November 14, 2016 from O’S News Service

Ever since Merck’s Vioxx was pulled from the market in 2004 because it was causing thousands of heart attacks and strokes, a cloud has hung over Pfizer’s Celebrex, which relieves pain and inflammation by the same mechanism —inhibiting Cox-2 enzymes. Celebrex remained on the market (and to this day is used by more than two million US Americans).  The FDA wanted reassurance and in 2006 asked Pfizer to conduct another trial.

The results of that trial —the goal of which was to establish “noninferiority” to ibuprofen and naproxen— were published online yesterday in the New England Journal of Medicine. Celebrex (celecoxib) was shown to cause slightly fewer grave adverse effects than its rivals. Some excerpts from the NEJM paper by Nissen et al:

The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke.

A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%)

Gina Kolata of the New York Times (Judi Bari’s sister), played up the good-for-Pfizer story today:

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

Kolata quoted a skeptic, Dr. Peter W.F. Wilson, of the Emory Clinical Cardiovascular Research Institute, who noted that the absence of a placebo would have obscured any  heart damage caused by all three drugs. Also, she wrote:

The study did have some real weaknesses, said Dr. Elliott M. Antman, a professor of medicine at Harvard Medical School and a past president of the American Heart Association. 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.

“They asked an important question, but the trial was hard to complete,” he said. The weaknesses of the study made him unable to be confident of its conclusions. Still, he said, “this is the best we will get,” adding “we will probably never see another study like this.”

Dr. Antman said he would continue to advise that any of these drugs be taken only by the lowest-risk patients in the lowest effective dose for the shortest possible time.

Erased from memory is the magnitude of the harm inflicted by Vioxx —57,000 deaths, according to David Graham of the FDA.  That’s 19 times the number of US Americans killed by the terrorists on 911! You can look it up (see graphic below).  Merck’s pr team should get an award for Most Underplayed Story of All Time.