Rofecoxib

[2] In September 2004, Merck voluntarily withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use.

Merck withdrew the drug after disclosures that it withheld information about rofecoxib's risks from doctors and patients for over five years, allegedly resulting in between 88,000 and 140,000 cases of serious heart disease.

[4] In 2005, the FDA issued a memorandum concluding that risks for serious cardiovascular (CV) events seem to be as great for nonselective NSAIDs as for COX-2–selective agents such as rofecoxib, according to long-term, controlled clinical trials.

[5] Based on data up to 2015, the FDA reasserted the likelihood of an increased risk of serious adverse CV events from COX-2–selective and nonselective NSAIDs, dependent on dose and duration.

Traditional NSAIDs are avoided in this population due to their effects on platelet aggregation and risk of gastrointestinal ulcers,[8] and high potency opioids are the current standard of care in treating HA.

[10] At the time of its withdrawal, rofecoxib was the only coxib approved in the United States with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs.

This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen.

The VIGOR (Vioxx GI Outcomes Research) study, conducted by Bombardier, et al., compared the efficacy and adverse-effect profiles of a supratherapeutic dose of rofecoxib (50 mg/day) vs. a common dose of naproxen (500 mg/BID), had indicated a significant four-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, relative risk 0.25) over a mean duration of 9 months.

[22][citation needed] The Martin Report excused senior management by stating they believed they were victims of Pfizer's alleged manipulation of test results to promote their product as a safer alternative.

[23] Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference,[24] and some outside scientists warned Merck that this claim was implausible before VIGOR was published.

NEJM editor Gregory Curfman explained that the quick release was due to the imminent presentation of his deposition testimony, which he feared would be misinterpreted in the media.

Furthermore, they said that the additional data did not qualitatively change any of the conclusions of the study, and the results of the full analyses were disclosed to the FDA and reflected on the Vioxx warning label.

[36] Phil Fontanarosa, executive editor of the prestigious Journal of the American Medical Association, welcomed the editorial, saying "this is another in the long list of recent examples that have generated real concerns about trust and confidence in industry-sponsored studies".

[45] In summary, the APPROVe study suggested that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo.

Preapproval phase III clinical trials, like the APPROVe study, showed no increased relative risk of adverse cardiovascular events for the first 18 months of rofecoxib usage (Merck, 2004).

Furthermore, a more recent meta-study of 114 randomized trials with a total of 116,000+ participants, published in JAMA, showed that Vioxx uniquely increased risk of renal (kidney) disease, and heart arrhythmia.

[48] In 2005, the FDA issued a memo concluding that along with the other approved COX-2 selective NSAIDs available at the time (i.e., celecoxib, and valdecoxib), rofecoxib was associated with an increased risk of serious adverse cardiovascular events compared to placebo.

For example, in 2005, EU regulators required the following changes to the product information and/or packaging of all COX-2 inhibitors:[50] Since the withdrawal of Vioxx it has come to light that there may be negative cardiovascular effects with not only other COX-2 inhibitiors, but even the majority of other NSAIDs.

[55][56] In addition to its own studies, on September 23, 2004, Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004).

One FDA analyst estimated that, based upon his mathematical model, Vioxx may have caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market.

The report found that Merck's senior management acted in good faith, and that the confusion over the clinical safety of Vioxx was due to the sales team's overzealous behavior.

[66] In 2015, the FDA reinforced this conclusion, stating that the available data support a dose and duration dependent class effect of an increased risk of serious adverse cardiovascular events for COX-2 selective and non-selective NSAIDs.

[68] On August 19, 2005, a jury in Texas voted 10–2 to hold Merck liable for the death of Robert Ernst, a 59-year-old man who allegedly died of a rofecoxib-induced heart attack.

The trial ended on December 12, 2005, when Judge Eldon E. Fallon of U.S. District Court declared a mistrial because of a hung jury with an eight to one majority, favoring the defense.

Upon retrial in February 2006 in New Orleans, where the Vioxx multidistrict litigation (MDL) is based, a jury found Merck not liable, even though the plaintiffs had the NEJM editor testify as to his objections to the VIGOR study.

[72] On January 30, 2006, a New Jersey state court dismissed a case brought by Edgar Lee Boyd, who blamed Vioxx for gastrointestinal bleeding that he experienced after taking the drug.

The Texas Courts of Appeals in San Antonio later ruled Garza's fatal heart attack probably resulted from pre-existing health conditions unrelated to his taking of Vioxx, thus reversing the $32 million jury award.

[83] Under the terms of the settlement, Merck agreed to pay two-thirds of a previously recorded $950 million reserve charge in exchange for release from civil liability.

Under separate criminal proceedings, Merck pleaded guilty to a federal misdemeanor charge relating to the marketing of the drug across state lines, incurring a fine of $321.6 million.