The drugs seemed miraculous when they were introduced in 1999, and they soon became blockbusters, with billion-dollar sales. Vioxx, made by Merck, and Celebrex, made by Pfizer, could quell pain and inflammation just as well as drugs like ibuprofen and naproxen, but they did not cause ulcers and gastrointestinal bleeding.
A Merck clinical trial asking if Vioxx could also prevent colon cancer revealed that the drug increased the risk of heart attacks, and the company pulled it off the market in 2004. Ever since, a question has hung over Celebrex. Did it cause heart attacks, too?
Now, at long last, the resulting clinical trial is done.
Most medical researchers, including the study’s principal investigator, thought Celebrex would be riskier than either ibuprofen or naproxen.
Instead, it was at least no worse and may even be safer than the alternatives.
This is more evidence of how even “scientific truth” and “evidence-based” medicine are in constant flux. Scientific facts are regularly updated and changed by new data or new studies.
Evidence-based treatments that rely on the outcomes of these studies are often put in place just in time for the evidence to change.
Then, due to the inertia of our huge medical system, these obsolete treatments linger on long after they’ve been proven wrong.
An estimated two million people in the United States take Celebrex or generic celecoxib, said Dr. Milton Pressler, a cardiologist in charge of clinical affairs for Pfizer Essential Health. The drug is available only by prescription; as the trial dragged on its patent expired, so now generic companies also sell it.
He and others emphasized that the findings apply only to people taking the drugs every day for months or years and who are at high risk for heart disease or already have it. They do not apply to someone who pops an occasional ibuprofen like Advil for a pulled muscle or takes a naproxen such as Aleve for a headache.
When the trial was designed, many thought, based on data from small studies, that naproxen was safest and celecoxib was likely to be the riskiest.
But an advisory committee that met in 2015 said to wait for the results of the new trial and warnedthat none of the drugs were risk-free.
The main purpose of the study was to investigate “noninferiority” — to see if celecoxib was at least as safe as the other two drugs. It was.
The study found that during the trial
- 188 of the celecoxib patients (2.3 percent) died of heart disease or hemorrhage, or had a heart attack or a stroke,
- 201 patients taking naproxen (2.5 percent) and
- 218 patients (2.7 percent) taking ibuprofen.
When the differences are so small, lifestyle adjustments can more than make up for the “greater risk” of the much cheaper drugs.
The real surprise was in other outcomes the study investigated.
- Significantly more patients taking ibuprofen had worsening kidney function.
- Patients taking either ibuprofen or naproxen were significantly more likely to be hospitalized for high blood pressure.
- And despite the assumption that naproxen was the safest, there were 25 percent more total deaths with naproxen than celecoxib — 163 with naproxen compared with 132 with celecoxib.
- As expected, because celecoxib was intended to avoid bleeding problems, both ibuprofen and naproxen patients had significantly more gastrointestinal bleeding and ulcers.
Dr. Wilson took issue with stressing the secondary outcomes. The rules of clinical trial research say what counts is the outcome you designed your study to find. “To then drill into secondary endpoints and find superiority — that’s not really fair,” he said.
The study did have some real weaknesses.
Only a minority of the patients actually had documented heart disease and it is those patients who are most worrisome. Many dropped out, making it hard to interpret the data.
Others, like Dr. Blaha, accepted the conclusions. “I would not feel comfortable saying it is perfectly safe to take celecoxib,” he said. “But if you need to take a daily pill it might be safer to take this one than the other two.”
“On average it looks like celecoxib is safer,” he said. “If you need to be on it for more than a couple of months, I would think strongly about celecoxib.”
As usual, science ignores the financial realities of a broken healthcare system and patient budgets. Especially because it requires a prescription, Celebrex is far more expensive than the common OTC alternatives.
This study said nothing about the comparative effectiveness of these medications and I suspect that would be determined by the individual patient’s body chemistry.