxx for years. I wonder why these particular data finally convinced them to pull the drug.

According to the NYT:

The Vioxx risk came to light during a three-year trial designed to evaluate the efficacy of taking the drug in preventing a recurrence of colorectal polyps in patients with a history of benign colorectal tumors, the company said.

The latest data came to light this week, but the evidence has been mounting for years. JAMA dropped the inital bombshell in 2001: Risk of cardiovascular events associated with selective COX-2 inhibitors. The authors wrote, "The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors. Further prospective trial evaluation may characterize and determine the magnitude of the risk."

The cardiovascular risks of Vioxx are no suprise to Merck. FDA warns Merck over its promotion of rofecoxib [BMJ]:

In its [2001] letter the FDA criticised Merck for playing down the possible risk of stroke associated with rofecoxib and for minimising potential drug interactions of rofecoxib with warfarin.

The risk of stroke was found in an analysis of a large study, dubbed the VIGOR (Vioxx gastrointestinal outcomes research) trial, which compared 50 mg a day of rofecoxib with 500 mg twice a day of naproxen in patients with rheumatoid arthritis (New England Journal of Medicine 2000;343:1520-8).

The VIGOR trial was a randomised, double blind, placebo controlled study of 4047 patients taking rofecoxib and 4029 taking naproxen. Patients were followed for an average of nine months.

The study found that rofecoxib was significantly less ulcerogenic than naproxen and that patients taking rofecoxib had a 60% lower risk of serious gastrointestinal eventssuch as perforations, obstructions, and upper gastrointestinal bleedsthan patients taking naproxen. The relative risk was 0.4 (95% confidence interval, 0.2 to 0.8; P=0.005).

The annual rate of these events was 1.4% among patients taking naproxen, compared with 0.6 % among patients taking rofecoxib.

However, an analysis of the VIGOR study by cardiologist Eric Topol and colleagues at the Cleveland Clinic in Ohio (JAMA 2001;286:954-9) showed that patients taking rofecoxib had a higher relative risk of developing adverse cardiovascular events such as ischaemic strokes, unstable angina, and myocardial infarctions than the patients taking naproxen (relative risk 2.38 (95% confidence interval 1.39 to 4.00; P=0.002).

Their study suggested that rofecoxib might be prothrombotic and urged further research to see if this was so. The FDA charged that Merck was aware of the cardiovascular risk associated with rofecoxib and minimised it in a press release and in its promotional materials.

In a press release Merck responded that the VIGOR study's data falsely inflated the cardiovascular risk of rofecoxib because it compared the drug with naproxen, which has blood thinning properties similar to aspirin. [Emphasis added.]

Note Merck's specious justification for the elevated incidence of cardiovascular evenets in rofecoxib patients. They suggested that the rofecoxib patients had more strokes because the comparator medication (naproxen) has slight cardioprotective effects. I should add that before Merck's experts started theorizing, nobody believed that naproxen had any cardiovascular benefits.

In fact, Merck's apologia would be almost as damning as if Vioxx actually caused thromboses. The rationale for taking Vioxx instead of a traditional NSAID is that Vioxx is less likely to cause ulcers in longterm users. But other studies have shown that patients taking COX-2 inhibitors and low-dose aspirin have the same risk of ulcers as patients taking NSAIDs. We know that low dose aspirin saves lives. So, if Merck's hypothesis is true, Vioxx patients would have to forgo other potentially lifesaving treatments in order to use their product.

The whole COX-2 industry is largely a marketing phenomenon. [BMJ] These drugs aren't more effective painkillers than the old, cheap NSAIDs. Yet, doctors prescribe billions of dollars worth of COX-2s every year. Worse, they often prescribe them to young, healthy people with acute pain. There is simply no evidence that the GI benefits of the COX-2s extend to anyone except very longterm users.

The COX-2s soured me on big pharma and industry-sponsored research. These drugs are costing insurers and consumers billions of dollars for marginal benefits supported by dubious research. I used to work on a Celebrex-related project. It was embarassing because the largest and most impressive study, CLASS, suffered from methodological irregularities that less delicate commenters would have described as fraud. Sometimes I just want to scream "The emperor has no cyclooxgenase!"

Comments

[Chris Rangel MD]

Ahh, but what about the big question. Is Merck liable? Should they be sued for hundreds of millions of dollars for a very small side effect risk? And remember, studies have yet to show a difference in mortality rates so at least from a statistical standpoint Vioxx has not been killing off patients.

[Lindsay Beyerstein]

Hi, Doc. Thanks for the comment.

You raise several key questions. The first is technical/legal--Is Merck liable? I don't know. I hope some of our legally savvy readers will weigh in.

The first question can't be answered without knowing the empirical facts. Do the data establish a link? When did Merck realize that this link existed. What did they do about it?

Then there's the question of fairness. Suppose that Vioxx did contribute to the deaths of a statistically specifiable number of people. However, we can't identify which individuals were harmed because of Vioxx. It's difficult to gage the extent to which Vioxx was responsible for any particular person's CV event. So, there are a lot of thorny legal and ethical issues about who deserves to be compensated for what.

[g smith]

i have taken naproxen 500 mg
what harme will this have done to me
thank you
gord